PHARMACEUTICAL COMPOSITIONS WITH TETRABENAZINE
The present invention provides for a pharmaceutical composition that includes tetrabenazine and a release-retarding agent; and a method of treating a hyperkinetic movement disorder (e.g., Huntington's disease, chorea associated with Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, myoclonus, dystonia and/or Tourette's syndrome). The method includes administering an effective amount of the pharmaceutical composition, for a period of time effective to treat the hyperkinetic movement disorder.
1 . A pharmaceutical composition comprising tetrabenazine and a release-retarding agent, wherein a ratio of plasma concentrations for a dihydrotetrabenazine metabolite relative to tetrabenazine is lower after administration of the composition than after administration of an immediate release formulation.
2 . The pharmaceutical composition of claim 1 , in an oral unit dosage form.
3 . The pharmaceutical composition of claim 1 , wherein the tetrabenazine is the sole therapeutic agent.
4 . The pharmaceutical composition of claim 1 , wherein the tetrabenazine is combined with a second therapeutic agent.
5 . The pharmaceutical composition of claim 4 , wherein the second therapeutic agent is an antidepressant, anticholinergic, antiepileptic, anti-Parkinsons agent, antipsychotic, aricept, baclofen, barbiturate, benzodiazepine, beta-blocker, botulinum toxin, calcium channel antagonist, catecholamine-depleting agent, clomiplamine, clonidine, clonazepam, clozapine, diphenhydramine, dopaminergic drug, dopamine agonist, fluphenazine, guanfacine, haloperidol, 5-hydroxytryptophan, keppra, L-dopa, methylphenidate, metoclopramide, mirapex, muscle relaxant, neuroleptics, olanzapine, perphenazine, phenyloin, pimozide, piquindone, piracetam, primidone, psychostimulant, requip, risperidone, selegiline, serotonin reuptake inhibitor, sertraline, sodium valproate, sulpiride, tiapride, tricyclic antidepressants, trihexyphenidyl, trihexyphenidyl-hydrochloride (Pakisonal)), ziprasidone, or a combination thereof.
6 . The pharmaceutical composition of claim 1 , which is a tablet, powder, capsule, sachet, troche or lozenge.
7 . The pharmaceutical composition of claim 1 , further comprising at least one of a diluent, disintegrant, glidant and lubricant.
8 . The pharmaceutical composition of claim 7 , wherein the diluent is a sugar.
9 . The pharmaceutical composition of claim 8 , wherein the sugar is lactose.
10 . The pharmaceutical composition of claim 7 , wherein the diluent comprises about 30% (w/w) to about 40% (w/w) of the composition.
11 . The pharmaceutical composition of claim 7 , wherein the disintegrant is starch.
12 . The pharmaceutical composition of claim 7 , wherein the disintegrant comprises about 15% (w/w) to about 30% (w/w) of the composition.
13 . The pharmaceutical composition of claim 7 , wherein the glidant is talc, colloidal silicon dioxide, or a combination thereof.
14 . The pharmaceutical composition of claim 7 , wherein the glidant comprises about 1% (w/w) to about 2% (w/w) of the composition.
15 . The pharmaceutical composition of claim 7 , wherein the lubricant is magnesium stearate.
16 . The pharmaceutical composition of claim 7 , wherein the lubricant comprises about 0.1 (w/w) to about 2% (w/w) of the composition.
17 . The pharmaceutical composition of claim 1 , wherein the tetrabenazine comprises about 5% (w/w) to about 20% (w/w) of the composition.
18 . The pharmaceutical composition of claim 1 , wherein the composition or unit dosage form:
(i) contains about 10 mg of tetrabenazine; or
(ii) contains about 12.5 mg of tetrabenazine; or
(iii) contains about 15 mg of tetrabenazine; or
(iv) contains about 20 mg of tetrabenazine; or
(v) contains about 25 mg of tetrabenazine; or
(vi) contains about 30 mg of tetrabenazine; or
(vii) contains about 50 mg of tetrabenazine.
19 . The pharmaceutical composition of claim 1 that exhibits a food effect.
20 . The pharmaceutical composition of claim 1 , wherein the release-retarding agent comprises an agent selected from a cellulose derivative, a polyoxyalkylene block co-polymer, and mixtures thereof.
21 . The pharmaceutical composition of claim 1 , wherein:
(i) the release-retarding agent comprises a cellulose derivative; or
(ii) the release-retarding agent is a cellulose derivative.
22 . The pharmaceutical composition of claim 1 , wherein the release-retarding agent comprises hydroxypropyl methyl cellulose (HPMC).
23 . The pharmaceutical composition of claim 1 , wherein the release-retarding agent comprises about 20% (w/w) to about 40% (w/w) of the composition.
24 . The pharmaceutical composition of claim 1 , which is a modified-release dosage unit form, a controlled-release dosage unit form, an extended release dosage unit form, a prolonged-release dosage unit form, a delayed release dosage unit form, an enhanced absorption dosage unit form, a pulsatile release dosage unit form, a gastro-retention unit dosage form, or a sustained-release dosage unit form.
25 . The pharmaceutical composition of claim 1 , wherein the plasma concentrations of the dihydrotetrabenazine metabolite and the tetrabenazine are ng·hr/mL.
26 . The pharmaceutical composition of claim 1 , wherein the ratio of AUC 0-∞ values for dihydrotetrabenazine metabolite relative to tetrabenazine is lower after administration of the composition than after administration of an immediate release formulation without the release retarding agent.
27 . The pharmaceutical composition of claim 1 , wherein the ratio of AUC 0-∞ values for tetrabenazine to dihydrotetrabenazine metabolite is about 1.1 to about 3.0 higher after administration of the composition than after administration of an immediate release formulation without the release retarding agent.
28 . The pharmaceutical composition of claim 1 , wherein the metabolite is α-dihydrotetrabenazine.
29 . The pharmaceutical composition of claim 1 , wherein the metabolite is β-dihydrotetrabenazine.
30 . The pharmaceutical composition of claim 1 , wherein the immediate release tetrabenazine formulation contains tetrabenazine, lactose, maize starch, talc, and magnesium stearate or the immediate release tetrabenazine formulation contains tetrabenazine, corn starch, lactose, talc, magnesium stearate, and iron oxide.
31 . A method of treating a hyperkinetic movement disorder, the method comprising administering an effective amount of the pharmaceutical composition of claim 1 , for a period of time effective to treat the hyperkinetic movement disorder.
32 . The method of claim 31 , wherein the hyperkinetic movement disorder comprises at least one of Huntington's disease, chorea associated with Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, myoclonus, dystonia and Tourette's syndrome.
33 . The method of claim 31 , wherein the pharmaceutical composition comprises a second therapeutic agent.
34 . The method of claim 33 , wherein the second therapeutic agent is an antidepressant, anticholinergic, antiepileptic, anti-Parkinsons agent, antipsychotic, aricept, baclofen, barbiturate, benzodiazepine, beta-blocker, botulinum toxin, calcium channel antagonist, catecholamine-depleting agent, clomiplamine, clonidine, clonazepam, clozapine, diphenhydramine, dopaminergic drug, dopamine agonist, fluphenazine, guanfacine, haloperidol, 5-hydroxytryptophan, keppra, L-dopa, methylphenidate, metoclopramide, mirapex, muscle relaxant, neuroleptics, olanzapine, perphenazine, phenyloin, pimozide, piquindone, piracetam, primidone, psychostimulant, requip, risperidone, selegiline, serotonin reuptake inhibitor, sertraline, sodium valproate, sulpiride, tiapride, tricyclic antidepressants, trihexyphenidyl, trihexyphenidyl-hydrochloride (Pakisonal), ziprasidone, or a combination thereof.
35 . The method of claim 31 , wherein the pharmaceutical composition is administered within about 1 hour, before or after, ingesting food.
36 . The method of claim 31 , wherein the pharmaceutical composition is administered within about 1 hour, before or after, ingesting a high-fat food or a high-fat beverage.
37 . The method of claim 31 , wherein the pharmaceutical composition is administered when food has not been ingested for at least 2 to 3 hours.
38 . The method of claim 31 , wherein the Fed/Fast ratio of the systemic exposure (AUC) of each of the active metabolites alpha- and beta-dihydrotetrabenazine is at least about 140%.
39 . The method of claim 31 , wherein the Fed/Fast ratio of the peak concentration (Cmax) of each of the active metabolites alpha- and beta-dihydrotetrabenazine is at least about 220%.
40 . The method of claim 39 , wherein the Cmaxof each of the active metabolites alpha- and beta-dihydrotetrabenazine in the blood is obtained between about 3 hours and about 6 hours after administration of the composition.
41 . The method of claim 31 , wherein the pharmaceutical composition is administered about once a day (q.d.).
42 . The method of claim 31 , wherein the pharmaceutical composition is administered about twice a day (b.i.d.).
43 . The method of claim 31 , wherein the method reduces the incidence of hyperkinetic movement in the patient.
44 . The method of claim 31 , wherein the method reduces the severity of hyperkinetic movement in the patient.
45 . The method of claim 31 , wherein the patient experiences a lower incidence of adverse effects, as compared to an immediate release composition that contains tetrabenazine.
46 . The method of claim 31 , wherein the patient experiences a lower severity of adverse effects, as compared to an immediate release composition that contains tetrabenazine.
47 . The method of claim 46 , wherein the adverse effects comprise at least one of akathisia, depression, suicidal thoughts, suicidal behavior (suicidality), dizziness, drowsiness, sedation, somnolence, insomnia, fatigue, nervousness, anxiety, nausea and Parkinsonism.
48 . A method of lowering a ratio of plasma concentrations for a dihydrotetrabenazine metabolite relative to tetrabenazine in a patient comprising administering to the patient a composition comprising tetrabenazine and a release-retarding agent, wherein the composition is administered at a frequency or dosage that lowers the ratio of plasma concentrations for a dihydrotetrabenazine metabolite relative to tetrabenazine when compared to administration of an immediate release tetrabenazine formulation.
49 . A method of avoiding peak and/or trough plasma concentrations of an active metabolite of tetrabenazine in a patient comprising administering to the patient a composition comprising tetrabenazine and a release-retarding agent, wherein the composition is administered at a frequency and/or dosage that lowers the ratio of plasma concentrations for the active dihydrotetrabenazine metabolite relative to tetrabenazine when compared to administration of an immediate release tetrabenazine formulation.
50 . The method of claim 49 , wherein the composition is administered to treat a hyperkinetic movement disorder.
51 . The method of claim 50 , wherein the hyperkinetic movement disorder comprises at least one of Huntington's disease, chorea associated with Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, myoclonus, dystonia and Tourette's syndrome.
52 . The method of claim 49 , wherein the pharmaceutical composition comprises a second therapeutic agent.
53 . The method of claim 52 , wherein the second therapeutic agent is an antidepressant, anticholinergic, antiepileptic, anti-Parkinsons agent, antipsychotic, aricept, baclofen, barbiturate, benzodiazepine, beta-blocker, botulinum toxin, calcium channel antagonist, catecholamine-depleting agent, clomiplamine, clonidine, clonazepam, clozapine, diphenhydramine, dopaminergic drug, dopamine agonist, fluphenazine, guanfacine, haloperidol, 5-hydroxytryptophan, keppra, L-dopa, methylphenidate, metoclopramide, mirapex, muscle relaxant, neuroleptics, olanzapine, perphenazine, phenyloin, pimozide, piquindone, piracetam, primidone, psychostimulant, requip, risperidone, selegiline, serotonin reuptake inhibitor, sertraline, sodium valproate, sulpiride, tiapride, tricyclic antidepressants, trihexyphenidyl, trihexyphenidyl-hydrochloride (Pakisonal), ziprasidone, or a combination thereof.
54 . The method of claim 49 , wherein the pharmaceutical composition is administered within about 1 hour, before or after, ingesting food.
55 . The method of claim 49 , wherein the pharmaceutical composition is administered within about 1 hour, before or after, ingesting a high-fat food or a high-fat beverage.
56 . The method of claim 49 , wherein the pharmaceutical composition is administered when food has not been ingested for at least 2 to 3 hours.
57 . The method of claim 49 , wherein the Fed/Fast ratio of the systemic exposure (AUC) of each of the active metabolites alpha- and beta-dihydrotetrabenazine is at least about 140%.
58 . The method of claim 49 , wherein the Fed/Fast ratio of the peak concentration (Cmax) of each of the active metabolites alpha- and beta-dihydrotetrabenazine is at least about 220%.
59 . The method of claim 58 , wherein the Cmaxof each of the active metabolites alpha- and beta-dihydrotetrabenazine in the blood is obtained between about 3 hours and about 6 hours after administration of the composition.
60 . The method of claim 49 , wherein the pharmaceutical composition is administered about once a day (q.d.).
61 . The method of claim 49 , wherein the pharmaceutical composition is administered about twice a day (b.i.d.).
62 . The method of claim 49 , wherein the method reduces the incidence of hyperkinetic movement in the patient.
63 . The method of claim 49 , wherein the method reduces the severity of hyperkinetic movement in the patient.
64 . The method of claim 49 , wherein the patient experiences a lower incidence of adverse effects, as compared to an immediate release composition that contains tetrabenazine.
65 . The method of claim 49 , wherein the patient experiences a lower severity of adverse effects, as compared to an immediate release composition that contains tetrabenazine.
66 . The method of claim 65 , wherein the adverse effects comprise at least one of akathisia, depression, suicidal thoughts, suicidal behavior (suicidality), dizziness, drowsiness, sedation, somnolence, insomnia, fatigue, nervousness, anxiety, nausea and Parkinsonism.
67 . The method of claim 49 , wherein the immediate release tetrabenazine formulation contains tetrabenazine, lactose, maize starch, talc, and magnesium stearate or the immediate release tetrabenazine formulation contains tetrabenazine, corn starch, lactose, talc, magnesium stearate, and iron oxide.