Pharmaceutical formulations

Patent metadata

Field	Value
Publication number	US-10166183-B2
Application number	US-201515116970-A
Country	US
Kind code	B2
Filing date	Feb 5, 2015
Priority date	Feb 7, 2014
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

Abstract

The present invention relates to new extended release pharmaceutical compositions and methods of use thereof for the treatment of disorders. In certain embodiments, disclosed herein is an extended-release pharmaceutical formulation 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 an active ingredient; between about 70% and about 96% of one or more diluents; between about 1% and about 10% of a water-soluble binder and between about 0.5 and about 2% of a surfactant.

First claim

What is claimed is:

1. An extended-release pharmaceutical formulation 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 an active ingredient that is tetrabenazine;
between about 70% and about 96% of one or more diluents selected from the group consisting of mannitol powder, spray dried mannitol, microcrystalline cellulose, lactose, dicalcium phosphate, tricalcium phosphate, starch, pregelatinized starch, compressible sugars, silicified microcrystalline cellulose, and calcium carbonate;
between about 1% and about 10% of a water-soluble binder selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), corn starch, pregelatinized starch, gelatin, and sugar; and
between about 0.5 and about 2% of a surfactant selected from the group consisting of polysorbate, sodium lauryl sulfate, and docusate sodium.

2. The extended-release pharmaceutical formulation of claim 1 , wherein:
the diluent is mannitol, lactose, or microcrystalline cellulose;
the binder is a polyvinylpyrrolidone; and
the surfactant is a polysorbate.

3. The extended-release pharmaceutical formulation of claim 1 comprising between about 2.5% and about 11% of the active ingredient.

4. The extended-release pharmaceutical formulation of claim 1 , comprising:
between about 60% and about 70% of mannitol or lactose;
between about 15% and about 25% of microcrystalline cellulose;
about 5% of polyvinylpyrrolidone; and
between about 1 and about 2% of polysorbate 80.

5. An extended-release pharmaceutical formulation comprising, in a solid dosage form for oral delivery of between about 100 mg and about 1 g total weight:
between about 70 and about 95% of a granulation of an active ingredient that is tetrabenazine, wherein the active ingredient comprises between about 1% and about 15% of the granulation;
between about 5% and about 15% of one or more diluents;
between about 5% and about 20% of a sustained-release polymer; and
between about 0.5 and about 2% of a lubricant.

6. The extended-release pharmaceutical formulation of claim 5 comprising:
between about 5% and about 15% of one or more spray-dried mannitol or spray-dried lactose;
between about 5% and about 20% of a sustained-release polymer; and
between about 0.5 and about 2% of a magnesium stearate.

7. The extended-release pharmaceutical formulation of claim 5 , wherein the sustained-release polymer is a polyvinyl acetate-polyvinylpyrrolidone mixture.

8. The extended-release pharmaceutical formulation of claim 5 , wherein the sustained-release polymer is a poly(ethylene oxide) polymer.

9. The extended-release pharmaceutical formulation of claim 5 , wherein the extended-release pharmaceutical formulation comprises from about 5 mg to about 250 mg of the active ingredient.

10. A method of alleviating or abrogating a VMAT-mediated disease, comprising administering to a subject in need thereof the extended release pharmaceutical composition as recited in claim 1 , wherein the dose-normalized C max of the active ingredient resulting from the administration of the extended-release pharmaceutical formulation is lower than the dose-normalized C max resulting from the administration of the immediate release formulated or unformulated active ingredient.

11. The method of claim 10 , wherein the ratio of extended release formulated C max to immediate release formulated or unformulated C max is less than 1.

12. A method of alleviating or abrogating a VMAT2-mediated disease, comprising administering to a subject in need thereof the extended release pharmaceutical composition as recited in claim 1 , wherein the T max of the active ingredient resulting from the administration of the extended-release pharmaceutical formulation occurs later than the T max resulting from the administration of the immediate release formulated or unformulated active ingredient.

13. The method of claim 12 , wherein the ratio of immediate release formulated or unformulated T max to extended release formulated T max is less than 1.

14. A method of alleviating or abrogating a VMAT-mediated disease, comprising administering to a subject in need thereof the extended release pharmaceutical composition as recited in claim 1 , wherein the extended release pharmaceutical composition is administered with food and the ratio of fed to fasted C max of the total combined amount of the active ingredient is greater than 1.

15. A method of alleviating or abrogating a VMAT-mediated disease, comprising administering to a subject in need thereof the extended release pharmaceutical composition as recited in claim 1 , wherein the ratio of fed to fasted AUC inf of the active ingredient is greater than 1.

16. A method of alleviating or abrogating a VMAT2-mediated disease, comprising administering to a subject the extended release pharmaceutical composition as recited in claim 1 , wherein the composition is administered with food and the ratio of fed to fasted AUC t of the active ingredient is greater than 1.

17. The method as recited in claim 15 , wherein the ratio of fed to fasted AUC inf of the active ingredient is greater than 1 and the T max of dihydrotetrabenazine resulting from the administration of the extended-release pharmaceutical formulation occurs later than the T max resulting from the administration of immediate release formulated or unformulated tetrabenazine.

18. The method of claim 17 , wherein the ratio of immediate release formulated or unformulated T max to extended release formulated T max is less than 1.

19. The method as recited in claim 15 , wherein the composition is administered with food, the ratio of fed to fasted AUC inf of the active ingredient is greater than 1, and the ratio of fed to fasted C max of the total combined amount of dihydrotetrabenazine is greater than 1.

20. The method as recited in claim 15 , wherein the composition is administered with food, the ratio of fed to fasted AUC inf of the active ingredient is greater than 1, and the ratio of fed to fasted AUC inf of the total combined amount of dihydrotetrabenazine is greater than 1.

21. The method as recited in claim 15 , wherein the composition is administered with food, the ratio of fed to fasted AUC inf of the active ingredient is greater than 1, and the ratio of fed to fasted AUC t of the total combined amount of dihydrotetrabenazine is greater than 1.

Assignees

• Auspex Pharmaceuticals Inc

Inventors

• Sommer Andreas
• Zhang Chengzhi
• Carter John
• Arthur John
• Bradbury Margaret

Classifications

• A61K9/2027

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K31/133

  having hydroxy groups, e.g. sphingosine · CPC title

• A61K31/135

  having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)} · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K9/284

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone · CPC title