WO2008035177A2

WO2008035177A2 - Combination of mt1 and mt2 melatonin receptor agonists and a norepinephrine/dopamine reuptake inhibitor

Info

Publication number: WO2008035177A2
Application number: PCT/IB2007/002712
Authority: WO
Inventors: Guy Jadot
Original assignee: Copharm
Current assignee: Copharm
Priority date: 2006-09-18
Filing date: 2007-09-13
Publication date: 2008-03-27
Anticipated expiration: 2009-03-18
Also published as: WO2008035177A3

Abstract

The present invention relates to the use of a combination of a MTl and MT2 melatonin receptor agonists and a norepinephrine/dopamine reuptake inhibitor (NDRI) for the treatment of depression and other affective disorders. It specifically relates to the use of a combination of agomelatine and bupropion for the treatment of depression and other affective disorders.

Description

COMBINATION OF MTl AND MT2 MELATONIN RECEPTOR AGONISTS AND A NOREPINEPHRINE/DOPAMINE REUPTAKE INHIBITOR

FIELD OF THE INVENTION

The present invention relates to the use of a combination of a MT1/MT2 melatonin receptor and a norepinephrine/ dopamine reuptake inhibitor for the treatment of CNS disorders.

BACKGROUND OF THE INVENTION

Agomelatine is known to be well tolerated, have a favourable safety profile and to induce little sexual dysfunction. Clinical studies on depression indicate that the non-response to agomelatine is similar to the selective serotonin reuptake inhibitors (SSRIs), were non response is in the range of 30%. SSRIs have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias but suffer from a number of side effects, among them sexual dysfunction. Antidepressants in general demonstrate a delay in the therapeutic effect of up to 4 weeks.

The two major unmet medical needs in the field of antidepressants are:

- Lack of efficacy: in clinical trials as much as 30 - 40% of trial subjects do not respond - Delay in onset of action: response is usually achieved after 2 - 5 weeks of treatment

There is thus a need for an improved antidepressant treatment and one approach is augmentation strategies. Augmentation of antidepressant therapy may be accomplished through the coadministration of mood stabilizers such as lithium carbonate or triiodothyronin or by the use of electroshock. There is also a need for an antidepressant treatment that shortens the onset of action.

It has now surprisingly been found that bupropion or its metabolites including radafaxine, or pharmaceutically acceptable salt, solvate, clathrate, polymorph or co-crystal thereof, may be used to augment and also provide faster onset of the therapeutic effect of agomelatine in a synergistic way.

DECSRIPTION OF THE INVENTION

The present invention thus provides:

The present invention relates to the use of bupropion, or any other NDRI, or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition to be used in combination with agomelatine or any other MTl and MT2 melatonin receptor agonists with any pharmaceutically acceptable salt, solvate, clathrate, polymorph or co-crystal of the compounds .

In particular, the present invention relates to the use of bupropion, or its metabolites including radafaxine or any other NDRI, or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition useful for augmenting and/or providing faster onset of the therapeutic effect of agomelatine or any other MTl and MT2 melatonin receptor agonists in a synergistic way.

More particularly, the present invention relates to the use as above, of bupropion, or a pharmaceutically acceptable salt thereof, for the treatment of depression, recurrent depression, resistant depression, bipolar disorders, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, sleep disorders, stress-related disorders, attention deficit hyperactivity disorder and drug abuse, in particular depression with agomelatine or any other MTl and MT2 melatonin receptor agonists.

The anxiety disorders mentioned above include, but are not limited to, general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post trauma stress disorder or social anxiety disorder.

As used herein, the term augmenting covers improving the therapeutic effect and/or potentiating the therapeutic effect of agomelatine or any other MTl and MT2 melatonin receptor agonists in a synergistic way.

In a further embodiment, the invention relates to the use of bupropion or a pharmaceutically acceptable salt thereof and a compound, which is agomelatine, or any other MTl and MT2 melatonin receptor agonists, for the preparation of a pharmaceutical composition or kit for' the treatment of diseases or disorders responsive to the therapeutic effect of agomelatine, or any other MTl and MT2 melatonin receptor agonists . The diseases responsive to agomelatine, or any other MTl and MT2 melatonin receptor agonists, include, but are not limited to, depression, bipolar disorders, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, in particular depression.

The term anxiety disorders is as defined above.

In one embodiment, the present invention relates to the use of bupropion, or its metabolites including radafaxine or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition as above, which is adapted for simultaneous administration of the active ingredients. In particular, such pharmaceutical compositions may contain the active ingredients within the same unit dosage form, e.g. in the same tablet or capsule. Such unit dosage forms may contain the active ingredients as a homogenous mixture or in separate compartments of the unit dosage form.

In another embodiment, the present invention relates to the use of bupropion or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition or kit as above, which is adapted for sequential administration of the active ingredients. In particular, such pharmaceutical compositions may contain the active ingredients in discrete unit dosage forms, e. g. discrete tablets or capsules containing either of the active ingredients. These discrete unit dosage forms may be contained in the same container or package, e.g. a blister pack.

As used herein the term kit means a pharmaceutical composition containing each of the active ingredients, but in discrete unit dosage forms.

The invention also relates to a pharmaceutical composition or kit comprising bupropion or a pharmaceutically acceptable salt thereof and a compound, which is agomelatine, or any other MTl and MT2 melatonin receptor agonists, and optionally pharmaceutically acceptable carriers or diluents.

The pharmaceutical composition or kit of the invention may be adapted for simultaneous administration of the active ingredients or for sequential administration of the active ingredients, as described above.

Finally, the present invention relates to a method for the treatment of diseases or disorders responsive to agomelatine, or any other MTl and MT2 melatonin receptor agonists, comprising administering bupropion or a pharmaceutically acceptable salt thereof and agomelatine, or any other MTl and MT2 melatonin receptor agonists, to an individual in need thereof.

In particular, the present invention relates to a method for augmenting and/or providing faster onset of the therapeutic effect of agomelatine, or any other MTl and MT2 melatonin receptor agonists, comprising administering bupropion or a pharmaceutically acceptable salt thereof to an individual to be treated with or undergoing treatment with agomelatine, or any other MTl and MT2 melatonin receptor agonists.

The individuals, which may benefit from treatment with a combination as above, may suffer from depression, recurrent depression, resistant depression, bipolar disorders, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, premenstrual syndrome, dysthymia, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, in particular depression.

As mentioned above, anxiety disorder includes, but are not limited to, general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post trauma stress disorder or social anxiety disorder.

Agomelatine and the norepinephrine/dopamine reuptake inhibitor may be administered simultaneously as described above. Alternatively, the active ingredients may be administered sequentially, e.g. in two discrete unit dosage forms as described above.

Bupropion and pharmaceutically acceptable salts thereof claimed therein are described as blocking both norepinephrine and dopamine reuptake inhibitors.

Because bupropion is a selective norepinephrine and dopamine reuptake inhibitor with no serotonergic activity, common antidepressant-associated side effects, such as sexual dysfunction, weight gain, and sedation, are not associated with bupropion therapy. The only other norepinephrine/dopamine reuptake inhibitor NDRI is radafaxine (GSK 353162) now in phase III.

It has now, surprisingly, been found that co-administration of bupropion and agomelatine produces a synergistic improvement on both response and time to onset, in the chronic mild stress model in rats (Willner P. Psychopharmacology 1997 134:319- 329), the conditioned fear test (Borsini et al. Psychopharmacology 2002, 163: 121-141) and the forced swimming test in rats, Borsini Neurosci Biobehav Rev. 1995 19:377-395) compared to the administration of agomelatine and bupropion alone.

Agomelatine, as other antidepressants suffers from a delayed onset of action. Even in responders to agomelatine, several weeks of treatment are necessary to achieve a relief in symptoms. Bupropion may provide fast onset of the therapeutic effect of agomelatine.

The use of a combination of bupropion and agomelatine may provide a synergistic effect in the treatment of depression and other affective disorders compared to administration of agomelatine and bupropion alone while maintaining agomelatine' s favourable tolerance and safety profile, particularly absence of sexual dysfunction.

Co-administration of bupropion and agomelatine may also be useful for the treatment of refractory depression, i. e. depression, which cannot be treated appropriately by administration of agomelatine alone. Typically, bupropion may be used as add-on therapy for the augmentation of the response to agomelatine in patients where at least 40-60% reduction in symptoms has not been achieved during the first 6 weeks of treatment with an SSRI. Co-administration of bupropion and agomelatine may also be useful for the treatment of recurrent depression.

Any pharmacologically active compound which primarily or partly exerts its therapeutic effect via the MTl and MT2 melatonin receptor agonists pathway in the CNS, may benefit from augmentation with bupropion.

The following list contains a number of MTl and MT2 melatonin receptor agonists, which may benefit from augmentation with bupropion: agomelatine, ramelteon, TAK-375 (N, N, 6-trimethyl-2- (4-methylphenyl) - imidazo [1, 2-a] pyridine-3-acetamide) , VEC- 162, PD-6735, GR 196429, 5-Methoxy-N-cyclopropanoyltryptamine, 8M-PDOT (8-Methoxy-2-propionamidotetralin) , 2-phenylmelatonin, N-propionylmelatonin, N-butanoylmelatonin, 6-chloromelatonin.

The above list of MTl and MT2 receptor agonists may not be construed as limiting.

The compounds mentioned above may be used in the form of the base or a pharmaceutically acceptable acid addition salt, solvate, clathrate, polymorph or co-crystal thereof thereof.

The active ingredients according to the invention, i. e. bupropion and agomelatine or any other MTl and MT2 receptor agonists, may be used in the free base form (except agomelatine which is an amide) or in the form of a pharmaceutically acceptable acid addition salt thereof, the latter being obtainable by reaction of the base form with an appropriate acid.

As mentioned above, the combination of bupropion with agomelatine unexpectedly shows a synergistic effect on the central nervous system (CNS) . As a consequence, combination therapy using bupropion and agomelatine may provide a more effective therapeutic option, without affecting agomelatine' s favourable tolerance and safety profile.

Additionally, combination therapy with bupropion and a normal dose of agomelatine has the advantage that an effective CNS effect may be obtained in the often large number of patients who do not respond to conventional monotherapy with agomelatine.

It is expected that the combination therapy with bupropion and agomelatine will restore sleep quality and prevent sexual dysfunction which are the two major drawbacks of many of the antidepressants belonging to the most important classes; SSRI and SNRI.

The amount of bupropion used in combination therapy may range from about 50 to about 1000mg/day, particularly from about 100 to about 600 mg/day and more particularly from about 150 to about 450 mg/day. The amount of agomelatine used in combination therapy may range from 0.1 to about 300mg/day, particularly from about 1 to about 200 mg/day and more particularly from about 5 to lOOmg/day.

To prepare the pharmaceutical compositions of this invention, an appropriate amount of the active ingredient (s) , in salt form or base form, is combined in an intimate admixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable for administration orally, rectally, percutaneously or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. As used in the specification and claims, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient (s) calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets) , capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

Bupropion may be administered before, during or after the administration of agomelatine provided that the time between the administration of bupropion and agomelatine is such that ingredients are allowed to act synergistically on the CNS. When simultaneous administration of bupropion and agomelatine is envisaged, a composition containing both bupropion and agomelatine may be particularly convenient. Or, bupropion and agomelatine may be administered separately in the form of suitable compositions.

The present invention also comprises products containing bupropion and agomelatine as a combination preparation for simultaneous, separate or sequential use in psychiatric drug therapy. Such products may comprise, for example, a kit comprising discrete unit dosage forms containing bupropion and discrete unit dosage forms containing agomelatine, all contained in the same container or pack, e.g. a blister pack.

Claims

1. A method for treating a CNS disorder or condition that can be treated by a combination comprising administering to a patient in need of such treatment: (i) a MT1/MT2 melatonin receptor agonist or pharmaceutical acceptable salt, solvate, clathrate, polymorph or co-crystal thereof; and (ii) a norepinephrine/ dopamine reuptake inhibitor or pharmaceutical acceptable form thereof, wherein the NDRI is selected from the group consisting of bupropion, radafaxine or other bupropion' s racemic or chiral metabolites or pharmaceutical acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.

2. A method for treating depression and other affective disorders in a patient, comprising administering to a patient in need of such treatment: (i) a MT1/MT2 melatonin receptor agonist or pharmaceutical acceptable salt, solvate, clathrate, polymorph or co-crystal thereof; and (ii) a norepinephrine/ dopamine reuptake inhibitor or pharmaceutical acceptable form thereof, wherein the norepinephrine/dopamine reuptake inhibitor is selected from the group consisting of bupropion or radafaxine or other bupropion's racemic or chiral metabolites or pharmaceutical acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.

3. The method of claim 2, wherein the disorder or condition is depression, recurrent depression, resistant depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, sleep disorders, stress-related disorders, attention deficit hyperactivity disorder and drug abuse.

4. The method of claim 3, wherein the anxiety disorders are compulsive disorder, acute stress disorder, post trauma stress disorder or social anxiety disorder.

5. The method of claim 1, wherein the said combination is useful to restore the sleep quality in a patient suffering from depression.

6. The method of claim 1, wherein the said combination is useful to prevent sexual dysfunction in a patient suffering from depression.

7. The method of claim 2, wherein the MT1/MT2 melatonin receptor agonist or pharmaceutical acceptable salt, solvate, clathrate, polymorph or co-crystal thereof is selected from the group consisting of agomelatine, ramelteon, TAK-375

(N, N, 6-trimethyl-2- (4-methylphenyl) - imidazo [1, 2-a] pyridine-3- acetamide), VEC-162, PD-6735, GR 196429, or pharmaceutically acceptable salt, solvate, clathrate, polymorph or co-crystal thereof.

8. The method of claim 2, wherein the MT1/MT2 melatonin receptor agonist is agomelatine.

9. The method of claim 2, wherein the norepinephrine/dopamine reuptake inhibitor or pharmaceutically acceptable salt, solvate, clathrate, polymorph or co-crystal thereof, useful for augmentation of the said MT1/MT2 melatonin receptor agonist, is bupropion.

10. The method of claim 2, wherein the MT1/MT2 melatonin receptor agonist and the norepinephrine/dopamine reuptake inhibitor are administered simultaneously in a pharmaceutical composition.

11. The method of claim 2, wherein the MT1/MT2 melatonin receptor agonist and the norepinephrine/dopamine reuptake inhibitor are administered sequentially, e. g. in two discrete unit dosage forms.

12. The method of claim 2, wherein the amount of agomelatine used in combination therapy may range from 0.1 to about 300mg/day, particularly from about 0.1 to about 200mg/day and more particularly from about 5 to lOOmg/day.

13. The method of claim 2, wherein the amount of bupropion used in combination therapy may range from about 50 to about 1000mg/day, particularly from about 100 to about 600mg/day and more particularly from about 150 to about 450mg/day.