WO1999032108A1 - Traitement pour la depression - Google Patents

Traitement pour la depression Download PDF

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Publication number
WO1999032108A1
WO1999032108A1 PCT/EP1998/008539 EP9808539W WO9932108A1 WO 1999032108 A1 WO1999032108 A1 WO 1999032108A1 EP 9808539 W EP9808539 W EP 9808539W WO 9932108 A1 WO9932108 A1 WO 9932108A1
Authority
WO
WIPO (PCT)
Prior art keywords
depression
treatment
pharmaceutically acceptable
oxepino
dibenz
Prior art date
Application number
PCT/EP1998/008539
Other languages
English (en)
Inventor
John Stuart Andrews
Original Assignee
Akzo Nobel N.V.
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 Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to AU24184/99A priority Critical patent/AU2418499A/en
Publication of WO1999032108A1 publication Critical patent/WO1999032108A1/fr

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Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine

Definitions

  • This invention relates to a new method of treating depression and to a new medical use of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H-dibenz [2,3:6,7] oxepino[4,5-c]pyrrole, or a pharmaceutically acceptable acid addition salt or solvate thereof.
  • Depression is a major health problem in our society and also poses a tremendous financial burden on society due to lost self-support of persons suffering from depression. Life time prevalence for major depression is estimated to be between 5 to 10 %. Various forms of depression are distinguished which are separately diagnosed according to criteria given in handbooks for psychiatry, for example in the Diagnostic and Statistical Manual of Mental Disorders 4 th edition published by the American Psychiatric Association, Washington, D.C. (1994) and in the International Classification of Diseases (ICD-10) published by the World Health Organisation (Geneva).
  • ICD-10 International Classification of Diseases
  • Anti- depressants are distinguished from other classes, such as anxiolytics and antipsychotics. Drugs in one category may have side-effects aggravating other psychiatric diseases not belonging to the category for which the drug treatment is given.
  • Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H-dibenz [2,3:6,7] oxepino[4,5-c]pyrrole is a drug known from US 4,145,434 for the treatment psychosis and anxiety.
  • trans-5-chloro-2-methyl-2,3,3a,12b- tetrahydro-1 H-dibenz [2,3:6,7] oxepino[4,5-c]pyrrole is useful for the treatment or prophylaxis of depression. Accordingly, the present invention provides the use of a compound of formula (A):
  • Formula A which is trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H-dibenz [2,3:6,7] oxepino[4,5-c]pyrrole, or a pharmaceutically acceptable acid addition salt or solvate thereof, for the manufacture of a medicament for the treatment or prophylaxis of depression.
  • depression is used here for the psychiatric disorder or the symptom characterised by chronic low mood and loss of capacity to experience pleasure.
  • This disease or symptom is well-recognised by a physician and can also be quantified, for example with the Hamilton Rating Scale for depression or with the Montgomery and Asberg Depression Rating Scale.
  • An important characteristic of presently and frequently diagnosed depression, for example major depression and dysthymia, is that an organic disorder causing the depression cannot be detected.
  • a depression due to identified pathology in the physiology or anatomy of a person is usually treated by therapeutic strategies aimed at correcting or compensating for such an organic disorder.
  • Org 5222 in medicaments for treatment of mental disorders associated with a cerebrovascular disorder is known from EP 0 730 865 A1.
  • Suitable acid addition salts include hydrochloric, fumaric, maleic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation.
  • a preferred salt is maleic acid, in which case the compound is known as Org 5222.
  • the present invention provides a method of treating depression with a therapeutically effective amount of trans-5-chloro-2- methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz [2,3:6,7] oxepino[4,5-c]pyrrole.
  • a suitable daily dose will be in the range of 0.005 to 60 mg of a compound of the present invention per person. Preferably this dose will be in the range of from 0.03 to 2 mg.
  • a preferred route of administration for treatment is the sublingual route. With this route, a method of providing therapy using the pharmaceutical composition of the present invention comprises the insertion of a dosage form according to this invention in the buccal pouch or under the tongue of a person.
  • the present invention further provides a pharmaceutical formulation for use in the treatment of depression comprising a compound of formula A or a pharmaceutically acceptable acid addition salt or solvate thereof, together with a pharmaceutically acceptable carrier therefor and optionally other therapeutic agents.
  • the carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof.
  • suitable carriers are various carbohydrates, gum acacia, calcium phosphate, gelatin, talc, magnesium stearate or mineral oil.
  • the invention further includes a pharmaceutical formulation as herein described, in combination with packaging material adapted for the pharmaceutical formulation, said packaging material including facilities for the use of the pharmaceutical formulation in the treatment of depression.
  • packaging material including facilities for the use of the pharmaceutical formulation in the treatment of depression.
  • facilities can include precautions limiting the total dose contained in the package handed over to the person for treatment in order to reduce the risk of overdosing due the misuse of the available supply.
  • Suitable formulations include those adapted for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the sublingual route of administration is most preferred in view of the disclosure in WO 95/23600, which is incorporated herein by reference.
  • a dosage unit may contain between 0.005 mg and 15 mg of a compound of the present invention.
  • the dosage unit contains 0.03 to 0.50 mg of Org 5222.
  • dosage units of the pharmaceutical formulation of the invention per day is sufficient for obtaining a therapeutic effect.
  • the therapy may be continued for as long as necessary or desired.
  • the formulations may be prepared by any of the methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18 th ed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical Preparations and their manufacture). Such methods include the process of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients, carrying out said process by exclusion of contamination with traces of pathogens and harmful chemicals. Accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents and wetting agents.
  • Formulations adapted for sublingual administration may be presented as liquid, solids or lozenges, which can comprise a rapidly disintegrating composition of a pharmaceutically acceptable water-soluble or water-dispersible carrier material.
  • carrier materials are well known in the art and can be polysaccharides like hydrolysed dextran, dextrin, mannitol, and alginates, or mixtures thereof, or mixtures thereof with other carrier materials like polyvinylalcohol, polyvinylpyrrolidone and water-soluble cellulose derivatives, like hydroxypropyl cellulose.
  • the adaptation of a formulation for sublingual administration is characterised by properties which are in favor of drug delivery within the buccal cavity and which are unfavourable for swallowing the formulation by the treated person.
  • Such properties for a sublingual formulation may be obtained by methods available and/or known to the skilled person and comprise, for example the adjustment of the taste, the size or amount, the dosage, the surface, the viscosity and the disintegration time of the formulation.
  • a small amount of a fluid formulation will be insufficient to swallow the administered dose.
  • a solid formulation a pleasant taste, a very small size unsuitable for swallowing, a low dose insufficient for a therapeutic effect by oral administration but sufficient for sublingual administration, a rough or sticky surface in a moist environment, and disintegration time in a moist environment within 30 seconds or preferably 10 seconds, are all specific possibilities for implementing the adaptation for sublingual administration of the formulation.
  • An example of a preferred carrier material for rapid disintegration of the formulation is gelatin, especially partially hydrolysed gelatin.
  • the partially hydrolysed gelatin can be prepared be heating of a solution of gelatin in water, for example in an autoclave at about 120°C for up to 2 hours.
  • the hydrolysed gelatin is used in concentrations of about 1 to 6 % (w/v), and preferably in concentrations of about 2 to 4 % (w/v).
  • methods for preparation of sublingual dosage forms and packages are known to the skilled person and require no further elucidation. The details of preparing specific, preferred formulations and packages can be learned from the previously incorporated WO 95/23600, and the references mentioned therein.
  • Formulations adapted for oral administration may be presented as discrete units such as tablets or capsules each containing a predetermined amount of active ingredient; as powder or granulates; as a solution or suspension.
  • the active ingredient may also be presented as a bolus or paste, or may be contained within liposomes or microparticles.
  • Formulations adapted for rectal administration may be presented as a suppository or enema.
  • suitable formulations include aqueous and non- aqueous sterile injection.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.
  • Formulation adapted for nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.
  • Formulations may, for example, be presented in a suitable sustained release form, for example, in a device such as the MinipumpTM.
  • the compounds of the invention may be prepared by any method known in the art for the preparation of a compound of similar structure. Typically the compounds are prepared by the methods described in US 4,145,434, which is incorporated herein by reference.
  • Antidepressant-like drugs show a similar profile of action in this test: there is a decrease in overall responding, an increase in the number of food pellets earned per session and in the overall efficiency of performance (O'Donnell and Seiden J Pharmacol Exp Ther 224: 80-88; 1983).
  • mice Male rats of the Long Evans strain, weighing between 300-425g, are used in these experiments. The experiments are run in standard Skinner boxes. All rats have previous training in the DRL-72 procedure. Rats are divided into separate groups and the experiment undertaken using an independent groups design. The number of lever presses and pellets obtained in each 1 hour session are recorded and an efficiency score (pellets earned/responses) is calculated. Statistical analysis is by one factor independent groups ANOVA, followed by post hoc Tukey HSD tests where overall significance is obtained. Vehicle: Mulgofen (5% m/v) and NaCI (0.9% m/v) in water. Route of administration: intraperitoneally (30 mins before session begins) Results
  • the numbers in the table are means of 12 rats;
  • Desipramine suppresses lever pressing in a dose-related manner and significantly increases the number of food pellets obtained and overall efficiency per session. This reflects the antidepressant effect of desipramine.
  • the numbers in the table are means of 9 rats;
  • ORG 5222 suppresses lever pressing in a dose-related manner and significantly increased the number of pellets obtained and overall efficiency per session. This reflects the antidepressant effect of Org 5222.

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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)

Abstract

La présente invention concerne une nouvelle utilisation médicale du trans-5-chloro-2-méthyle-2,3,3a,12b-tétrahydro-1H-dibenz [2,3:6,7] oxépino [4,5-c]pyrolle, ou un sel d'addition acide pharmaceutiquement acceptable ou un solvate de ce dernier. L'invention concerne également un nouveau procédé de traitement de la dépression.
PCT/EP1998/008539 1997-12-19 1998-12-15 Traitement pour la depression WO1999032108A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24184/99A AU2418499A (en) 1997-12-19 1998-12-15 Org-5222 in the treatment of depression

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97204026.5 1997-12-19
EP97204026 1997-12-19

Publications (1)

Publication Number Publication Date
WO1999032108A1 true WO1999032108A1 (fr) 1999-07-01

Family

ID=8229089

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/008539 WO1999032108A1 (fr) 1997-12-19 1998-12-15 Traitement pour la depression

Country Status (2)

Country Link
AU (1) AU2418499A (fr)
WO (1) WO1999032108A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008516925A (ja) * 2004-10-15 2008-05-22 ナームローゼ・フエンノートチヤツプ・オルガノン 双極性障害および随伴症状の治療
JP2008534656A (ja) * 2005-04-07 2008-08-28 ナームローゼ・フエンノートチヤツプ・オルガノン アセナピン・マレイン酸塩の結晶形
WO2009135091A1 (fr) * 2008-04-30 2009-11-05 Medivation Technologies, Inc. Utilisation d’asénapine et composés associés pour le traitement de maladies ou de conditions neurales ou non
EP2154134A1 (fr) 2005-04-07 2010-02-17 N.V. Organon Processus de préparation de trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
US7741358B2 (en) 2005-04-14 2010-06-22 N.V. Organon Crystal form of asenapine maleate
US7750167B2 (en) 2006-07-05 2010-07-06 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
US7872147B2 (en) 2005-04-07 2011-01-18 N. V. Organon Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
US7875729B2 (en) 2007-01-05 2011-01-25 Synthon Bv Process for making asenapine
WO2012013766A1 (fr) 2010-07-29 2012-02-02 Laboratorios Lesvi, S.L. Nouveau procédé de synthèse de l'asénapine
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11154510B2 (en) 2015-06-11 2021-10-26 Alrise Biosystems Gmbh Process for the preparation of drug loaded microparticles
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4002632A (en) * 1974-01-31 1977-01-11 Akzona Incorporated Tetracyclic piperidino derivatives
EP0357126A1 (fr) * 1988-08-26 1990-03-07 Akzo Nobel N.V. Antidépresseurs tétracycliques
WO1995023600A1 (fr) * 1994-03-02 1995-09-08 Akzo Nobel N.V. Composition pharmaceutique sublinguale ou buccale
EP0730865A1 (fr) * 1995-01-12 1996-09-11 Sumitomo Pharmaceuticals Company, Limited Utilisation des bloquers de récepteurs de la sérotonine et de la dopamine pour le traitement des maladies mentales associées à des maladies cérébrovasculaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4002632A (en) * 1974-01-31 1977-01-11 Akzona Incorporated Tetracyclic piperidino derivatives
EP0357126A1 (fr) * 1988-08-26 1990-03-07 Akzo Nobel N.V. Antidépresseurs tétracycliques
WO1995023600A1 (fr) * 1994-03-02 1995-09-08 Akzo Nobel N.V. Composition pharmaceutique sublinguale ou buccale
EP0730865A1 (fr) * 1995-01-12 1996-09-11 Sumitomo Pharmaceuticals Company, Limited Utilisation des bloquers de récepteurs de la sérotonine et de la dopamine pour le traitement des maladies mentales associées à des maladies cérébrovasculaires

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BENGT ANDREE ET AL.: "Central 5-HT2A and D2 dopamine receptor occupancy after sublingual administraion of ORG 5222 in healthy men", PSYCHOPHARMACOLOGY, vol. 131, no. 4, June 1997 (1997-06-01), pages 339 - 345, XP002069566 *
SPERLING, W._DEMLING, J.: "NEW TETRACYCLIC ANTIDEPRESSANTS", DRUGS TODAY, vol. 33, no. 2, March 1997 (1997-03-01), pages 95 - 102, XP002100053 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008516925A (ja) * 2004-10-15 2008-05-22 ナームローゼ・フエンノートチヤツプ・オルガノン 双極性障害および随伴症状の治療
US7956202B2 (en) 2005-04-07 2011-06-07 Gerardus Johannes Kemperman Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3A,12B-tetrahydro-1H-dibenz[2,3:6,7]-oxepino[4,5-C]pyrrole
JP2008534656A (ja) * 2005-04-07 2008-08-28 ナームローゼ・フエンノートチヤツプ・オルガノン アセナピン・マレイン酸塩の結晶形
KR101422843B1 (ko) * 2005-04-07 2014-07-24 머크 샤프 앤 도메 비.브이. 아세나핀 말레에이트의 결정형
EP2154134A1 (fr) 2005-04-07 2010-02-17 N.V. Organon Processus de préparation de trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
US7872147B2 (en) 2005-04-07 2011-01-18 N. V. Organon Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
US7741358B2 (en) 2005-04-14 2010-06-22 N.V. Organon Crystal form of asenapine maleate
US8227623B2 (en) 2006-07-05 2012-07-24 Msd Oss B.V. Process for the preparation of asenapine and intermediate products used in said process
US7750167B2 (en) 2006-07-05 2010-07-06 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
US7875729B2 (en) 2007-01-05 2011-01-25 Synthon Bv Process for making asenapine
WO2009135091A1 (fr) * 2008-04-30 2009-11-05 Medivation Technologies, Inc. Utilisation d’asénapine et composés associés pour le traitement de maladies ou de conditions neurales ou non
WO2012013766A1 (fr) 2010-07-29 2012-02-02 Laboratorios Lesvi, S.L. Nouveau procédé de synthèse de l'asénapine
US8653280B2 (en) 2010-07-29 2014-02-18 Laboratories Lesvi, S.L. Process for the preparation of asenapine
US11154510B2 (en) 2015-06-11 2021-10-26 Alrise Biosystems Gmbh Process for the preparation of drug loaded microparticles
US11931466B2 (en) 2015-06-11 2024-03-19 Ferring B.V. Process for the preparation of drug loaded microparticles
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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