FR2527077A1 - NEW MEDICINAL PRODUCT BASED ON AN ANTI-DEPRESSANT AND AN ERGOPEPTIDE ALKALOID - Google Patents

Abstract

The object of the invention is a medicament comprising an anti-depressant of the dibenzocycloheptadian type and codergocrine.

Description

The subject of the present invention is a new medicament containing a

  anti-depressant in combination with an ergopeptide alkaloid;

  Depression is one of the psy-

  the most common chiatrics encountered by the doctor, especially in elderly patients

  treatment of depression has generally been noted

  significantly improved by the development of anti-depres-

  Tricyclic sisters such as dibenzocycloheptadiene type antidepressants Unfortunately, the therapeutic effect of these antidepressants is often accompanied by side effects such as anticholinergic, cardiovascular and

  effects on the central nervous system These effects are

  condales are especially problematic in senescent patients, requiring the use of lower daily doses of antidepressants It is however common that these lower doses

  do not produce the desired therapeutic effect.

  The Applicant has now found

  surprising lesson that the co-administration of an anti

  di-benzocycloheptadienic depressant with coder-

  gocrine is particularly advantageous in the treatment of depression and makes it possible to reduce the dose of dibenzocycloheptadienic antidepressant and thus to reduce the appearance and the severity of unwanted side effects. This is particularly the case for the co-administration of a compound of IR 2 formula

R 1 "R 3)

CHCH 2 CH 2 N R 4

R 5

  in which R1, R 2 and R 3 each represent, independently of one another, hydrogen, chlorine or bromine, and R 4 and R 5 each represent, independently of one

  on the other, hydrogen, a C 1 -C 6 alkyl group.

  C 3 -C 8 benzyl or cycloalkyl, or a pharmaceutically acceptable acid addition salt thereof, with codergocrine in the form of the free base or in the form of a pharmaceutically acid addition salt

acceptable.

  According to one aspect, the invention therefore relates to a medicament comprising, as active principles a) a compound of formula I R 2 R 3 j R 3 (I)

R IC 2 CR $

CHCH CH 2 4

2 H 2 N R 5

  in which R 1, R 2 and R 3 each represent, independently

  pendant from one another, hydrogen, chlorine or bromine, and R 4 and R 5 each represent, independently of one another, hydrogen or a C 6 -C 6 alkyl group, benzyl or C 3 -C 8 cycloalkyl, or a pharmaceutically acceptable acid addition salt of such a compound, and b) codergocrin as free base or as

  form of a pharmaceutical acid addition salt-

acceptable.

  The compounds of formula I are known and can be prepared for example as described in the

U.S. Patent No. 3,922,305.

  A preferred anti-depressant of formula I is

  5- (3-methyl-aminopropylidene) -l O, 111-dihydro-5 H-

  dibenzola, dlcycloheptene known under the name

common nortriptyline.

  Codergocrine used in the compounds

  pharmaceutical tions of the invention is a mixture

  including dihydroergocryptine (2: 1, a :,), di-

  hydroergocornine and dihydroergocristine in the weight ratio of 1: 1: 1; it can be used in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt. A particularly preferred salt is the methanesulfonate known under the name "mesergate of codergocrine '" or "mesylate of ergololde" (USAN , United States Adopted Name). The active ingredients can be administered under

  form of pharmaceutical compositions These pharmaceutical compositions

  can be prepared in a known manner using

  the usual diluents and vehicles and operating according to the tech-

usual galenic nics.

  Appropriate forms for administration

  tion by oral route include for example the

  award-winning, dispersible powders, granules, capsules, syrups and elixirs; suitable forms for parenteral administration include, for example, solutions such as

  than sterile injectable solutions

  pharmaceuticals for route administration

  oral may contain one or more adjuvants

  tuels, such as sweeteners, flavorings, colors and preservatives, in order to provide an acceptable and palatable composition The tablets may contain the active substance in admixture with the usual pharmaceutically acceptable excipients, such as example of inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents such as starch and alginic acid, binders such as starch, gelatin and the

  gum arabic, and lubricants such as stearara-

  te of magnesium, stearic acid and talc The tablets can be uncoated or coated depending

  the usual techniques, in order to delay the des-

  integration and adsorption in the gastrointestinal tract

  intestinal and thus produce a delayed action over a long period Similarly, suspensions, syrups and elixirs may contain the principles

  active in combination with one of the excipients

  tuels used in the preparation of such composi-

  tions, for example suspending agents such as methylcellulose, gum tragacanth and sodium alginate, wetting agents such as lecithin, polyoxyethylene stearate and monooleate

  polyoxyethylenesorbitan, and preservatives

  tion such as methyl, ethyl or propyl p-hydroxybenzoate The capsules can contain the active ingredients alone or as a mixture in an inert solid diluent such as for example calcium carbonate, calcium phosphate and kaolin Injectable compositions are formulated according to known methods The pharmaceutical compositions can contain up to approximately 90% of the active principles in combination with the vehicle or the adjuvant The pharmaceutical preparations are preferably formulated in the form of unit doses,

  especially for oral administration.

  Such forms may contain the active substances separately, for example in separate layers in a co-hesou coated tablet, or

  in capsules with two compartments.

  The activity of the new combination has been demonstrated in the following clinical trials: In a study in hospitalized patients, 20 mg nortriptyline and 2 mg codergocrine mesylate were administered three times a day for 4 weeks to 5 patients aged 26 to 66 with depression and a score of 19 to 30 on the Hamilton depression scale (A

  Rating Scale for Depression, M Hamilton, Nerosurg.

  Psychiat 23, 56-62, 1960) The dose administered is

  lower than the minimum recommended therapeutic dose

  the idea for nortriptyline, which is 75 mg per day.

  All 5 patients reacted favorably and their condition improved significantly The score of each patient on the Hamilton depression scale fell below 8 and the onset of regression of the depressive state presented earlier than normal when the anti-depressant is administered alone Several patients noted a significant improvement at the end of the first week The frequency of side effects was very acceptable and their intensity ranged from very mild to low All 5 patients submitted in the study

  felt that they were receiving effective treatment

  cace of their depression These results were con-

  firmed in a multicenter study including 53

patients aged 18 to 55 years.

  The treatment is characterized by a rapid onset of activity, the constant improvement obtained often leading to complete remission and a low frequency of intense side effects.

  mild, compared to treatment using anti

  depressant alone The association according to the invention is

  therefore indicated for the treatment of depression.

  The association according to the invention is also

  indicated for use in treatment

  symptoms of senile dementia The association se-

  The invention is therefore particularly advantageous for the treatment of the elderly suffering from senile dementia associated with depression:

  An appropriate main weight ratio

  active ingredient a) to the active ingredient b) is between about 50: 1 and about 3: 1, preferably between 20: 1 and 5: 1, especially between 12: 1 and

8: 1.

  For the preferred co-administration of nor-

  codergocrine triptyline and mesylate, a report

  suitable is for example about 10: 1.

  The compounds of formula I alone are nor-

  improperly administered orally in doses

  taken between 30 and 300 mg per day The entry dose

  your after remission and for administration according to

  the invention is between 30 and 150 mg per day.

  In young and elderly patients, the dose may be lower, for example between 30 and 75 mg per day and represents the preferred dose range of

  the invention The dosage margin specially pre-

  is 50 to 60 mg per day When the compound of formula I is administered to patients with lower dosage margins in combination with 3 to 9 mg per day of codergocrine, for example as methanesulfonate, the response is essentially equivalent

  than that obtained with the higher doses of anti

  depressant Examples of daily doses are 30 to 150 mg of active ingredient a) combined with 3 to 9 mg of active ingredient b), especially 30 to 75

  mg, in particular 50 to 60 mg of nortriptyline

  bined with 3 to 9 mg of codergocrine mesylate A

  particular daily dose is 60 mg of nortrip-

  tyline combined with 6 mg codergocrine mesylate.

  Advantageously, the active ingredients are administered in a delayed-release form or in the form of fractionated doses four times a day containing for example 7.5 to 75 mg of active ingredient a) and, either additionally or in separate form, for example from 0.5 to 6 mg of active ingredient

  b) The unit doses are for example those contained

  10, 20, 25 or 75 mg of active ingredient a) and those containing, additionally or in a separate form, for example 0.5, 1.0, 1.5, 2 or 6 mg of active ingredient b) One dose particularly suitable unit contains 20 mg of nortriptyline and 2 mg of codergocrine mesylate, The invention also comprises a package containing separately a plurality of unit dose of each of the active ingredients a) and b) as well as

  instructions for their concomitant administration

  you. Pharmaceutical Composition Example Appropriate tablets and capsules for

  oral administration and having the composition

  tion indicated below, can be prepared according to usual methods These tablets and capsules can be used for the treatment for example of depression at a rate of 1 tablet

or one capsule three times a day.

  Constituents Tablet Capsule nortriptyline hydrochloride

(corresponding to 20 mg of nor-

  triptyline base) 22.7 mg 22.7 mg Codergocrine mesylate 2 mg 2 mg

Tragacanth 10 mg -

Lactose 172.8 mg 225.3 mg

Corn starch 25 mg -

Talc 15 mg -

Magnesium stearate 2.5 mg -

  250 mg 250 mg It is also possible, according to known methods, to prepare other tablets or capsules as well as, for example, suppositories, dispersible powders, syrups, elixirs, suspensions or solutions, using standard vehicles and diluents, view of enteral administration

or parenteral.

Claims (10)

  1. A medicament, characterized in that it contains, as active principles, a) a compound of formula I R 1 f R 3 () CHCH 2 CH 2 N "4 102 R 5   in which R 1, R 2 and R 3 each represent, independently of one another, hydrogen, chlorine or bromine and R 4 and R 5 each represent, independently of one another, l hydrogen, a C 1 -C 6 alkyl, benzyl or C 3 -C 8 cycloalkyl group,   or a pharmaceutically acceptable acid addition salt   table of such a compound, and b) codergocrine in free base form or under   form of a pharmaceutical acid addition salt- acceptable.   2. A medicament according to claim 1, characterized in that the active ingredient a) is nortriptyline in the form of the free base or in the form hydrochloride.   3. A medicament according to claim l or 2, characterized in that the active principle b) is codergocrine mesylate.   4. A drug according to any one of   claims 1 to 3, characterized in that the ratio   by weight of the active ingredient a) to the active ingredient b) is   between about 50: 1 and about 3: 1.   5. A medicament according to claim 4, characterized in that the weight ratio is about 10: 1.   6. A medicament according to any one   claims 1 to 5, for use as   anti-depressant and / or in the treatment of senile dementia.   7. A pharmaceutical composition, character-   terized in that it includes the active ingredients   specified in any one of claims 1 to   , in combination with vehicles or thinners   pharmaceutically acceptable.   8. A pharmaceutical composition according to the   claim 7, characterized in that it pre-   smells in the form of unit doses.   9. A composition according to claim 8, characterized in that it contains from 10 to 25 mg active ingredient a).   10. A pharmaceutical composition according to claim 7, characterized in that it is   present in the form of a package comprising separate   a plurality of unit doses of each of the active ingredients a) and b) specified in any one   of claims 1 to 4, as well as the instructions   for their concomitant administration.