NZ186402A - Pharmaceutical compositions containing 7-(10,11-dihydro-dibenzo(a,d)cyclohepten-5-ylamino)-heptanoic acid - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 86402 1 v ft. 7 Priority Dats{s): .7.* ^.'.17. * *"7 ,47 "iJL CcmpSeto Spsc-iftcats'on Filed: .......

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P.O. Jc-.;rnd, No: .&hQ • V:" Si?;5 S1 »9fti if*. P is ci y Hi LLL-L5-LLLL2 ' ..PATENT ACQ? 1955 COMPLETE^SPEGIPICATICII "HOVEL PHAPJll&CEtJTICAI< COMPOSITIONS AND METHODS PCJR USING- THE SAME" 9* V/e, SCIENCE UNION ET Cie, S00IET3 PHANCAISE BE HECHBRCHE a -Prer<Jr) $oci'efe c?r> no^ Coll«crf"i£/ MJ?J)IC£LEr/of 14, rue du Val d'Qr - SURESKES 92150 France, hereby declare the invention, for which we pray that; a patent may "be granted to us, and the method "by which it is to he performed to he particularly described in and "by the f cllo-wing statement:~ ~ 1 - This invention relates to pharmaceutical compositions having psychotropic properties., British Patent Specification No. 1269551 describes pharmaceutical preparations which, in unit dosage form, contain from 10 to 100 mg of, inter alia! 7-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylamino)-heptanoic acid or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier.

Such preparations possess psychostimulant, antidepressive, analgesic, antitussive, antihistaminic and gastric anti-secretory properties.

The present invention is based on the surprising observation that pharmaceutical compositions containing greater arnoiints of such active ingredients possess other valuable pharmacological properties.

The present invention therefore provides pharmaceutical compositions in unit dosage form comprising, as active ingredient# 7-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylamino) heptanoic acid or a physiologically tolerable salt thereof in an amount of more than 100 mg but not more than 400 mg, preferably not more than 300 mg, calculated as the free acid, in admixture or conjunction with a pharmaceutically suitable carrier.

The pharmaceutical compositions in accordance with the invention may be in a form suitable for parenteral, buccal, sublingual or rectal administration, for example in the form 186402 of tablets, coated tablets, capsules, soft gelatin, capsules or drinkable emulsions, suspensions or solutions for oral administration, suspensions or solutions packed in ampouls, phials or auto-injectible syringeslfor parenteral administration, or sublingual tablets or suppositories.

The carrier will depend on the particular route and method of administration, and may be, for" example talc, magnesium stearate, calcium carbonate, magnesium phosphate, lactose, sugar or silica.

More especially, solid compositions may be included a filler or a diluent, or a binder such as ethylcellulose, dihydroxypropylcellulose, carboxymethylcellulose, gum ara£>ic, tragacanth or gelatin. Solid compositions may also be flavoured, coloured or coated with a v/ax or a plasticizer.

For liquid drinkable or injectible compositions, water or saline solutions are the most convenient. For suppositories, cocoa butter or polyethylene glycol stearates are suitable carriers.

The particular form of the active ingredient will depend to some extent on the route of administration and the form of the composition. Thus, it may be convenient to use the acid form itself, or to use a more soluble form, such as an acid addition salt or a base addition salt. When a less soluble or insoluble active material is required, the compound may be ■'. \ o ' /* n ^ In the form of a non-toxic salt, withjan inorganic or organic base, for example a calcium, strontium, aluminium or ferrous salt or a salt of a non-toxic organic base, for example phenylethylamine, benzyl-amine, triethylamine, ethanolamine, morpholine, piperazine, N-methylpiperazine, N-hydroxyethylpiperazine, cyclopropyl methylamine, ethylene diamine, 3-dimethylamino-1-aminopropane, or 3-tert.butylamino-2-hydroxy-1-aminopropane.

As acid addition salts, there may be- mentioned salts with mineral acids, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid, and with organic acids, for example acetic acid, valeric acid, caproic acid, benzoic acid, 3,5-dichlorobenzoic acid, f3-naphthoic acid, pyrrolidone-carboxylic acid, 2-methyl-thi>&zole-5-carboxylic, nicotinic acid, isonicotinic acid, benzene-sulphonic acid and glucose 1-phosphoric acid. 7-(1O,11-dihydro-dibenzo[a,d]cyclohepten-5-ylamino)-heptanoic acid and salts thereof, and a process for their preparation are described in British Patent Specification No. 1269551. • As stated above, the pharmaceutical compositions of the present invention have psychotropic properties, especially, an advantageous effect on the oxidative metabolism of the brain which allows them to be used in the treatment of patients suffering from disturbances of brain performances of vascular, metabolic or traumatic origin.

More especially, the active ingredient 7-(1O,11-dihydro- dibenzo[a,d]cyclohepten-5-ylamino)-heptanoic acid - hereinafter referred to as Amineptine - is endowed with very specific properties which enable it and its salts to be classified as psychoanaleptics. Its pharmacological properties are intermediate those of nooanaleptic agents and those of thymo-analeptic agents, and it exhibits some of the properties of both. For example, like the nooanaleptics, Amineptine produces a central alerting effect in all laboratory animals, which results in an increase in exploratory motor behaviour, an acceleration of conditioned learning, and an EEG alerting effect.

/ However, unlike the classical nooanaleptics, it does not i induce sleep or influence temperature regulation or food intake, it v does not cause any group toxicity, and it has little peripheral activity on the blood pressure.

Similarly, like the thymoanaleptics, it antagonises in animals depression induced experimentally by reserpine, it antagonises the cataleptic effects of neuroleptics (chlorprornazine, prochlorperazine), and it stimulates the catecholaminergic system.

However, in contrast to the standard tricyclic antidepressants, it has no sedative effect at high doses and it has no central or peripheral anticholinergic effect.

H <H; /* ~ ^ i GL-' 'v ' - / ~, In addition, Amineptine differs from the stimulants and the thymoanaleptics by its effects upon sleep, in that it relieves abnormalities of sleep (de Villard-Mouret-Jouvet) by inducing sleep in cases of initial insomnia due to overactivity of the catecholaminergis system, being effective in somnambulism, and producing an increase of REM sleep.

A study of the mode of action of Amineptine at the level of the metabolism of the central neuro-transmitters shows that Amineptine increases the release of dopamine and inhibits, its uptake. A lesser effect is seen in the release of serotonin and the effects upon noradrenaline are unimportant.

Thus Amineptine differs from the tricyclic antidepressants, which inhibit the uptake both of dopamine and of serotonin, from nomifensine, which is a recent drug for the treatment of depression and which markedly inhibits the uptake of dopamine and of noradrenaline, and from amphetamine, which has an effect upon the release and uptake of noradrenaline, dopamine and serotonin.

The effect of Amineptine upon the dopaminergic system may account for both its thymoahaleptic and its stimulant properties and also explain its action in REM sleep.

During clinical trials it has been found the pharmaceutical compositions of the present invention are useful in neuro-surgery and reanimation for increasing or improving I the awareness in the post-traumatic and post-surgery comatose states, in neurology in the treatment of psychic disturbances after vasculo-cerebral illness, in reeducation of neurological sets after hemiplegia or paraplegia, and in neuropsychiatry in the severe psychiatric diseases such as bradykynesia, bradypsychia, schizophrenia, nevrotic states, psychiasthenia and depressive states. They are also useful for treating motor infirmities from brain origin, mental debility and psycho-motor delays in children.

Moreover in general practice, the pharmaceutical compositions of the present invention have been found very useful as nooanaleptics, thymoanaleptics and for balancing the psychism.

The posology of the compositions will vary depending on the age of the patient, the severity of the illness to be treated and the route of administration. In man, the daily oral dosage may be up to 400 mg and preferably up to 200 mg of active ingredient. For reanimation and in neurosurgery, the daily parenteral dosage may be up to 300 mg of active ingredient. In children, the daily dosage may be up to 200 mg of active ingredient. The unit dosages may preferably be aldministered from one to three times a day. In anesthesiology and in neurosurgery, injectible solutions may be administered from 2 to 12 times a day for from 2 to 4 days.

The following tests and Examples illustrate the invention.

TOXICITY TESTS 7-(1O,11-dihydro-dibenzo[a,d]cyclohepten-5-ylamino)-heptanoic acid and the salts thereof were tested on several species to determine the average lethal dose by oral, parenteral and intraperitoneal administration.

The animals received increasing doses of each compound in aqueous solution and were kept under survey for 10 days. The deaths, if any, were recorded. The average lethal dose and the statistical deviation were determined by calculation according to the method described by Litchfield and Wilcoxon.

The following results have been obtained: administration species Sodium 7-(1O,11-dihydro-dibenzo [a ,d]cyclo-hepten-5-ylamino)-heptanoate intravenous intraperitoneal mxce rats mice rats 161-203 118-125 279-324 220-239 mxce rats guinea pigs 833-1276 716-765 1103-1412 7-(10,11-dihydro -dibenzo[a,d]cyclo- oral hepten-5-ylamino)-heptanoic acid, hydrochloride PHARMACOLOGICAL TESTS (a), The protective effect of pharmaceutical compositions containing Amineptine against psycho-depressive effects and the decrease of vigilance resulting from the use of some therapeutic agents, was studied.

The nooanaleptic properties of pharmaceutical compositions containing 7-(10,11-dihydro-dibenzo[a,d]cyclo-hepten-5-ylamino)-heptanoic acid and salts thereof were illustrated by treating patients who concomitantly received either an anxiolytic agent such as Lorazepari (sold under the trade name 'Temesta'), and an appetite-increasing agent such as Cyproheptadine hydrochloride (sold under the trade name 'Periactin*), an anti-migrainous agent such as Dimetotiazin (sold under the trade name 'Migristene') or an anti-allergy agent such as Dexchlorpheniramine maleate (sold under the ■ trade name 'Polaramine').

The efficiency of 7-(lO,11-dihydro~dibenzo[a,d]cyclo-hepten-5-ylamino)-heptanoic acid and salts thereof was te/sted in double-blind studies. Some patient3 received pharmaceutical compositions according to the present invention in the form of tablets. The others received only a placebo together v/ith one of the above drugs. • In total, 58 patients were treated for a week; 14 received 7.5 mg Lorazepam, 16 received 12 mg cyproheptadine hydrochloride, 16 received 60 mg Dimetotiazine and 12 received 12 mg Dexchlorpheniramine maleate, per day.

To 28 of the 58 patients there were administered 2Q0 mg > of 7-(10,ll-dihydro-dibenzo/a/d/cyclohepten-S-ylamino)-heptanoic acid. The other patients received the placebo twice a day. 19 AUG I960 | XGMED 4 i* ;rt /?• v..'- The treatment was continued for one week. The patients were tested on a clinical and psychometric basis before and after treatment and divided into 4 groups, according to the Eysenck (personality) test. The criteria of psychometric improvement were based on 5 tests: Test 1 accuracy and quickness of the understanding; test 2 attentiveness and memory (adapted Wechsler's test); test 3 ability of spatial gathering and memory (test of calculation); test 4 resistance to irrelevant information (Stroop's test); test 5 immediate memory.

The results were as follows: - in test 1 The patient who received only the placebo, took significantly longer to perform the test than the patients treated with the compositions according to the invention (statistical significance p<"O.Ol)„ The patients receiving concomitantly either cypro-heptadiene hydrochloride or Dexchlorpheniramine hydrochloride, as well as the permanently introvearted subjects, were the most improved.

The pharmaceutical compositions containing 100 mg Amineptine per unit dosage produce a corrective effect which is not found in the patients who receive only the placebo (statistical significance p^O.Ol).

The same improvement also appears for the patients receiving simultaneously Lorazepam or Dexchlorpheniramine maleate and Amineptine, as well as for the whole group of introverted patients. - in test 2 There are significant differences among the group. The patients receiving simultaneously Dexchlorpheniramine, cyproheptadine or Lorazepam and Amineptine, as well as the whole group of introverted patients are significantly improved. - in test 3 There are no significant differences between the various groups. However, for the patients who receive simultaneously another therapeutic agent, the average number of operations is higher in the group of patients receiving 7-(lO,11-dihydro-dibenzo[a,d]cyclohepten-5-ylamino)-heptanoic acid than in the group of patients receiving only the placebo. - in test 4 The optimum result is obtained for the patients who received simultaneously cyproheptadine and the pharmaceutical compositions containing Amineptine and for the permanently introverted patients and the neurotic extroverted patients. i vv*cy As regards the number of mistakes, all patients receiving Lorazepam, cyproheptadine and Dexchlorpheniramine were greatly improved when Amineptine was simultaneously administered. The patients receiving Dimetotiazine were less improved.

In contrast to previous tests, the extroverted patients were those who were the most improved by simultaneous treatment. in test 5 The improvement was greater for the patients who received simultaneously cyproheptadine or Lorazepam and the pharmaceutical compositions according to the present invention than for the neurotic introverted patients and for the stable extroverted patients.

The pharmaceutical compositions containing 7—(10,11— dihydro-dibenzo[a,d]cyclohepten-5-ylamino)-heptanoic acid or a salt thereof therefore exert a protective effect against the depressive side-effect of some drugs which depress vigilance.

The speed of performance and the accuracy of answering in calculation tests and of resistance to irrelevant information are greatly improved compared with the results obtained in patients who received the placebo.

The most favoui*able effect was for patients receiving simultaneously Dexchlorpheniramine or cyproheptadine and for V the patients having introverted characteristics, receiving the pharmaceutical compositions containing Amineptine. (b) Treatment of physical or intellectual Asthenia.

The effectiveness of Amineptine alone or associated with medicinal synergist, the optimum dosage, the clinic acceptability, and the mean and long term effectiveness were evaluated, while codifying the preferential indications.

The tests were carried out on 100 patients (61 men, 39 women) aged from 16 to 75 years. 97 were out-patients and only 3 in-patients. 9 patients were being treated with thymoaneptics and anxiolytics, 15 with anxiolytics only and 9 with sedatives and barbituates. Amineptine was administered to 49 patients at doses of 100 and 150 mg/day, to 34 patients at 200 mg/day, to 11 patients at 300 to 400 mg/day and to 6 patients at varying doses during the course of treatment. 16 patients were treated for 2 to 3 weeks, 36 for 4 to 6 weeks, 33 for 7 weeks to 2 months, and 15 for 3 to 19 months.

As a systematic precaution and in spite of the absence of formal contra-indications, patients with cardiopathies or renal or severe hepatic failure or with evolutive neurologic disease were eliminated.

The different disorders treated with Amineptine covered a group of states where the notion of intellectual or physical asthenia was predominant and also the thymic restoration of the depressive states where it was known that the control of £ f-~> \\ I I Lf w v ^ the central nucleus characterized by pessimism, moral sorrow and self-accusation was not always sufficient to allow social revival of a still asthenic patient who was anxious and feared any incitement to action. For this reason it was interesting to use a composition containing Amineptine to test beyond the notion of the underlying psycho-pathological structure. The indications included neurotic, reactive, endogenous, or psychotic depressions.

The strategy varied according to the clinical variety. Amineptine was administered sometimes immediately associated with thymoanaleptics and anxiolytics if dystonic or asthenic features prevailed, or in a second time (endogenous or psychotic depressions) while decreasing deliberately the amounts of antidepressants or neuroleptics.

The different indications investigated was as follows, although practical distinction was not always easy: - psychogenous asthenia = 22 patients - neurosis = 39 patients . psychasthenic and, more typically, obsessional psychasthenia = 23 patients . anxio-phobic asthenia = 16 patients - depressive states =16 patients . neurotic : 5 . reactive : 4 . endogenous : 3 . atypical : 2 . involution : 1 . manic-depressive psychasthenia : 1 - various indications = 23 cases The results -were evaluated as follows: - very good or excellent result : course clearly favourable with marked modification of behaviour? - good result : favourable evolution with real benefit on the level of symptoms: - fairly good result s incomplete action or only on some symptoms: - failure : no discernible modification; - failure by intolerance or aggravation of symptoms: worsening of the patient's status depending on a medicinal intolerance or the discrimination of the previous nooleptic, even of a thymoanaleptic (feeling of lack, previous symptoms' aggravation with appearance of intolerance symptoms)„ From the total group of one hundred patients, there v/ere obtained: - 30 excellent results - 28 good results - 15 fairly good results - 21 failures 1 is : 7 c V. - 6 failures by intolerance or aggravation.

Amineptine therefore gave 73 % positive results with 30 % excellent results.

Most of the patients reported physical and psychic asthenia reduction, better vigilance, greater lucidity concerning their problems with disappearance of irresolution, and an increase of their interest in the outside world. The overwhelming feeling of weariness, and of "vacuum" still more or less tied to taedium vitae, grows blurred and particularly the factors which condition morning polarity of distress cimong psychasthenic patients.

After the treatment was stopped, the benefits frequently continued. This remaining effect allows discontinuous cures or the ability to cease any therapeutic contribution for a determined period. (c) comparative test with maprotiline in the treatment of depressive conditions.

The tests were carried out on 70 patients (31 men, 39 women) aged from 19 to 79 with a mean age of 47.0 - 1.7 years. All were out-patients. 46 patients suffered from exogenous depression (35 neurotic, 11 reactive) and 24 from psychotic, involutional or endogenous depression (16 endogenous (4 PMD), 2 psychotic, 6 involutional).

Amineptine and maprotiline were administered in a controlled trial involving cross-over administration to the same patient of the two products alternately, with a sequence of 6 weeks duration. Amineptine was administered in an amount of 150 mg/day in three doses, and maprotiline in an amount of 75 mg/day in three doses. The two products were systematically associated with an anxiolytic and a sedative but with no other antidepressant.

Comparison between Amineptine and maprotiline was possible in 69 cases, since one patient was dropped from the test after the first treatment,, The results were as follows? t-CT Depression : neurotic reactive n = 46 Amineptine = maprotiline in 4 cases Amineptine < maprotiline in 9 cases Amineptine > maprotiline in 33 cases difference between the two products : S : p <0.0001 Depression : endogenous psychotic involutional n = 24 Amineptine = maprotiline in 5 cases Amineptine maprotiline in 5 cases Amineptine > maprotiline in 13 cases < (impossible comparison in 1 case) difference between the two products : not significant Total n = 70 (possible comparison n = 69) Amineptine = maprotiline in 9 cases Amineptine maprotiline in 14 cases Amineptine ^ maprotiline in 46 cases difference between the two products: S : p <0.0001 The superiority of Amineptine over maprotiline v/as very clearly shown in the treatment of neurotic and reactive depressions. In the treatment of endogenous depressions, Amineptine had a good action which may be explained by its double action of *5 r 2 (a) stimulation of arousal, vigilance; and (b) control of basal dysphoria which is a classical anti-depressant, apart from its mood stimulating action, does not have. The sedative effect of the classical anti-depressant certainly reduces anxiety but also limits the recovery of psychomotor function.

Under these conditions, Amineptine had an action at least identical to that of maprotiline but this action was usually much more rapid (between 3 and 5 days) and more acceptable for the same result on the mood. (d) comparative test with Amitryptiline.

The thymoanaleptic properties of Amineptine were tested in a double-blind study carried out on 51 patients and compared with Amitryptiline, a known anti-depressant. Of these patients, 26 received Amineptine in the form of tablets at a dose of 200 mg a day for 6 weeks and the remaining 25 patients received Amitryptiline at a daily oral dosage of 75 mg for 6 weeks.

These patients suffered with non-psychotic depressive states, namely neurotic or reactional depressive states; mono-polar endogenous depression states and depression states in delirious or non-delirious psychotic patients.

In some cases an anxiolytic agent or an hypnotic agent was administered at the same time.

The results were evaluated first from a broad clinical point of view and then more objectively through Hamilton's // Depression scale.

At the end of the test, the compositions containing Amineptine yielded 23 % excellent results, 31 % very good results, and 27 % good results. There were no results in 15 % of the case, and 4 % of the trials were stopped for patients suffering from side-effects.

A favourable result was therefore achieved in 81 % of the patients and very good results in 54 % of the patients.

The patients treated with Amitryptiline showed 56 % favourable results, and a very good or good result in 40 % of the cases. No result have been obtained in 24 % of the patients.

As regard to the diagnostic, it appeared that the compositions containing Amineptine were active in the neurotic or reactional depressive states as well in the melancholic states. Moreover they had some favourable effects on patients who had not previously been improved by other anti-depressant drugs.

The Hamilton's Depression scale showed a very statistically-significant improvement of the mean total score from the first trial and a persistance of the improvement after 30 and 45 days of treatment. The efficacy is increased in a statistically significant manner between 15 and 30 days of treatment and between 30 and 45 days of treatment.

The compositions containing Amineptine had a favourable effect on the depressive state and acted quickly and progressively and in an increasing manner for the 6 weeks of treatment* EXAMPLE I Tablets containing 150 mg of 7-(10#11-dihydro-dibenzo [a, d]cyclohepten-5-ylamino) -heptanoic acid per unit dosage® 7-(10,11-dihydro-dibenzo[a,d]cyclohepten- -ylaraino)-heptanoic acid, hydrochloride 33.250 kg Maize starch 8.900 kg Gelatin 006 kg Lactose 10 kg Magnesium stearate 0.6 kg Talc 1*8 kg Yellow lake 0.010 kg for 200,OOO tablets having an average weight of 0.260 ge EXAMPLE II Injectable solution containing 250 mg of sodium 7-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylamino)-heptanoate per unit dosage.

Sodium 7-(10,11-dihydro-dibenzo[a,d]cyclo~ hepten-5-ylamino)-heptanoate 2.66 kg Glycine 0.750 kg Malic Acid 0.03 kg Distilled water, qs for 30 litres This solution is divided into 10,000 ampuls which are lyophilized. /r ^ \ EXAMPLE III Tablets containing 200 mg of 7-(10,11-dihydro-dibenzo [a,d]cyclohepten-5-ylamino)-heptanoic acid per unit dosageo 7-(10/11-dihydro-dibenzo[a,dJcyclohepten- -ylamino)-heptanoic acid 20 kg Kaolin 8.2 kg Magnesium silicate 3.5 kg Magnesium phosphate 2.5 kg Silica 0.2 kg Methyl cellulose 0.05 kg Magnesium stearate 0.5 kg for 10„000 tablets having an average weight of 0.350 g„ IU4-0Z-

Claims (8)

WHAT WE CLAIM IS:

1. A pharmaceutical composition having both nooanaleptic and thymoanaleptic properties'in unit dosage form compris- V ing as active ingredient 7-(1O,11-dihydro-dibenzo[a,dJcyclo-hepten-5-ylamino )-heptanoic acid or a physiologically tolerable salt thereof in an amount of more than 100 mg but not more than 400 mg, calculated on the free acid, in admixture or conjunction with a pharmaceutically suitable carrier. •

2. A pharmaceutical composition according to claim 1 , wherein the active ingredient is 7-(10,11-dihydro-dibenzo [a,d]cyclohepten-5-ylamino)-heptanoic acid.

3. A pharmaceutical composition according to claim 1, wherein the active ingredient is a salt of .7-(10,11-diliyc^ro-dibenzo[a,d]cyclohepten-5-ylamino)-heptanoic acid with a physiologically tolerable inorganic or organic base.

4. A pharmaceutical composition according to claim 1 , wherein the active ingredient is sodium 7-(10,11-dihydro-dibenzo [a ,d]cyclohepten-5-ylamino)- heptanoate.

5. A pharmaceutical composition according to.claim 1, wherein the active ingredient is a salt of 7-(10,11-dihydro-dibenzo[a ,d]cyclohepten-5-ylamino)-heptanoic acid with a physiologically tolerable mineral or organic acid.

6. A pharmaceutical composition according to claim 1 , wherein.the active ingredient is the hydrochloric acid addition salt of 7-(10,11-dihydro-dibenzo [a, d]cyclohepten-5-ylamino)- heptanoic acid*

7. A pharmaceutical composition according to claim 1, which contains the active ingredient in an amount of more than 100 rag but not more than 300 mg, calculated as the free acid«,

8. A pharmaceutical composition according to claim 1, substantially as described in any one of the Examples herein„ DATED THIS"*'" DAYOFft^"-* A. J. PARM; SON PER „ AGENTS FOR THE APPLICANTS r. y r •r&xv - 24 -