WO2005097138A2 - Combinaisons comprenant de l'oxcarbazepine pour le traitement de troubles affectifs - Google Patents

Combinaisons comprenant de l'oxcarbazepine pour le traitement de troubles affectifs Download PDF

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Publication number
WO2005097138A2
WO2005097138A2 PCT/EP2005/003385 EP2005003385W WO2005097138A2 WO 2005097138 A2 WO2005097138 A2 WO 2005097138A2 EP 2005003385 W EP2005003385 W EP 2005003385W WO 2005097138 A2 WO2005097138 A2 WO 2005097138A2
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WO
WIPO (PCT)
Prior art keywords
combination
administered
active ingredients
affective disorder
pharmaceutically acceptable
Prior art date
Application number
PCT/EP2005/003385
Other languages
English (en)
Other versions
WO2005097138A3 (fr
Inventor
James Bond
Ferenc Martenyi
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Publication of WO2005097138A2 publication Critical patent/WO2005097138A2/fr
Publication of WO2005097138A3 publication Critical patent/WO2005097138A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Combinations comprising oxcarbazepine to treat affective disorders
  • the present invention relates to a new pharmaceutical use of oxcarbazepine.
  • the invention relates to a method for the treatment of affective disorders in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of the formula
  • the compound of the formula I is known as "oxcarbazepine" (10-oxo-10,11-dihydro-5H- dibenz[b,f]azepine-5-carboxamide) and is, e. g., marketed under the brand name Trileptal ® .
  • Oxcarbazepine is a known anticonvulsant drug useful in the treatment of seizures of, for example, epileptic origin. Its preparation is described, e. g., in US-3,642,775 and in WO-2001/56992, which are both herein incorporated by reference.
  • the effect of a combination which comprises a compound of the formula I or a pharmaceutically acceptable salt thereof and at least one compound selected from the group, consisting of lithium, a valproic acid salt, a conventional antipsychotic, an atypical antipsychotic, lamotrigine, an antidepressant and a central nervous stimulant, is greater than the effect of the single drugs, preferably greater than the additive effect of the combined drugs.
  • the combinations disclosed herein can be used to treat affective disorders which are refractory to monotherapy employing one of the combination partners alone.
  • the present invention provides a method for the treatment of affective disorders in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of formula
  • a compound selected from the group, consisting of lithium, a valproic acid salt, a conventional antipsychotic, an atypical antipsychotic, lamotrigine, an antidepressant and a central nervous stimulant optionally in combination with at least one pharmaceutically acceptable carrier, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and are administered simultaneously, separately or sequentially.
  • cogni- disorders includes, but is not limited to, depression and uni- and bipolar disorders, e. g. manic-depressive psychoses, pre-menstrual dysphoric disorder, post-partum depression, post-menopausal depression, neurodegeneration-related depressive symptoms, depression occurring following cessation of psychostimulant intake, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), extreme psychotic states, e. g. mania, schizophrenia and excessive mood swings where behavioural stabilization is desired.
  • ADD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • extreme psychotic states e. g. mania, schizophrenia and excessive mood swings where behavioural stabilization is desired.
  • lithium as used herein includes, but is not limited to, lithium acetate, lithium carbonate, lithium chloride, lithium citrate and lithium sulfate.
  • conventional antipsychotic as used herein includes, but is not limited to, haloperidol and fluphenazine.
  • typically antipsychotic as used herein includes, but is not limited to, olanzapine, quetiapine and risperidone.
  • antagonist as used herein includes, but is not limited to, selective serotonin reuptake inhibitors (SSRIs).
  • An SSRI suitable for the present invention is especially selected from the group, consisting of fluoxetine, fuvoxamine, sertraline, paroxetine and escitaloprann.
  • the term "central nervous stimulant” as used herein includes, but is not limited to, methylphenidate, amphetamine, methamphetamine and mixed amphetamine salts, such as amphetamine and dextroamphetamine.
  • Lithium acetate can be administered, e. g., in the form as marketed, e. g. under the trademark Quilonorm ® .
  • Lithium carbonate can be administered, e. g., in the form as marketed, e. g. under the trademark Eskalith ® .
  • Lithium citrate can be administered, e. g., in the form as marketed, e. g. under the trademark Litarex ® .
  • Lithium sulfate can be administered, e. g., in the form as marketed, e. g. under the trademark Lithium-Duriles , or, e. g., by transdermal release (US-6,375,990).
  • Valproic acid sodium salt can be administered, e. g., in the form as marketed, e. g. as divalproex sodium.
  • Haloperidol can be administered, e. g., in the form as marketed, e. g. under the trademark Halop&ridol STADA ® .
  • Olanzapine can be administered, e. g., in the form as marketed, e. g. under the trademark Zyprexa ® .
  • Risperidone can be administered, e. g., in the form as marketed, e. g. under the trademark Risperdal ® .
  • Quetiapine can be administered, e. g., in the form as marketed, e. g. under the trademark Seroquel ® .
  • Fluphenazine can be administered, e. g., in the form of its dihydro- chloride as marketed, e. g. under the trademark Prolixin ® .
  • Lamotrigine can be administered, e.
  • Fluoxetine can be administered, e. g., in the form of its hydrochloride as marketed, e. g. under the trademark Prozac ® .
  • Paroxetine can be administered, e. g., in the form as marketed, e. g. under the trademark Paxil ® .
  • Amphetamine and dextroamphetamine can be administered, e. g., in the form as marketed, e. g. under the trademark Adderall ® .
  • Methylphenidate which is commercially available under the trademark Ritalin ® from Novartis Pharmaceuticals Corporation, as a central nervous system stim lant, activates the brain stem arousal system to effect stimulation of the patient.
  • Methylphenidate is the most commonly prescribed psychotropic medication for children in the United States, primarily for the treatment of children diagnosed with attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), and thus, is widely available.
  • ADD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • Methylphenidate is described in US-2,838,519 and US-2,957,880.
  • US-5,922,736, US-5,908,850, US-5,773,478 and US- 6,113,879 describe administering d-threo methylphenidate to treat nervous system disorders.
  • US-5,936,091 and US-5,965,734 describe processes and intermediates for preparing 2-substituted d-threo piperidines.
  • US-6, 100,401, US-6, 121,453 and US-6, 162,919 describe processes for preparing substantially the single enantiorner d-threo methylphenidate.
  • US-5,874,090 and US-5,837,284 describe sustained release formulations of methylphenidate.
  • the structure of the active agents identified by code nos., generic names or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e. g. Patents International (e. g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference.
  • sertraline can be prepared as disclosed in US-4,536,518.
  • the present invention relates also to a pharmaceutical combination of a compound of the formula I and at least one compound selected from the group, consisting of lithium, a valproic acid salt, a conventional antipsychotic, an atypical antipsychotic, lamotrigine, an antidepressant and a central nervous stimulant, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt.
  • a pharmaceutical combination will be referred to hereinafter as a COMBINATION OF THE INVENTION.
  • the pharmacological activity of a COMBINATION OF THE INVENTION may be demonstrated in a clinical study.
  • Such clinical studies are preferably randomized, double- blind, clinical studies in patients with affective disorders.
  • Such studies demonstrate, in particular, the synergism of the active ingredients of a COMBINATI ON OF THE INVENTION.
  • the beneficial effects on affective disorders can be determined directly through the results of these studies or by changes in the study design which are known as such to a person skilled in the art.
  • the studies are, in particular, suitable to compare the effects of a monotherapy using the active ingredients and a COMBINATION OF THE INVENTION.
  • a further benefit is that lower doses of the active ingredients of a COMBINATION OF THE INVENTION can be used, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be adjusted in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
  • a COMBINATION OF THE INVENTION can be used, in particular, -for the treatment of affective disorders which are refractory to monotherapy.
  • Such a COMBINATION OF THE INVENTION can be a combined preparation or a pharmaceutical composition.
  • a combined preparation defines especially a "kit of parts" in the sense that the first and second active ingredient as defined above ca n be dosed independently or by use of different fixed combinations with distinguished amounts of the ingredients, i. e., simultaneously or at different time points.
  • the parts of the kit of parts can then, e. g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the active ingredients.
  • the ratio of the total amounts of the active ingredient 1 to the active ingredient 2 to be administered in the combined preparation can be varied, e. g., in order to cope with the different needs of a patient sub-population to be treated or the different needs of the single patient, which different needs can be due to age, sex, body weight, etc. of the patient(s).
  • there is at least one beneficial effect e. g., a mutual enhancing of the effect of the first and second active ingredient, in p rticular a synergism, e. g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutic effect in a non-effective dosage of one or both of the first and second active ingredient, and especially a strong synergism of the first and the second active ingredient.
  • references to the active ingredients are meant to also include the pharmaceutically acceptable salts. If these active ingredients have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
  • the active ingredients having an acid group (for example COOH) can also form salts with bases.
  • the active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
  • the present invention also provides • the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of affective disorders; • a pharmaceutical composition comprising a COMBINATION O F THE INVENTION and at least one pharmaceutically acceptable excipient; and • a commercial package comprising a COMBINATION OF THE INVENTION together with instructions for simultaneous, separate or sequential use thereof in the treatment of affective disorders.
  • a combination comprising a compound of the formula I and at least one compound selected from the group, consisting of lithium, a valproic acid salt, a conventional antipsychotic, an atypical antipsychotic, lamotrigine, an antidepressant and a central nervous stimulant, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use, is especially useful for the treatment of mania.
  • a combination comprising a compound of the formula I and at least one antidepressant, e. g. an SSRI, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use, is especially useful for the treatment of bipolar disorders.
  • at least one antidepressant e. g. an SSRI
  • the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use, is especially useful for the treatment of bipolar disorders.
  • It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against affective disorders, of a COMBINATION OF THE INVENTION and at least one pharmaceutically acceptable carrier.
  • the first and second active ingredient can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms.
  • the unit dosage form may also be a fixed combination.
  • a pharmaceutical composition according to the invention can be prepared in a manner known per se and is one of those suitable for enteral, such as oral or rectal, or parenteral administration to mammals (warm-blooded animals), including man, especially suitable for oral administration.
  • a pharmaceutical composition according to the invention can contain, for example, from about 10% to about 100%, preferably from about 20% to about 60%, by weight of the active ingredients.
  • Pharmaceutical compositions for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils or alcohols; or carriers such as starches, sugars, microcristalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules or tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • Haloperidol may be administered to a patient at a total daily dosage of between about 5 and about 100 mg.
  • Lithium can be administered to a patient at a total daily dosage of between about 0.5 and about 1 g.
  • Olanzapine can be administered to a patient atn a total daily dosage of between about 10 and about 20 mg.
  • Quetiapine can be administered to a patient at a total daily dosage of between about 500 and about 600 mg. Risperidone may be administered to a patient at a total daily dosage of between about 2 and about 6 mg.
  • Valproic acid sodium salt may be administered to a patient at a total daily dosage of between about 2'000 and about 3'000 mg.
  • Rats are deprived of water for 48 hours and are then placed individually into a transparent Plexiglas enclosure (15 cm x 32 cm x 34 cm) with a floor consisting of stainless steel bars (0.4 cm) spaced 1 cm apart.
  • the back wall of the enclosure is made of opaque Plexiglass thereby concealing the observer from the experimental animal.
  • a metal water spout protrudes into the cage and is connected to one pole of a shock generator (Apelex: Type 011346).
  • the other pole of the shock generator is connected to the metal grid floor.
  • the rat is left to explore until it founrd the water spout.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne le traitement de troubles affectifs par l'administration de combinaisons d'oxcarbazépine pharmaceutiques.
PCT/EP2005/003385 2004-04-01 2005-03-31 Combinaisons comprenant de l'oxcarbazepine pour le traitement de troubles affectifs WO2005097138A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0407468.8A GB0407468D0 (en) 2004-04-01 2004-04-01 Organic compounds
GB0407468.8 2004-04-01

Publications (2)

Publication Number Publication Date
WO2005097138A2 true WO2005097138A2 (fr) 2005-10-20
WO2005097138A3 WO2005097138A3 (fr) 2007-01-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1758600A1 (fr) * 2004-06-04 2007-03-07 Mood Management Sciences, LLC Compositions et methodes de traitement des troubles de l'humeur

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CABRERA J ET AL: "COMBINED PROPHYLACTIC TREATMENT OF MANIC-DEPRESSIVE DISEASE WITH LITHIUM AND CARBAMAZEPINE OR OXCARBAZEPINE" NERVENARZT, vol. 58, no. 4, 1987, pages 245-249, XP008065346 ISSN: 0028-2804 *
JOCA SAMIA R L ET AL: "The antidepressive-like effect of oxcarbazepine: Possible role of dopaminergic neurotransmission" EUROPEAN NEUROPSYCHOPHARMACOLOGY, vol. 10, no. 4, July 2000 (2000-07), pages 223-228, XP008065448 ISSN: 0924-977X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1758600A1 (fr) * 2004-06-04 2007-03-07 Mood Management Sciences, LLC Compositions et methodes de traitement des troubles de l'humeur
EP1758600A4 (fr) * 2004-06-04 2008-03-05 Mood Man Sciences Llc Compositions et methodes de traitement des troubles de l'humeur

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Publication number Publication date
GB0407468D0 (en) 2004-05-05
WO2005097138A3 (fr) 2007-01-04

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