Formulations and pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2

Patent metadata

Field	Value
Publication number	US-9296739-B2
Application number	US-201414245024-A
Country	US
Kind code	B2
Filing date	Apr 4, 2014
Priority date	Sep 18, 2012
Publication date	Mar 29, 2016
Grant date	Mar 29, 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, in a solid dosage form for oral delivery of between about 100 mg and about 1 g total weight:
between about 2% and about 18% of a mixture of compounds of structural Formula I

or a salt thereof, wherein:
R 1 -R 6 are independently selected from the group consisting of hydrogen and deuterium, and the composition has deuterium enrichment of at least 10% in the compounds of Formula I;
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.

2. The pharmaceutical composition as recited in claim 1 wherein said polyvinylpyrrolidone has an average molecular weight of about 58,000 and a K-value of 29 to 32.

3. The pharmaceutical composition as recited in claim 1 wherein said polysorbate is polyoxyethylene (20) sorbitan monooleate.

4. The pharmaceutical composition as recited in claim 1 wherein said poly(ethylene oxide) polymer is poly(ethylene) oxide polymer PEG-45M.

5. The pharmaceutical composition as recited in claim 1 further comprising an anti-oxidant.

6. The pharmaceutical composition as recited in claim 5 wherein said anti-oxidant is selected from the group consisting of butylated hydroxyanisole and butylated hydroxytoluene.

7. The pharmaceutical composition as recited in claim 1 further comprising an aqueous film coating.

8. The pharmaceutical composition as recited in claim 7 wherein said aqueous film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and a FD&C color additive.

9. The pharmaceutical composition as recited in claim 1 wherein the total weight is about 350 mg.

10. The pharmaceutical composition as recited in claim 1 comprising from about 5 mg to about 30 mg of said mixture of compounds of structural Formula I.

11. The pharmaceutical composition as recited in claim 10 comprising about 6 mg of said mixture of compounds of structural Formula I.

12. The pharmaceutical composition as recited in claim 10 comprising about 12 mg of said mixture of compounds of structural Formula I.

13. The pharmaceutical composition as recited in claim 10 comprising about 15 mg of said mixture of compounds of structural Formula I.

14. The pharmaceutical composition as recited in claim 10 comprising about 18 mg of said mixture of compounds of structural Formula I.

15. The pharmaceutical composition as recited in claim 1 comprising, in a solid dosage form for oral delivery of about 350 mg total weight:
about 15 milligrams of said mixture of compounds of structural Formula I;
about 62.0% mannitol;
about 17.7% microcrystalline cellulose;
about 4.0% of polyvinylpyrrolidine having an average molecular weight of about 58,000 and a K-value of 29 to 32;
about 1.1% of polyoxyethylene (20) sorbitan monooleate;
about 10.0% of poly(ethylene) oxide polymer PEG-45M; and
about 1.0% of magnesium stearate.

16. The pharmaceutical composition as recited in claim 15 further comprising an anti-oxidant selected from the group consisting of butylated hydroxyanisole and butylated hydroxytoluene.

17. The pharmaceutical composition as recited in claim 16 further comprising an aqueous film coating.

18. The pharmaceutical composition as recited in claim 17 wherein said aqueous film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and a FD&C color additive.

19. The pharmaceutical composition as recited in claim 1 comprising, in a solid dosage form for oral delivery of about 350 mg total weight:
about 6 milligrams of said mixture of compounds of structural Formula I;
about 63.6% mannitol;
about 18.3% microcrystalline cellulose;
about 4.0% of polyvinylpyrrolidine having an average molecular weight of about 58,000 and a K-value of 29 to 32;
about 1.1% of polyoxyethylene (20) sorbitan monooleate;
about 10.0% of poly(ethylene) oxide polymer PEG-45M;
about 1.0% of magnesium stearate;
about 0.1% of butylated hydroxyanisole; and
about 0.1% of butylated hydroxytoluene.

20. The pharmaceutical composition as recited in claim 19 further comprising an aqueous film coating.

21. The pharmaceutical composition as recited in claim 20 wherein said aqueous film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and a FD&C color additive.

22. The pharmaceutical composition as recited in claim 1 comprising, in a solid dosage form for oral delivery of about 350 mg total weight:
about 12 milligrams of said mixture of compounds of structural Formula I;
about 62.3% mannitol;
about 17.9% microcrystalline cellulose;
about 4.0% of polyvinylpyrrolidine having an average molecular weight of about 58,000 and a K-value of 29 to 32;
about 1.1% of polyoxyethylene (20) sorbitan monooleate;
about 10.0% of poly(ethylene) oxide polymer PEG-45M;
about 1.0% of magnesium stearate;
about 0.1% of butylated hydroxyanisole; and
about 0.1% of butylated hydroxytoluene.

23. The pharmaceutical composition as recited in claim 22 further comprising an aqueous film coating.

24. The pharmaceutical composition as recited in claim 23 wherein said aqueous film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and a FD&C color additive.

25. The pharmaceutical composition as recited in claim 1 comprising, in a solid dosage form for oral delivery of about 350 mg total weight:
about 18 milligrams of said mixture of compounds of structural Formula I;
about 60.5% mannitol;
about 18.0% microcrystalline cellulose;
about 4.0% of polyvinylpyrrolidine having an average molecular weight of about 58,000 and a K-value of 29 to 32;
about 1.1% of polyoxyethylene (20) sorbitan monooleate;
about 10.0% of poly(ethylene) oxide polymer PEG-45M;
about 1.0% of magnesium stearate;
about 0.1% of butylated hydroxyanisole; and
about 0.1% of butylated hydroxytoluene.

26. The pharmaceutical composition as recited in claim 25 further comprising an aqueous film coating.

27. The pharmaceutical composition as recited in claim 26 wherein said aqueous film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and a FD&C color additive.

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

• A61K9/0065

  Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus · CPC title

• A61K9/2013

  Organic compounds, e.g. phospholipids, fats · 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