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Patent Application

App. No. 14/080,531

METHODS AND COMPOSITIONS FOR TREATING SCHIZOPHRENIA

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App. No.: 14/080,531

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Abstract

The invention relates to methods and compositions for treating schizophrenia or bipolar disorder (in particular, mania) by using a combination of a synaptic vesicle protein 2A (SV2A) inhibitor and an antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs thereof. In some embodiments, the methods and the compositions are for treating one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia or bipolar disorder (in particular, mania).

Claims (80)

1 . A method for treating schizophrenia or bipolar disorder in a patient in need or at risk thereof, the method comprising the step of administering to said subject a therapeutically effective amount of a synaptic vesicle protein 2A (SV2A) inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph thereof and a therapeutically effective amount of an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate, polymorph thereof.

2 . The method of claim 1 , wherein the antipsychotic is administered at a dose that is subtherapeutic as compared to the dose at which it is therapeutically effective when administered in the absence of the SV2A inhibitor.

3 . The method of claim 1 , wherein the SV2A inhibitor is:

a) selected from the group of SV2A inhibitors referred to in International Patent Application PCT/US2009/005647; International Patent Application Publications WO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658; WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. patent application Ser. Nos. 12/580,464; 61/105,847; 61/152,631; and 61/175,536; U.S. Patent Application Publication Numbers 20090312333; 20090018148; 20080081832; 2006258704; and UK Patent Numbers 1,039,113; and 1,309,692; or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof; or

b) selected from the group consisting of levetiracetam, seletracetam, and brivaracetam and derivatives, analogs, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.

4 . (canceled)

5 . The method of claim 1 , wherein the SV2A inhibitor is administered every 12 or 24 hours at a daily dose of:

a) 0.001 mg/kg to 5 mg/kg;

b) 0.5 mg/kg to 5 mg/kg; or

c) 0.05 mg/kg to 0.5 mg/kg.

6 . (canceled)

7 . (canceled)

8 . The method of claim 1 , wherein the antipsychotic is selected from atypical and typical antipsychotics.

9 . The method of claim 8 , wherein the antipsychotic is:

a) an atypical antipsychotic;

b) selected from aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs thereof;

c) selected from aripiprazole, olanzapine and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

d) a typical antipsychotic;

e) selected from acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine, trihexyphenidyl, and zuclopenthixol, and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

f) a compound selected from dopaminergic agents, glutamatergic agents, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptor modulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors, NNOS inhibits, neurosteroids, and neurotrophic factors;

g) selected from the group of compounds referred to in U.S. Pat. Nos. 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573; 5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and 5,312,925, and EP Patents EP402644 and EP368388, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; or

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10 - 14 . (canceled)

15 . The method of claim 1 , wherein the antipsychotic is useful in treating at least one sign or symptom of schizophrenia or bipolar disorder.

16 . (canceled)

17 . (canceled)

18 . The method of claim 1 , wherein the SV2A inhibitor and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs are administered simultaneously, or sequentially, or in a single formulation, or in separate formulations.

19 - 21 . (canceled)

22 . The method of claim 1 , wherein the SV2A inhibitor is levetiracetam or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof and the antipsychotic is selected from aripiprazole, olanzapine and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

23 . The method of claim 1 ,

a) wherein the treatment has a longer therapeutic effect in the subject than is attained by administering the antipsychotic in the absence of the SV2A inhibitor by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about 10×; or

b) wherein the treatment has a longer therapeutic effect in the subject than is attained by administering the SV2A inhibitor in the absence of the antipsychotic by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about 10×.

24 . (canceled)

25 . A method of increasing the therapeutic index of an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in a method of treating schizophrenia or bipolar disorder in a subject in need or at risk thereof, comprising administering an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in combination with the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof to said subject.

26 . The method of claim 25 , wherein the increase in the therapeutic index of the antipsychotic is greater than the therapeutic index of the antipsychotic when administered in the absence of the SV2A inhibitor by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about 10×.

27 . The method of claim 25 , wherein the SV2A inhibitor is:

b) selected from the group consisting of levetiracetam, seletracetam, and brivaracetam, and derivatives, analogs, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.

28 . (canceled)

29 . The method of claim 25 , wherein the antipsychotic is selected from atypical and typical antipsychotics.

30 . The method of claim 29 , wherein the antipsychotic is:

a) an atypical antipsychotic;

c) selected from aripiprazole, olanzapine and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

d) a typical antipsyhotic;

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31 - 35 . (canceled)

36 . The method of claim 25 , wherein the antipsychotic is useful in treating at least one sign or symptom of schizophrenia or bipolar disorder.

37 . (canceled)

38 . (canceled)

39 . A pharmaceutical composition comprising a SV2A inhibitor and an antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates, or polymorphs.

40 . The pharmaceutical composition of claim 39 , wherein the SV2A inhibitor and the antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates, or polymorphs are in separate dosage forms or in a unit dosage form.

41 . The composition of claim 39 , wherein the composition is in a solid form, a liquid form, a suspension form, a sustained release form, a delayed release form, or an extended release form.

42 . The composition of claim 39 , wherein the SV2A inhibitor is:

b) selected from the group consisting of levetiracetam, seletracetam, and brivaracetam and derivatives, analogs, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.

43 . (canceled)

44 . The composition of claim 39 , wherein the SV2A inhibitor in the composition is present in an amount of:

a) 0.07-350 mg;

b) 50-250 mg;

c) 3-50 mg; or

d) less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1 mg, or less than 0.07 mg.

45 - 47 . (canceled)

48 . The composition of claim 39 , wherein the antipsychotic is selected from atypical and typical antipsychotics.

49 . The composition of claim 48 , wherein the antipsychotic is:

a) an atypical antipsychotic;

b) selected from aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone and ziprasidone, and the pharmaceutically acceptable salts, hydrates, solvates, polymorphs thereof;

c) selected from aripiprazole, olanzapine and ziprasidone, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

d) a typical antipsychotic;

e) selected from acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine, trihexyphenidyl, and zuclopenthixol, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

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50 - 54 . (canceled)

55 . The composition of claim 39 , wherein the antipsychotic is useful in treating at least one sign or symptom of schizophrenia or bipolar disorder.

56 . (canceled)

57 . (canceled)

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 8, 2022

From: KOH, MING TENG

To: THE JOHNS HOPKINS UNIVERSITY

Reel/Frame 059657/0650 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 29, 2018

From: GALLAGHER, MICHELA

To: THE JOHNS HOPKINS UNIVERSITY

Reel/Frame 044755/0572 →