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WO1997035574A1 - Composition containing milnacipran and idazoxan for use as a combined pharmaceutical preparation - Google Patents

Composition containing milnacipran and idazoxan for use as a combined pharmaceutical preparation Download PDF

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Publication number
WO1997035574A1
WO1997035574A1 PCT/FR1997/000522 FR9700522W WO9735574A1 WO 1997035574 A1 WO1997035574 A1 WO 1997035574A1 FR 9700522 W FR9700522 W FR 9700522W WO 9735574 A1 WO9735574 A1 WO 9735574A1
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WIPO (PCT)
Prior art keywords
idazoxan
milnacipran
pharmaceutical preparation
combined pharmaceutical
composition containing
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PCT/FR1997/000522
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French (fr)
Inventor
Francis Colpaert
Marc Marien
Wounter Koek
Thierry Imbert
Original Assignee
Pierre Fabre Medicament
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Publication date
Application filed by Pierre Fabre Medicament filed Critical Pierre Fabre Medicament
Priority to AU25119/97A priority Critical patent/AU2511997A/en
Publication of WO1997035574A1 publication Critical patent/WO1997035574A1/en

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles

Definitions

  • the present invention relates to products containing Milnacipran. of formula 1, and of Idazoxan, of formula 2 as a combined pharmaceutical preparation for simultaneous, separate or spread over time use to treat depression and its various forms, as well as the pathologies in which antidepressants are used.
  • Milnacipran I is a compound known from patent FR 2 508 035, for its structure, its preparation and its antidepressant activity. It has inhibitory properties of reuptake of monoamines (NA, 5-HT), in the central nervous system. The norepinephrine and serotonin reuptake inhibition properties induce the increase in the rate of these two neuromediators in the synaptic cleft, which makes it possible to compensate for the low rate, as is the case in depressive pathologies, and of dysfunction. synaptic transmission.
  • Idazoxan 2 is a compound known by patent GB 2 068 376 for its structure, its preparation, and precisely for its use as an antidepressant agent by virtue of its ⁇ 2 adrenergic antagonist activities.
  • the products according to the invention contain Milnacipran and / or Idazoxan in the form of a salt with a pharmaceutically acceptable mineral or organic acid. Its active ingredients can be present both in their racemic forms and in the form of a pure enantiomer.
  • the products of the invention contain the
  • Milnacipran together with Idazoxan i.e. the invention also extends, and preferably, to pharmaceutical compositions containing a synergistic mixture of Milnacipran and Idazoxan intended to be used in the treatment of different forms of depression.
  • the products according to the invention are in the form of unit dosages containing from 10 to 100 mg of Milnacipran and from 0.5 to 50 mg of Idazoxan
  • Idazoxan is exceptional, because it is not shared by other alpha 2 antagonist compounds, and in particular Efaroxan, whose dextrorotatory isomer having alpha 2 antagonist activity, does not cause not this potentiation with Milnacipran, as shown in Table II below:
  • NS Not significant compared to control, Milnacipran alone and Efaroxan alone. This potentiation of the antidepressant effect of Milnacipran is used in humans to treat depressive behavioral pathologies and their different forms.
  • Another characteristic of the present invention resides in the fact that the coadministation of the two compounds can be done, either by separate pharmaceutical compositions, the clinician thus having the choice of the dosage and of the mode of administration, according to the state and the characteristics. of the patient, either in a single pharmaceutical composition containing an excipient suitable, for oral administration, in capsules or tablets, parenteral, or isradermal, these pharmaceutical compositions being prepared according to conventional methods, at the dosages as described below .
  • Milnacipran can be administered in daily oral doses of between about 10 and 100 mg, together with Idazoxan in doses of between 0.5 and 50 mg, once or several times a day.
  • the two compounds can be incorporated into the pharmaceutical compositions in the form of mineral or organic salts and can also be present in the form of a pure enantiomer of one and / or of the other of the active entities.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

A composition containing milnacipran and idazoxan for simultaneous, separate or staggered use as a combined pharmaceutical preparation in antidepressive therapy, is disclosed.

Description

Produit contenant du Milnacipran et de l'Idazoxan comme préparation pharmaceutique combinée Product containing Milnacipran and Idazoxan as a combined pharmaceutical preparation
La présente invention est relative à des produits contenant du Milnacipran. de formule 1, et de l'Idazoxan, de formule 2 comme préparation pharmaceutique combinée pour une utilisation simultanée, séparée ou étalée dans le temps pour traiter la dépression et ses différentes formes, ainsi que les pathologies dans lesquelles les antidépresseurs sont utilisés.The present invention relates to products containing Milnacipran. of formula 1, and of Idazoxan, of formula 2 as a combined pharmaceutical preparation for simultaneous, separate or spread over time use to treat depression and its various forms, as well as the pathologies in which antidepressants are used.
Figure imgf000003_0001
Figure imgf000003_0001
Le Milnacipran I est un composé connu par le brevet FR 2 508 035, pour sa structure, sa préparation et son activité antidépressive. Il possède des propriétés inhibitrices de recapture de monoamines (NA, 5-HT), dans le système nerveux central. Les propriétés d'inhibition de recapture de noradrénaline et de sérotonine induisent l'augmention du taux de ces deux neuromédiateurs dans la fente synaptique, ce qui permet de compenser le faible taux, comme c'est le cas dans les pathologies dépressives, et de dysfonctionnement de la transmission synaptique.Milnacipran I is a compound known from patent FR 2 508 035, for its structure, its preparation and its antidepressant activity. It has inhibitory properties of reuptake of monoamines (NA, 5-HT), in the central nervous system. The norepinephrine and serotonin reuptake inhibition properties induce the increase in the rate of these two neuromediators in the synaptic cleft, which makes it possible to compensate for the low rate, as is the case in depressive pathologies, and of dysfunction. synaptic transmission.
Les composés ayant la propriété de bloquer les récepteurs α2 adrénergiques permettent une augmentation de la libération de noradrénaline également dans la fente synaptique dans les localisations cérébrales impliquées. L'Idazoxan 2 est un composé connu par le brevet GB 2 068 376 pour sa structure, sa préparation, et précisément pour son utilisation comme agent antidépressif en vertu de ses activités α2 antagonistes adrénergiques.The compounds having the property of blocking the α2 adrenergic receptors allow an increase in the release of noradrenaline also in the synaptic cleft in the cerebral localizations involved. Idazoxan 2 is a compound known by patent GB 2 068 376 for its structure, its preparation, and precisely for its use as an antidepressant agent by virtue of its α2 adrenergic antagonist activities.
Ceci est également montré dans les publications, telles que J.Med.Chem. 1983, 26, 823 J.Med.Chem 1985, 28, 1054 ; J.Med.Chem. 1986, 29, 2000. L'Idazoxan a été utilisé en clinique humaine pour soigner la dépression. Les résultats de ces études ont montré une activité antidépressive limitée, insuffisante pour permettre un développement complet dans cette indication en monothérapie.This is also shown in publications, such as J. Med.Chem. 1983, 26, 823 J. Med. Chem 1985, 28, 1054; J. Med. Chem. 1986, 29, 2000. Idazoxan has been used in human clinics to treat depression. The results of these studies have shown limited antidepressant activity, insufficient to allow complete development in this indication as monotherapy.
On sait également que l'isomère (+) de l'Idazoxan est l'isomère actif. Il a cependant la propriété de se racémiser en solution ( J.Med.Chem. 1986, 22, 2000 )We also know that the (+) isomer of Idazoxan is the active isomer. However, it has the property of racemising in solution (J. Med. Chem. 1986, 22, 2000)
Il a été trouvé maintenant de façon surprenante que l'administration conjointe, séparée ou étalée dans le temps du Milnacipran ainsi que de l'Idazoxan, provoquait une potentialisation de l'activité antidépressive de ces composés par rapport à leur activité après administration seule.It has now been surprisingly found that the joint, separate or spread over time administration of Milnacipran as well as Idazoxan, potentiates the antidepressant activity of these compounds compared to their activity after administration alone.
Selon une autre caractéristique, les produits selon l'invention renferment le Milnacipran et/ou l'Idazoxan sous la forme d'un sel avec un acide minéral ou organique pharmaceutiquement acceptable. Ses principes actifs peuvent être présents aussi bien sous leurs formes racemiques que sous la forme d'un énantiomère pur.According to another characteristic, the products according to the invention contain Milnacipran and / or Idazoxan in the form of a salt with a pharmaceutically acceptable mineral or organic acid. Its active ingredients can be present both in their racemic forms and in the form of a pure enantiomer.
Selon une autre caractéristique, les produits de l'invention contiennent leAccording to another characteristic, the products of the invention contain the
Milnacipran conjointement avec l'Idazoxan, c'est-à-dire que l'invention s'étend également, et de façon préférentielle, aux compositions pharmaceutiques renfermant un mélange synergique de Milnacipran et d'Idazoxan destiné à être utilisé dans le traitement de différentes formes de dépression.Milnacipran together with Idazoxan, i.e. the invention also extends, and preferably, to pharmaceutical compositions containing a synergistic mixture of Milnacipran and Idazoxan intended to be used in the treatment of different forms of depression.
Avantageusement, les produits selon l'invention se présentent sous la forme de dosages unitaires contenant de 10 à 100 mg de Milnacipran et de 0,5 à 50 mg d'IdazoxanAdvantageously, the products according to the invention are in the form of unit dosages containing from 10 to 100 mg of Milnacipran and from 0.5 to 50 mg of Idazoxan
Le phénomène de potentialisation de l'activité antidépressive a été mis en évidence dans les modèles pharmacologiques classiquement utilisés dans le domaine, en particulier dans le test de la nage forcée. (R. PORSOLT et al. Eur.J.Pharmacol. 47 : 379- 391 , 1978). Ce test effectué chez le rat est un test comportemental. Les rats sont soumis à nager dans un cylindre rempli d'eau, d'où ils ne peuvent s'échapper, et, après une période d'activité vigoureuse , adoptent une position immobile ("désespoir"). Cette immobilité est réduite par des composés antidépresseurs variés actifs en clinique humaine. Plus un produit est actif, plus le temps d'immobilité de l'anima! sera court.The phenomenon of potentiation of antidepressant activity has been highlighted in the pharmacological models conventionally used in the field, in particular in the forced swimming test. (R. PORSOLT et al. Eur.J. Pharmacol. 47: 379- 391, 1978). This test performed in rats is a behavioral test. The rats are subjected to swim in a cylinder filled with water, from which they cannot escape, and, after a period of vigorous activity, adopt an immobile position ("despair"). This immobility is reduced by various antidepressant compounds active in human clinic. The more active a product, the longer the immobility time of the anima! will be short.
Tous les produits sont administrés, soit per os, soit par voie sous cutanée, 60 min. avant le début du test.All products are administered either orally or subcutaneously, 60 min. before the start of the test.
Les résultats sont rassemblés dans le tableau I suivant:The results are collated in the following Table I:
TABLEAU ITABLE I
Figure imgf000005_0001
Figure imgf000005_0001
II résulte de ce tableau que le Milnacipran par administration seul réduit deIt follows from this table that Milnacipran by administration alone reduces
5 % l'immobilité de l'animal ce qui n'est pas significatif, tandis que l'Idazoxan administré seul réduit significativement de 34 % cette immobilité. La potentialisation est ainsi montrée par administration conjointe du Milnacipran et de l'Idazoxan, une réduction de l'immobilité de 61 % par rapport aux animaux n'ayant reçu aucun traitement, et cette réduction est significativement plus grande par rapport à ce qui est observé avec le Milnacipran ou l'Idazoxan administrés seuls, (p < 0,01).5% the immobility of the animal which is not significant, while Idazoxan administered alone significantly reduces this immobility by 34%. Potentiation is thus shown by joint administration of Milnacipran and Idazoxan, a reduction of immobility of 61% compared to animals which did not receive any treatment, and this reduction is significantly greater compared to what is observed with the Milnacipran or Idazoxan administered alone, (p <0.01).
L'effet synergique apporté par l'Idazoxan est exceptionnel, car il n'est pas partagé par d'autres composés alpha 2 antagonistes, et en particulier l'Efaroxan, dont l'isomère dextrogyre possédant l'activité alpha 2 antagoniste, ne provoque pas cette potentialisation avec le Milnacipran, comme il est montré dans le tableau II suivant:The synergistic effect provided by Idazoxan is exceptional, because it is not shared by other alpha 2 antagonist compounds, and in particular Efaroxan, whose dextrorotatory isomer having alpha 2 antagonist activity, does not cause not this potentiation with Milnacipran, as shown in Table II below:
TABLEAU TITI TABLE
Figure imgf000006_0001
Figure imgf000006_0001
N.S. : Non significatif par rapport au contrôle , au Milnacipran seul et à l'Efaroxan seul. Cette potentialisation de l'effet antidépresseur du Milnacipran est mise à profit chez l'homme pour soigner les pathologies comportementales dépressives et leurs différentes formes.NS: Not significant compared to control, Milnacipran alone and Efaroxan alone. This potentiation of the antidepressant effect of Milnacipran is used in humans to treat depressive behavioral pathologies and their different forms.
Une autre caractéristique de la présente invention réside dans le fait que la coadministation des deux composés peut se faire, soit par des compositions pharmaceutiques séparées, le clinicien ayant ainsi le choix du dosage et du mode d'administration, selon l'état et les caractéristiques du patient, soit dans une seule composition pharmaceutique contenant un excipient adapté, pour une administration orale, en gélules ou comprimés, parentérale, ou îransdermique, ces compositions pharmaceutiques étant préparées selon les méthodes conventionnelles, aux posologies telles qu'elles sont décrites ci-après.Another characteristic of the present invention resides in the fact that the coadministation of the two compounds can be done, either by separate pharmaceutical compositions, the clinician thus having the choice of the dosage and of the mode of administration, according to the state and the characteristics. of the patient, either in a single pharmaceutical composition containing an excipient suitable, for oral administration, in capsules or tablets, parenteral, or isradermal, these pharmaceutical compositions being prepared according to conventional methods, at the dosages as described below .
Le Milnacipran peut être administré à des doses quotidiennes par voie orale comprises entre environ 10 et 100 mg, en même temps que l'Idazoxan à des doses comprises entre 0,5 et 50 mg, et ceci une ou plusieurs fois par jour.Milnacipran can be administered in daily oral doses of between about 10 and 100 mg, together with Idazoxan in doses of between 0.5 and 50 mg, once or several times a day.
Il est entendu également que les deux composés peuvent être incorporés dans les compositions pharmaceutiques sous forme de sels minéraux ou organiques et peuvent se présenter également sous forme d'énantiomère pur de l'un et/ou de l'autre des entités actives. It is also understood that the two compounds can be incorporated into the pharmaceutical compositions in the form of mineral or organic salts and can also be present in the form of a pure enantiomer of one and / or of the other of the active entities.

Claims

REVENDTCATTONSRESENDTCATTONS
1 - Produit contenant du Milnacipran et de l'Idazoxan comme préparation pharmaceutique combinée pour une utilisation simultanée, séparée ou étalée dans le temps en thérapie antidépressive.1 - Product containing Milnacipran and Idazoxan as a combined pharmaceutical preparation for simultaneous, separate or spread over time in antidepressant therapy.
2.- Produit selon la revendication 1, en ce qu'il renferme le Milnacipran et/ou l'Idazoxan sous la forme d'un sel avec un acide minéral ou organique pharmaceutiquement acceptable.2. A product according to claim 1, in that it contains Milnacipran and / or Idazoxan in the form of a salt with a pharmaceutically acceptable mineral or organic acid.
3.- Produit selon l'une des revendications 1 et 2, en ce qu'il renferme le Milnacipran et/ou l'Idazoxan sous la forme d'un énantiomère pur.3.- Product according to one of claims 1 and 2, in that it contains Milnacipran and / or Idazoxan in the form of a pure enantiomer.
4.- Produit selon l'une des revendications 1 à 3, en ce qu'il contient le Milnacipran conjointement avec l'Idazoxan.4.- Product according to one of claims 1 to 3, in that it contains Milnacipran together with Idazoxan.
5.- Produit selon l'une des revendications 1 à 4, en ce qu'il se présente sous la forme de dosages unitaires contenant de 10 à 100 mg de Milnacipran.5.- Product according to one of claims 1 to 4, in that it is in the form of unit dosages containing from 10 to 100 mg of Milnacipran.
6.- Produit selon l'une des revendications 1 à 4, en ce qu'il se présente sous la forme de dosages unitaires contenant de 0,5 à 50 mg d'Idazoxan. 6.- Product according to one of claims 1 to 4, in that it is in the form of unit dosages containing from 0.5 to 50 mg of Idazoxan.
PCT/FR1997/000522 1996-03-25 1997-03-25 Composition containing milnacipran and idazoxan for use as a combined pharmaceutical preparation WO1997035574A1 (en)

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FR96/03674 1996-03-25
FR9603674A FR2746314B1 (en) 1996-03-25 1996-03-25 PRODUCT CONTAINING MILNACIPRAN AND IDAZOXAN AS A COMBINED PHARMACEUTICAL PREPARATION

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6602911B2 (en) 2001-11-05 2003-08-05 Cypress Bioscience, Inc. Methods of treating fibromyalgia
US6635675B2 (en) 2001-11-05 2003-10-21 Cypress Bioscience, Inc. Method of treating chronic fatigue syndrome
US7005452B2 (en) 2003-02-14 2006-02-28 Pierre Fabre Medicament Use of the dextrogyral enantiomer of milnacipran for the preparation of a drug
US7074833B2 (en) 2003-02-14 2006-07-11 Pierre Fabre Medicament Use of the (1S,2R) enantiomer of milnacipran for the preparation of a drug
WO2006083204A1 (en) * 2004-12-27 2006-08-10 Alpha 2 Pharmaceutical Ab Antidepressant medicament comprising idazoxan and a selective serotonin reuptake inhibitor
WO2012059933A1 (en) 2010-11-03 2012-05-10 Arch Pharmalabs Limited A new process for preparing optically pure milnacipran and its pharmaceutically acceptable salts.
US8481598B2 (en) 2009-11-06 2013-07-09 Rahul Surana Stable dosage forms of levomilnacipran

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2861299B1 (en) 2003-10-28 2006-01-27 Pf Medicament PHARMACEUTICAL COMPOSITIONS BASED ON IDASOXAN DERIVATIVES IN POLYMORPHIC FORMS
US7595335B2 (en) 2003-10-28 2009-09-29 Pierre Fabre Medicament Pharmaceutical composition based on idazoxan, salts, hydrates or polymorphs thereof
US8476307B2 (en) 2003-10-28 2013-07-02 Pierre Fabre Medicament Pharmaceutical composition based on idazoxan, salts, hydrates or polymorphs thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0510837A2 (en) * 1991-04-23 1992-10-28 Pfizer Inc. Synergistic combinations in the treatment of anxiety
EP0687472A2 (en) * 1994-06-16 1995-12-20 Eli Lilly And Company Potentiation of drug response by a serotonin 1A receptor antagonist
US5492907A (en) * 1992-12-09 1996-02-20 The United States Of America As Represented By The Department Of Health & Human Services Antipsychotic composition and method of treatment

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0510837A2 (en) * 1991-04-23 1992-10-28 Pfizer Inc. Synergistic combinations in the treatment of anxiety
US5492907A (en) * 1992-12-09 1996-02-20 The United States Of America As Represented By The Department Of Health & Human Services Antipsychotic composition and method of treatment
EP0687472A2 (en) * 1994-06-16 1995-12-20 Eli Lilly And Company Potentiation of drug response by a serotonin 1A receptor antagonist

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6602911B2 (en) 2001-11-05 2003-08-05 Cypress Bioscience, Inc. Methods of treating fibromyalgia
US6635675B2 (en) 2001-11-05 2003-10-21 Cypress Bioscience, Inc. Method of treating chronic fatigue syndrome
US6992110B2 (en) 2001-11-05 2006-01-31 Cypress Bioscience, Inc. Methods of treating fibromyalgia syndrome, chronic fatigue syndrome and pain
EP1908461A1 (en) 2003-02-14 2008-04-09 Pierre Fabre Medicament Use of (1S, 2R) enantiomer of milnacipran for the preparation of a medicine
US7074833B2 (en) 2003-02-14 2006-07-11 Pierre Fabre Medicament Use of the (1S,2R) enantiomer of milnacipran for the preparation of a drug
US7005452B2 (en) 2003-02-14 2006-02-28 Pierre Fabre Medicament Use of the dextrogyral enantiomer of milnacipran for the preparation of a drug
EP2305225A1 (en) 2003-02-14 2011-04-06 Pierre Fabre Medicament Use of (1S, 2R) enantiomer of milnacipran for the preparation of a medicine
USRE43879E1 (en) 2003-02-14 2012-12-25 Pierre Fabre Medicament Use of the dextrogyral enantiomer of milnacipran for the preparation of a drug
WO2006083204A1 (en) * 2004-12-27 2006-08-10 Alpha 2 Pharmaceutical Ab Antidepressant medicament comprising idazoxan and a selective serotonin reuptake inhibitor
US8481598B2 (en) 2009-11-06 2013-07-09 Rahul Surana Stable dosage forms of levomilnacipran
US8865937B2 (en) 2009-11-06 2014-10-21 Mahendra G. Dedhiya Crystalline forms of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide
US9259403B2 (en) 2009-11-06 2016-02-16 Forest Laboratories Holdings Ltd. Crystalline forms of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide
WO2012059933A1 (en) 2010-11-03 2012-05-10 Arch Pharmalabs Limited A new process for preparing optically pure milnacipran and its pharmaceutically acceptable salts.

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FR2746314B1 (en) 1998-06-12
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