Formulations And Pharmacokinetics Of Deuterated Benzoquinoline Inhibitors Of Vesicular Monoamine Transporter 2
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.
1 . A solid d 6 -tetrabenazine oral dosage form comprising d 6 -tetrabenazine and a poly(ethylene oxide) polymer.
2 . A solid, extended-release d 6 -tetrabenazine oral dosage form comprising:
about 1-15% by weight, based on the weight of the dosage form, of d 6 -tetrabenazine; and
about 5-20% by weight, based on the weight of the dosage form, of a poly(ethylene oxide) polymer.
3 . The oral dosage form according to claim 2 in the form of a tablet comprising a tablet core and a coating, wherein the d 6 -tetrabenazine and poly(ethylene oxide) polymer are in the tablet core.
4 . The oral dosage form according to claim 2 that releases the d 6 -tetrabenazine over a period of up to about 4 hours.
5 . The oral dosage form according to claim 2 that releases the d 6 -tetrabenazine over a period of up to about 8 hours.
6 . The oral dosage form according to claim 2 further comprising one or more of a filler, a lubricant, a binder, an absorbent, an antioxidant, a solubilizing agent, a dispersant, or a colorant.
7 . The oral dosage form according to claim 2 , further comprising:
about 60-70% by weight, based on the weight of the dosage form, of a filler;
about 15-25% by weight, based on the weight of the dosage form, of an absorbent;
about 1-10% by weight, based on the weight of the dosage form, of a dispersant;
about 0.5-2% by weight, based on the weight of the dosage form, of a solubilizing agent; and
about 0.5-2% by weight, based on the weight of the dosage form, of a lubricant.
8 . The oral dosage form according to claim 7 , further comprising about 0.1-0.2% by weight, based on the weight of the dosage form, of an antioxidant.
9 . The oral dosage form according to claim 8 , wherein the antioxidant is one or both of butylated hydroxyanisole and butylated hydroxytoluene.
10 . The oral dosage form according to claim 9 , comprising
about 60-70% by weight, based on the weight of the dosage form, of mannitol;
about 15-25%, based on the weight of the dosage form, by weight of microcrystalline cellulose;
about 1-10% by weight, based on the weight of the dosage form, of a polyvinylpyrrolidone;
about 0.5-2% by weight, based on the weight of the dosage form, of a polysorbate;
about 0.5-2% by weight, based on the weight of the dosage form, of magnesium stearate; and
about 0.1-0.2% by weight, based on the weight of the dosage form, of one or both of butylated hydroxyanisole and butylated hydroxytoluene.
11 . A method for treating a VMAT2-mediated disorder, comprising administering to a subject having or suspected of having such a disorder, a therapeutically effective amount of a composition of claim 1 .
12 . The method of claim 11 , wherein the VMAT2-mediated disorder is a chronic hyperkinetic movement disorder, Huntington's disease, hemiballismus, senile chorea, a tic disorder, tardive dyskinesia, dystonia, Tourette's syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis, or asthma.
13 . A method for treating a VMAT2-mediated disorder, comprising administering to a subject having or suspected of having such a disorder, a therapeutically effective amount of a composition of claim 2 .
14 . The method of claim 13 , wherein the VMAT2-mediated disorder is a chronic hyperkinetic movement disorder, Huntington's disease, hemiballismus, senile chorea, a tic disorder, tardive dyskinesia, dystonia, Tourette's syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis, or asthma.