Details for Patent: 9,346,800

Title:	Formulations pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2
Abstract:	The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.
Inventor(s):	Sommer; Andreas (Carlsbad, CA), Zhang; Chengzhi (San Diego, CA), Carter; John (Vista, CA), Arthur; John (Vista, CA), Bradbury; Margaret (Vista, CA), Gant; Thomas (Carlsbad, CA), Shahbaz; Manouchehr (San Diego, CA)
Assignee:	Auspex Pharmaceuticals, Inc. (La Jolla, CA)
Filing Date:	Sep 18, 2013
Application Number:	14/030,322
Claims:	1. A pharmaceutical composition comprising: a deuterated analogue of tetrabenazine; between about 60% and about 70% mannitol; between about 15% and about 25% microcrystalline cellulose; between about 1% and about 10% of a polyvinylpyrrolidone; between about 0.5% and about 2% of a polysorbate; between about 5% and about 20% of a poly(ethylene oxide) polymer; and between about 0.5% and about 2% of magnesium stearate; which yields, when orally administered to a subject, at least one of the following: an increase of the AUC of the total combined amount of deuterated dihydrotetrabenazine of at least 50% as compared to a pharmaceutical composition comprising an equivalent amount of non-deuterated tetrabenazine; or an increase in half-life of deuterated dihydrotetrabenazine of at least 50%; as compared to a pharmaceutical composition comprising an equivalent amount of non-deuterated tetrabenazine. 2. The pharmaceutical composition as recited in claim 1, wherein the deuterated analogue of tetrabenazine is selected from the group consisting of (3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpro- pyl)-2H-benzo[a]quinolizin-2-one, (3R,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpro- pyl)-2H-benzo[a]quinolizin-2-one, (3S,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpro- pyl)-2H-benzo[a]quinolizin-2-one, and (3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpro- pyl)-2H-benzo[a]quinolizin-2-one. 3. The pharmaceutical composition as recited in claim 1, wherein the deuterated analogue of tetrabenazine is d.sub.6-tetrabenazine. 4. The pharmaceutical composition as recited in claim 1, wherein the deuterated analogue of tetrabenazine is (+/-)-trans-d.sub.6-tetrabenazine. 5. The pharmaceutical composition as recited in claim 3, which yields an increase of the AUC of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine of at least 100%; or an increase in half-life of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine of at least 70%; as compared to a pharmaceutical formulation comprising an equivalent amount of non-deuterated tetrabenazine. 6. The pharmaceutical composition as recited in claim 5, which yields an increase in half-life of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine at least 100% as compared to a pharmaceutical composition comprising an equivalent amount of non-deuterated tetrabenazine. 7. The pharmaceutical composition as recited in claim 3, which yields a reduced AUC or C.sub.max of O-desmethyl metabolites of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine as compared to a pharmaceutical composition comprising an equivalent amount of non-deuterated tetrabenazine. 8. The pharmaceutical composition as recited in claim 7, wherein the AUC of 9-O-desmethyl metabolites of deuterated alpha-dihydrotetrabenazine and 9- and 10-O-desmethyl metabolites of deuterated beta-dihydrotetrabenazine is reduced by at least 25%. 9. The pharmaceutical composition as recited in claim 8, wherein the AUC of 9-O-desmethyl metabolites of deuterated alpha-dihydrotetrabenazine and 9- and 10-O-desmethyl metabolites of deuterated beta-dihydrotetrabenazine is reduced by at least 50%. 10. The pharmaceutical composition as recited in claim 9, wherein the AUC of 9-O-desmethyl metabolites of deuterated alpha-dihydrotetrabenazine and 9- and 10-O-desmethyl metabolites of deuterated beta-dihydrotetrabenazine is reduced by at least 70%. 11. The pharmaceutical composition as recited in claim 7, wherein the C.sub.max of O-desmethyl metabolites of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine is reduced by at least 25%. 12. The pharmaceutical composition as recited in claim 11, wherein the C.sub.max of O-desmethyl metabolites of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine is reduced by at least 40%. 13. The pharmaceutical composition as recited in claim 12, wherein the C.sub.max of O-desmethyl metabolites of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine is reduced by at least 55%. 14. The pharmaceutical composition as recited in claim 3, which yields a reduced ratio of C.sub.max to AUC of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine as compared to a pharmaceutical composition comprising non-deuterated tetrabenazine. 15. The pharmaceutical composition as recited in claim 14, wherein the ratio of C.sub.max to AUC of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine is reduced by at least 20% as compared to a pharmaceutical composition comprising non-deuterated tetrabenazine. 16. The pharmaceutical composition as recited in claim 14, wherein the ratio of C.sub.max to AUC of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine is reduced by at least 40% as compared to a pharmaceutical composition comprising non-deuterated tetrabenazine. 17. The pharmaceutical composition as recited in claim 3, wherein the C.sub.max of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine is reduced compared the C.sub.max of the total combined amount of alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine at a dose of non-deuterated tetrabenazine that yields an equivalent AUC of total combined alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine and total combined deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine. 18. The pharmaceutical composition as recited in claim 17, wherein the C.sub.max of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine is reduced by at least 25% as compared the C.sub.max of the total combined amount of alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine at a dose of non-deuterated tetrabenazine that yields an equivalent AUC of total combined alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine and total combined deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine. 19. The pharmaceutical composition as recited in claim 1, which yields, when orally administered to a patient population, reduced interpatient variability in AUC of the total combined amount of alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine as compared with non-deuterated tetrabenazine. 20. The pharmaceutical composition as recited in claim 1, which yields, when orally administered to a patient population, reduced interpatient variability in AUC of the total combined amount of alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine between CYP2D6 poor metabolizers and CYP2D6 extensive and intermediate metabolizers as compared with non-deuterated tetrabenazine.