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Sommaire du brevet 1197465 

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Disponibilité de l'Abrégé et des Revendications

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  • lorsque la demande peut être examinée par le public;
  • lorsque le brevet est émis (délivrance).
(12) Brevet: (11) CA 1197465
(21) Numéro de la demande: 424059
(54) Titre français: COMPOSES PHARMACEUTIQUES CONTENANT UN DIBENZOCYCLOHEPTADIENE ANTIDEPRESSEUR ET UN ALCALOIDE DE L'ERGOT
(54) Titre anglais: PHARMACEUTICAL COMPOSITION CONTAINING A DIBENZOCYCLOHEPTADIENE ANTI-DEPRESSANT AND AN ERGOT ALKALOID
Statut: Périmé
Données bibliographiques
(52) Classification canadienne des brevets (CCB):
  • 167/223
(51) Classification internationale des brevets (CIB):
  • A61K 31/495 (2006.01)
  • A61K 31/025 (2006.01)
  • A61K 31/06 (2006.01)
  • A61K 31/13 (2006.01)
  • A61K 31/135 (2006.01)
  • A61K 31/435 (2006.01)
  • A61K 31/48 (2006.01)
  • C07D 519/02 (2006.01)
(72) Inventeurs :
  • GRIFFITH, ROBERT W. (Etats-Unis d'Amérique)
  • SINGER, JACK (Etats-Unis d'Amérique)
(73) Titulaires :
  • SANDOZ LTD. (Suisse)
(71) Demandeurs :
(74) Agent: KIRBY EADES GALE BAKER
(74) Co-agent:
(45) Délivré: 1985-12-03
(22) Date de dépôt: 1983-03-21
Licence disponible: Oui
(25) Langue des documents déposés: Anglais

Traité de coopération en matière de brevets (PCT): Non

(30) Données de priorité de la demande:
Numéro de la demande Pays / territoire Date
360,463 Etats-Unis d'Amérique 1982-03-22

Abrégés

Abrégé anglais




Pharmaceutical composition containing a dibenzocycloheptadiene
anti-depressant and an ergot alkaloid
Abstract
Concomitant administration of a dibenzocycloheptadiene-type
anti-depressant such as nortriptyline and codergocrine for example
in the form of codergocrine mesylate (BAN). Concomitant administra-
tion enhances the anti-depressant effect e.g. of the nortriptyline
and is effective in treating depression especially in association
with senile dementia.

Revendications

Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.


-8-
Claims:
1. A pharmaceutical preparation comprising as active
agents
(a) a compound of formula I


Image
I
wherein R1, R2 and R3 represent independently hydrogen,
chloro or bromo, and
R4 and R5 represent independently hydrogen,
C1-6alkyl, benzyl or C3-8cycloalkyl,
or a pharmaceutically acceptable acid addition salt
thereof, and
b) codergocrine in free base or pharmaceutically
acceptable acid addition salt form.

2. A preparation according to Claim 1, wherein active
agent a) is nortriptyline or the hydrochloride thereof.

3. A preparation according to Claim 1, wherein active
agent b) is codergocrine mesylate.

4. A preparation according to Claim 1, 2 or 3, wherein
the ratio of active agent a) to active agent b) is from
about 50 : 1 to about 3 : 1 parts by weight.

5. A preparation according to Claim 1, 2 or 3, wherein
the ratio of active agent a) to active agent b) is about
10 : 1 parts by weight.

6. A preparation according to Claim 1 in unit dosage form.


- 9 -

7. A preparation according to Claim 6 containing 10
to 25 mg of active agent a).

8. A process for the production of a pharmaceutical
preparation according to Claim 1 which comprises
formulating active agent a) with active agent b) as
defined in Claim 1.

9. A pack comprising separately a plurality of dosage
units of each of active agents a) and b) as defined in
Claim 1, 2 or 3, together with instructions for their
concomitant administration.

Description

Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.



Case 600-6936

Pharmaceutica1 compositions containing a dibenzocycloheptadiene
anti-depressant and an ergot alkaloid

The present invention relates t~ pharmaceutical preparations
active as anti-depressants as well as to methods of treating
depression.
Depression is one of the most common psychiatric disturbances
5 seen by the physician, especially in the elderly patient. The
treatment of depression has generally been improved dramatically
by the development of tricyclic anti-depressive agents such as
the di-benzocycloheptadiene-type anti-depressants. Unfortunately,
the therapeutic effect of such agents is often accompanied by
10 troublesome side effects such as anticholinergic, cardiovascular
and central nervous system (CNS) reactions. In the geriatric patient,
these side effects are especially problematical, necessitating
the use of lower daily doses of the anti-depressant. At lower
doses, however, the effect of the drug is often less than that
15 desired.
In accordance with the present invention it has now surprisingly
been found that co-administration of a di-benzocycloheptadiene anti-
depressant with codergocrine is particularly advantageous in the
treatment of depression, allowing dosages of the di-benzocyclohep-
20 tadiene to be lowered thus reducing occurrence and severity ofundesired side-effects.
This is particularly so on co-administration of a compound of
formula I
Rl2




Rl ~ R3

CH2CH2N~



.' ~

7~

- 2 - 600-69
wherein Rl, R2 and R3 represent independently hydrogen,
chloro or bromo, and
R4 and R5 represent independently hydrogen, Cl 6alkyl,
benzyl or C3 8cycloalkyl or
5 a pharmaceutically acceptable acid addition salt thereof
with codergocrine in free base or pharmaceutically acceptable
acid addition salt form.

Accordingly in one aspect of the invention there is provided
a pharmaceutical preparation comprising as active agen~
a) a compound of formula I
R2




Rl ~ R~3

2 2 ~
R5
wherein Rl, R2 and R3 represent independently hydrogen, chloro
or bromo, and
R4 and R5 represent independently hydrogen, Cl 6-
alkyl, benzyl or C3 8cycloalkyl,
15 or a pharmacetically acceptable acid addition salt thereof,
and
b) codergocrine in free base or pharmaceutically acceptable acid
addition salt form

i5

~ 3 ~ 600-6936
The compounds of formula I are known and can be prepared e.g.
as described in USP 3,922,305.
A preferred anti-depressant agent of ~ormula I is 5-(3 methyl-
aminopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene referred
5 to herein as nortriptyline.
Codergocrine as used herein stands for a mixture comprising
dihydroergocryptine (2:1, a:~), dihydroergocornine and
dihydroergocristine in the ratio of 1 : 1 : 1 by weight
and may be employed in free base form or in pharmaceutically
10 acceptable acid addition salt form. A particularly preferred form
is the mesylate known as "codergocrine mesylate" (BAN) or
"ergoloid mesylates" (USAN).
The preparation according to the invention may be prepared in
conventional manner using conventional diluents, carriers and
15 conventional galenical techniques.
Forms suitable for oral administration are for example tablets,
dispersible powders, granules, capsules, syrups and elixirs or for
parental administration e.g. solutions such as sterile injectible
solutions. Compositions for oral use may contain one or more
2D conventional adjuvants, such as sweetening agents, flavoring agents,
coloring agents and preserving agents, in order to provide an
elegant and palatable preparation. Tablets may contain the active
ingredients in admixture with conventional pharmaceutically
acceptable excipients, e.g., inert diluents, such as calcium
25 carbonate, sodium carbonate, lactose, and talc, granulating and
disintegrating agents, e.g., starch and alginic acid, binding agents,
e.g., starch gelatin and acacia, and lubricating agents, e.g.,
magnesium stearate, stearic acid and talc. The tablets may be
uncoated or coated by known techniques to delay disintegration and
30 adsorption in the gastrointestinal tract and thereby provide a



;t

~79~6~

- 4 - 600-6936
sustained action over a longer period. Similarly, suspensions,
syrups and elixirs may con~ain the ac~ive ingredients in admixture
with any of the conventional excipients utilized in the preparation
of such compositions, e.g., suspending agents such as methyl-
5 cellulose, tragacanth and sodium alginate; wetting agents such aslecithin, polyoxyethylene s~earate and polyoxyethylene sorbitan
monooleate; and preservatives such as ethyl p-hydroxybenzoate.
Capsules may contain the active ingrledients alone or admixed with
an inert solid diluent, e.g., calcium carbonate, calcium phosphate
lO and kaolin. The injectable compositions are formulated as known
in the art. These pharmaceutical preparations may contain up to
about 90% of the active ingredients in combination with the carrier
or adjuvant. Preferably the preparations are put up in unit dosage
form particularly in unit dosage form for oral administration. Such
15 forms may contain the active ingredients separately, e.g. in
separate layers in a layer or mantle tablet or in split capsules~
A further aspect of the invention concerns a process for the
production of a pharmaceutical preparation as stated above which
comprises formulating active agent a) with active agent b) as stated
above and optionally putting up the preparation in unit dosage form.
In an in-patient study, five patients ranging in age from 26
to 66 years suffering from depression and having a score of l9 to
30 on the Hamilton Depression Scale (A Rating Scale for Depression,
M. Hamilton, Nerosurg. Psychiat. 239 56-62, 1960) were given
25 20 milligrams of nortriptyline and 2 milligrams of codergocrine
mesylate three times a day for 4 weeks. [This dosage is below the
recommended minimum therapeutic dose for nortriplyline of 75 mg/day.]
All five patients had a good response and improved significantly on
the combination. The Hamilton Depression Scale score for each patient
30 dropped below 8 and the onset oF relief from the depression came



- 5 - 600-6936
much earlier than is normal with the antidepressant alone. Several
patients noticed a significant improvement at the end of the first
week. The incidence of side effects was very accepta~le and their
seYerity was mtnimal to mild. All five patients in the study felt they
were getting effective treatment for their depress;on. These results
were confirmed in a multi-centre trial involving 53 patients whose
ages range from 18 to 55 years.
Treatment is characterised by a rapid onset of action, steady
continued improvement often leading to complete remission and low
10 incidence and intensity of side effects compared with treatment using
anti-depressant alone.
The combined administration according to the invention is thus
indicated for the treatment of depression.
The combined administration according to the invention is also
15 indicated for use in the treatment of the symptoms of senile dementia.
The combined administration according to the invention is thus
particularly advantageous for the treatment of elderly people
suffering from senile dementia associated with depression.
The co-administration of active agents a) and b) is accordingly
20 indicated in the treatment of depression and senile dementia parti-
cularly when associated with each other.
Accordingly the invention further provides a method of treating
depression and senile dementia with depression in a subject in need
of such treatment, which method comprises concomitantly administering
25 to said subject an effective amount of an active agent a) and an
active agent b) as stated above.
An indicated weight ratio of active agent a) to active agent b)
is from about 50 : 1 to about 3 : 1, preferably 20 : 1 to 5 : I,
especially 12 : 1 to 8 : 1.

7~L~ii5

- 6 - 600-6936
For the preferred co-administration of nortriptyline and
codergocrine mesylate a suitable ratio is e.g. ca. 10 : 1.
Compounds of formula I alone are normally administered orally in
dosages ranging from 30 to 300 milligrams per day. The Maintainance
5 dosage range after remission and for administration according to the
invention is from 30 to 150 milligrams per day. In the adolescent
and elderly patient~ the dosage range may be much lower e.g. between
30 and 75 milligrams per day, the preferred range of the invention.
The especially preferred range is 50 to 60 milligrams per day. When
10 the compound of formula I is administered to the patient at the
lower ranges in combination with 3 to 9 milligrams per day of
codergocrine e.g. as codergocrine mesylate, the response is
essentially equivalent to that obtained with the higher doses of
anti-depressant. Examples of combined daily dosages are 3~ to 150 mg
15 of active agent a) with 3 to 9 mg of active agent b); espe~ially 30
to 75 mg, particularly 50 to 60 mg of nortriptyline with 3 to 9 mg of
codergocrine mesylate. A particular combined daily dosage is 60 mg of
nortriptyline ~ith 6 mg of codergocrine mesylate.
Conveniently the active agents are administered in sustained
20 release form or alternatively in divided doses 2 to 4 times a day
containing e.g. 7.5 to 75 mg of active agent a) and either addition-
ally or as a separate dosage form e.g. 0.5 to 6 mg of actiYe agent b).
Examples are dosage forms containing 10, 20, 25 or 75 mg of
active agent a) and those containing additionally or as a separate
25 dosage form e.g. 0.5, 1.0, 1.5, 2 or 6 mg of active agent b). A parti-
cular dosage form contains 20 mg of nortriptyline and 2 mg of
codergocrine mesylate.
The invention also provides a pack comprising separately a
plurality of dosage units of each of active agents a) and b) together
30 with instructions for their concomitant administration.
The following Example is illustrative of compositions for use in
the invention.



- 7 ~ 600-6936
EXAMPLE
Tablets and Caesules Suitable for Oral Administration
Tablets and capsules containing the ingredients indicated below
may be prepared by conventional techniques and are useful in treat-
ing e.g. depression at a dose of one tablet or capsule three times
a day.
Weight (mg.)
Ingredient TaBle
Nortriptyline HCL (-20 mg Base) 22.7 22.7
Ergoloid mesylate 2 2
10 Tragacanth lo
Lactose 172.8 225.3
Corn Starch 25
Talcum 15
Magnesium Stearate 2.5
250 ~ 250
Other capsules and tablets as well as e.g. suppositories,
dispersible powders, syrups, elixirs, suspensions or solutions
may also be made using conventional carriers and diluents for the
desired formulation and may be administered enterally or parenterally
20 as apporpriate to a patient.




.~,.j
. . ~ ..

Dessin représentatif

Désolé, le dessin représentatatif concernant le document de brevet no 1197465 est introuvable.

États administratifs

Pour une meilleure compréhension de l'état de la demande ou brevet qui figure sur cette page, la rubrique Mise en garde , et les descriptions de Brevet , États administratifs , Taxes périodiques et Historique des paiements devraient être consultées.

États administratifs

Titre Date
Date de délivrance prévu 1985-12-03
(22) Dépôt 1983-03-21
(45) Délivré 1985-12-03
Correction de l'état expiré 2002-12-04
Expiré 2003-03-21

Historique d'abandonnement

Il n'y a pas d'historique d'abandonnement

Historique des paiements

Type de taxes Anniversaire Échéance Montant payé Date payée
Le dépôt d'une demande de brevet 0,00 $ 1983-03-21
Titulaires au dossier

Les titulaires actuels et antérieures au dossier sont affichés en ordre alphabétique.

Titulaires actuels au dossier
SANDOZ LTD.
Titulaires antérieures au dossier
S.O.
Les propriétaires antérieurs qui ne figurent pas dans la liste des « Propriétaires au dossier » apparaîtront dans d'autres documents au dossier.
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Description du
Document 
Date
(yyyy-mm-dd) 
Nombre de pages   Taille de l'image (Ko) 
Dessins 1993-07-15 1 8
Revendications 1993-07-15 2 38
Abrégé 1993-07-15 1 13
Page couverture 1993-07-15 1 18
Description 1993-07-15 7 240