Formulations pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2

Patent metadata

Field	Value
Publication number	US-9346800-B2
Application number	US-201314030322-A
Country	US
Kind code	B2
Filing date	Sep 18, 2013
Priority date	Sep 18, 2012
Publication date	May 24, 2016
Grant date	May 24, 2016

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.

First claim

What is claimed is:

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 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one, (3R,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one, (3S,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one, and (3S,11bS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.

3. The pharmaceutical composition as recited in claim 1 , wherein the deuterated analogue of tetrabenazine is d 6 -tetrabenazine.

4. The pharmaceutical composition as recited in claim 1 , wherein the deuterated analogue of tetrabenazine is (+/−)-trans-d 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 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 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 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 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 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 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 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 max of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine is reduced compared the C 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 max of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine is reduced by at least 25% as compared the C 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.

Assignees

• Auspex Pharmaceuticals Inc

Inventors

• Sommer Andreas
• Zhang Chengzhi
• Carter John
• Arthur John
• Bradbury Margaret
• Gant Thomas
• Shahbaz Manouchehr

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61K9/2077

  Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets · CPC title

• C07D455/06 Primary

  containing benzo [a] quinolizine ring systems · CPC title

• A61K9/28

  Dragees; Coated pills or tablets {, e.g. with film or compression coating (A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209)} · CPC title