NZ190028A - Pharmaceutical compositions containing a dibenzothiazepine - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 90028 19002 8 Priority Dstr.(s): . ..

Cnrv*.p?Gta Spsc^icstscn Filed: "?f Ai3$ PubKoetl-c;'} Data . t""r 5 ^ » r -r-T " p 1 r . 31'may;I9»| fS52 ...... >7«* jFifffH NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION "NOVEL PHAR*£*cs?r-Tica:L COMBOS iriO'-is ccxiriurx^G ^*T AMINO JlCin DERIVE S'lVJ?" Js PAr^?\ %1 ®-so. jj/we, SCTV^CR tj:n;cre cy, •qociP!"t: m agorasc."' MEPIcaiiT?/ n French company orcaniS'S'l untor fciie French laws, of 14, rue du Val d'Or 92150 Suresnes, France, hereby declare the invention for which / we pray that a patent may be granted to^fffe/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- 1 900 28 PREFERRED EMBODIMENTS This invention relates to novel pharmaceutical compositions intended for improving or restoring the gastro-intestinal motility.

More precisely this invention provides novel pharmaceutical compositions containing as active ingredient a dibenzothiazepinic derivative in conjunction or admixture with a non-toxic, inert, pharmaceutically-accepta-ble carrier diluent or vehicle.

Specifically the subject matter of this invention relates to pharmaceutical compositions intended for use in gastro-intestinal therapy containing as active ingredient a dibenzothiazepine selected from the group consisting of 7- [(3.chloro 6-methyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepin - 1,2 11-yT) amino]] heptanoic acid, the salts thereof with a therapeutically compatible organic or mineral base and the salts thereof with a therapeutically-compatible organic or mineral acid.

The active ingredient may be in the racemic form or in an optically-active form.

The selection of the active-ingredient mainly depends on the way of administration and on the utilized pharmaceutical composition. 190028 For the injectible or drinkable solutions it may be advantageous to use a water-soluble easily diffusible salt such as a salt of an organic or mineral salt, an alkali metal salt as for example the sodium or the potassium salt, a salt with a mono lower alkyl, a di lower alkyl or a trilo-wer alkyl amine as for example methy.lamine, isopropylamine^diethylamine, a-minoethanol, di (ethylamino) ethanol , di(amino ethanol), triethylamine, phe-nylethylamine, phenylmethylamine, N-methyl benzylamine, a salt with a (hete-rocyclyl) lower alkylamine, for example 2-(N-ethylamino-pyridine) a salt with a lower cycloalkylamine as for example cyclopropylamine, a lower' cycloalkyl lower alkylamine as for example 1-cyclopropyl 1-athylamine, a salt with a be-taine or with a quaternary ammonium salt as for example chloline.

For other purposes it may be advantageous to use a water-insoluble active ingredient which may be easily made soluble in the body fluids as is 7-[ (3-chloro 6-methyl 5,5-dioxo 6,11-dihydro dibenzo (C,f) thiazepin 1,2-llyl) amino] heptanoic acid. i For further purposes it may be advisable to use an active ingredient , which is slightly soluble or sparingly soluble either for sake of sapidity or in order to reduce the resorption of the active ingredient. As poorly or spa11 ringly water soluble active ingredients it may be cited a salt with a earth-alkaline base, with alumina, with titanium oxyde, with a non-toxic rare earth, with a metal of the iron family such as a ferrous or ferric salt, with a tran- 1 sition metal, with a base giving water insoluble salts such as highermolecular weight organic bases for example arylamines, aryl lower alkylamime, hetero a-ryl lower alkyl amines, alkenylamines such as triallyl methyl amine, the salts with proteins, as for example clupreine, salmine, protamine. The salts with an amino acid, such as agmatine, cysteine, cystine^proline, hydro^proline or guanidine are also useful ; further the salts with derivatives of biological organic bases such as N-methyl Valine, N-methyl leucine, O-methylserine or gramine are of value.

Water insoluble salts, are also obtained with high molecular weight quaternary arroionium salts, namely with the aryl - or heteroaryl trialkyl ammonium salts as for example benzalkonium bromide or chloride, cetrimonium bromide of chloride, cetrimonium bromide, cetalkonium chloride or cethexonium bromi de. 1 900 2 8 the form of The active ingredient may also be in/addition salts with the mineral or organic acids such as hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid, phosphoric acid iodic acid, acetic acid, valeric acid, caproic acid, benzoic acid, 3,5-dichlorobenzoic acid, X-naph-toic acid, pyrrolidone carboxylic acid, 2-methyl thiazolyl 5-carboxylic acid, 5-methyl thiazolidinyl-4 carboxylic acid, nicotinic acid, isonicoti-nic acid, ascorbic acid, benzene sulphoriic acid, glucose 1-phosphoric a-cid or embonic acid.

In view of the therapeutic use in human or Veterinary medicine, the compositions according to the invention also incorporate one or more excipients inert carriers, binding agents, diluents agent which influence the speed of the release of the active ingredient namely in the dry compositions, flavouring agents, colouring matters, emulsifying agents, jellifying agents or tensio active agents. They may also be added conservative agents^stabilizers, anti-oxydizing agents and the like.

The active ingredient, 7- [3-chloro 6-methyl 5,5-dioxo 6,11-dihy-drodibenzo (c,f) thiazepin 1,2-11 yl) amino] heptanoic acid and the salts thereof, is a known compound already disclosed in US patent 3,821,249 (to Science Union). This patent discloses a broad class of tricyclic derivatives bearing an alkyl amino alkylcarboxylic side chain. These compounds have been shown as endowed with a broad range of pharmacological activities such as psychostimulant, antidepressant, analgetic, anti-cough, anti-his-taminic and inhibitors of the gastric secretions.

It has now been found that 7- ^(3-chloro 6-mathyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepin 1,2-11-yl) amino] heptanoic acid and the salts thereof are endowed with interesting and very specific properties.

They have to be considered as constituting a distinct genus amongst a broad class of tricyclic derivatives previously known.

The pharmacological studies and the clinical-trials have evidenced that these active ingredients shown a signifiarit antispasmodic activity and are able to restore the normal and well-coordinated motility of the digestive tract. Hence they antagonize the atonia of the unstripped muscles' of the digestive tract. Further they show a anti-serotonine effect on the said unstripped muscles and protect the animals against restraint ulcers. Due to the fact that the active ingredient is devoid of any antisecretory effect, this protective effect against ulcer has^iS be correlated to it and has to be attributed to an effect on the Central Nervous System. - 1 900 28 For this specified therapeutic purposes the pharmaceutical compositions are those which are more particularly suitable for parenteral oral, or rectal routes of administration.

More precisely it may be cited the tablets, the coated tablets, the dragees, the pills, the soft gelatine capsules, the sachets, the powders, the drinkable suspensions or solutions , the syrups, the jellies, the injectible solutions or suspensions packed in ampuls, anto-injectible syringes or multidosis flasks, the suppositories...

This invention also relates to a method for treating gastro-intes-tinaldue^nsufficient motility of the stomach or small intestine which consists in administrating to said patients a safe but effective amount of 7- [(3-chloro 6-rnethyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepin 1,2 - 11 yl) aminoj heptanoic acid/or a salt thereof, in a racemic form or in an optically-active from.

In humans this safe and effective amount ranges from 12 ito 75 mg daily. Preferably it may be divided in two or three doses per day. For the children the doses will be adjusted in relation to the age and the weight of the patients. In veterinary medicine the doses will range from 0.2 mg to 1,25 mg/Kg .. i, ' / The following examples are merely intended to illustrate the invention. They do not limit it in any manner. . i Example I Coated tablets containing 25 mg of active ingredient expressed as 7- [(3-chloro 6-methyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepin 1,2 - 11 yl) amino] heptanoic acid[dl sodium 7- [^(3-chloro 6-methyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepine 1,2-11 yl) amino]) heptanoate 26,2 g Mais starch 2,5 g Mannito! 88,5 g Magnesium stearate 2,5 g Talc 6,5 g This mass is for about 1000 tablets 1 900 28 Coatinc Sodium Bicarbonate Sodium Carboxymethyi Cellulose White wax Glyceryl oleate Titanium oxide Polyethylene glycol polysorbate Polyvinyl pyrrolidone Saccharose Colloidal Silica Talc \ V / J enough to coat the previously-formed cores until an average weight of .17 g dosage Example II Coated tablets containing 12,5 mg of active ingredient per unit dl sodium 7 - [j3-chloro 6-methyl 5,5-dioxo dibenzothiazepin 11-yl amino} heptanoate Mais starch Mannitol Magnesium stearate Talc 13,1 g 2,5 g 101 g 2,5 g 6,5 g for about 1000 tablets Coating sodium bicarbonate sodium Carboxymethyi cellulose white wax glyceryl oleate titanium oxide polyethylene glycol polysorbate polyvinyl pyrrolidone saccharose colloidal silica micronized talc enough to coat the previously-formed cores until an average weight of .175 g 1 900 28 Example III Drinkable suspension containing .25 g of active ingredient per cent ml. dl 7- Q3.chloro 6-methyl 5,5 dioxo 6,11-dihydro dibenzo (c,f) thiazepin 1,2-11 yl) amino] heptanoic acid .0250 g Saccharose 1 .5 g Sorbitol 2.5 g Methyl p.hydroxybenzoate .095 g Propyl p.hydrobenzeate .025 g Flavouring agents .005 g Tragacanth gum -45 g Water enough for 100 ml Example IV Clinical studies of 7- [(3-chloro 6"-methyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepin 1,2 - 11 yl) amino] heptanoic acid in the form of pharmaceutical compositions on the gastro-intestinal1 disturbances.

A) §y!2i§££_of_these_studies These studies were carried out in order to determine the efficiency of the active ingredient at three different dosologies and along several types of administrations in a cfcuble-blind comparison with a placebo.

The testing method was the. external myographic digestive study. It was performed in 24 subjects suffering from hyposthenic dyspepsia correlated with a state of depression or psychasthenia. These tests were performed according to the double blind method.

B) M§thod_of_testing The patients received either 50 mg/day in two administrations either 25 mg/day in one or two administrations or 12.5 mg/day in one administration.

They were divided in two groups of 12 patients - one group successively received a tablet containing 12.5 mg of active ingredient then one tablet of 25 mg active ingredient per day 1 900 2 - the other fjroup successively received two tablets per day, i.e. twice 12.5 mg then twice 25 mg of active ingredient per day.

X The administrations of the tablets of active ingredient lasted each 15 days followed with a wash out period of 15 days during which the patient merely received the placebo. c) P§£fQ™aQ£§_2f_tb§_syccessiye_administrations GROUP I GROUP II Duration group A (5 patients) group B / [6 patients) group C (6 patients) group D (6 patients) TO 2 weeks 2 weeks 2 weeks 2 weeks 1 X 25 mg 1 X placebo 1 X 12.5 mg 1 X . placebo ! 1 X 12.5 mg 1 X placebo 1 X 25 mg | placebo r ! • 1 i 2 X 12.5 mg 2 X placebo 2 X 25 mg 2 X placebo 1 » ' 2 X 25 mg 2 X placebo 2 X 12.5 ng pllclbo before testing external electro myography T1 I external electromyography M T2 T2 external electro myography I T3 clinical examination clinical clinical clinical examination examination examination 1 900 2 8 The repartition of the patients into the four subgroups been made by drawing of lots.

All the patients were ambulatory. They shown a syndrom of hypos-thenic dyspepsia and an external digestive electromyograph quite patholo-5 gic with a delay in the appearance of the gastric contraction wawes after the meals, of about 2 hours.

The clinical symptoms are quoted from 0 to 3 based on the severity . of these symptom's. In normal subjects the gastric wawes appear immediately after the ingestion of a normal meal and last about 5 hours. This case was 10 ■ quoted zero.

In the dyspeptic patients^ the lack of gastric wawes during the postprandial period may last more than 3 hours. This situation was quoted 2.

When after treatment the delay in the appearance of the gastric contraction decreased, the situation was quoted 1.

Results Grou|j_I Dosology : 1 tablet of 12.5 g or 25 mg active ingredient per day in comparaison with 1 tablet placebo for 15 days each. a) §ub_2roup_A The tablets containing 12.5 mg of active ingredient induce a very significant improvement of the whole symptoms as well as the external electro myographs in 45 % of the patients and a significant improvement in 55 % of the patients.

B) sub_groug_B The patients receiving 25 mg of active ingredient once a day show a very good therapeutic effect in 81,8 % of the patients. The lack of effect has been noticed in two patients.

C) placebo .For the two periods of wash out with the placebo two patients have 30 shown a clinical inprovement i.e. 18 % of the patients. For the remaining patients the placebo was totally inefficient.

Groug_II Dosology : 2 tablets of 12.5 mg or 25 mg active ingredient in comparison with 2 tablets of Placebo per day for 15 days. subgroug_C Good therapeutic effect in 8 patients out 12. For the remainder the therapeutic effect was moderate. subgroug_D With the .dosology of 2 tablets of 25 mg per day the efficacy was very good in 10 patients out 12 (i.e. 82.3 %). For the two remaining patients, the effect was only moderate.

In contrast thereof the placebo induced a positive effect in only one case for each period.

Conclusively the three different dosologies induce each time a significative therapeutic, improvement as evidenced by the external elec-trorcjyographs. There is always a significatively higher effect than the placebo. There is also a direct correlation between the dosology and the therapeutic effect. The higher the dosage, the more significative is the improvement in the clinical symtoms.

Example V Clinical Trial with the drinkable suspension containing 250 mg dl 7- [(3-chloro 6-methyl 5,5-dioxo 6.11-dihydro dibenzo (c,f) thiazepin 1,2-11 yl) amino] heptanoic acid per 100 ml.

This suspension has been tested in patients suffering from gastric disturbances and namely gastraljva. 38 patients have been treated with the drinkable suspension in comparison with a drinkable suspension without active ingredient.

The 38 patients have been divided in two groups. Each group received either the active ingredient or the placebo for twowweeks. The treate'd patients received the active ingredient at a daily dosage of 25 mg (i.e. 12.5 mg in the morning and 12.5 mg at midday) 1 900 28 was appreciated The efficacy of the treatment/o'f the improvement of the digestive symptoms : abdominal pain, nauseas, burns due to hyperacidity, distension of the stomachy eructations,feeling of difficult digestion or constipation.

The quotation of the symptoms depending of their severity,ranges from 0 to 3. A notation of the digestive, cardio-vascular, neurological tolerance of the pharmaceutical composition has also been determined. Further the bio- the basis of logical tolerance has also been estimated based on/the whole hemogramm hepatic and renal check-up before and after two weeks of treatment.

All the patients dishow the symptoms of the hypos tenic dyspepsia without any organic lesion evidenced by fibroscopy or radiologic examination performed before the treatment.

Results The "treatment shows a very good efficiency in 10 patients out 18 (i.e. 55 % of the patients), a moderate activity in one patient and a weak activity in 7 patients.

With the placebo a good activity has been seen in 6 patients out 20 (i.e. 30 % of the patients), a moderate activity in two patients and a lack of activity in 12 patients (i.e. 60 % of the patients). P^ 0.01 It appears thus that the drinkable suspension containing .250 mg of active ingredient per 100 ml provides good results far superior than those obtained with the placebo. It must also be noticed that the active ingredient provides very good results whilst the placebo, when active, provides only good or moderate results.

In cases of epigastric pain the efficiency of the pharmaceutical composition was very good in 66.6 % of the patients and in the case of gastric burns the pharmaceutical compositions v/ere efficient in 69 % of the patients.

In the patdehts suffering from nauseas a very good effect was noticed in 64 % of the patients.

In the patients suffering from constipation, 3 were improved and the remaining people did not state any increase of the constipation.

The pharmaceutical compositions do not aggravate or cause any constipation, evidencing a good tolerance of the drug. t 900 28 Exemple VI Effect of the pharmaceutical compositions according to the invention on the blood level of Prolactin in the man. 12 volunteers (6 men and 6 women) devoid of any known ofganic disease have been retained for this study.

They received after a two-week period of wash-out, either a known agent active on the level of prolactin (sulpiride) or a tablet containing 12,5 mg of dl 7- ^(3-chloro 7, 11-dihydro dibenzo (c,f) thiazepin 1,2-11 yl) amino^] heptanoic acid three thimes a day,Sulpiride was administered at a dosis of 50 mg each time.

Before administration a control blood test was performed, immediately after, absorption of the drug to be tested. 120 mn later a new test was done to determine the variations of prolactinemia after.a single dose of drug.

They received the drug for 7 days. On the 7 th, new control and past absorption test were performed.

The blood samples are received in heparinized test tubes, centrifuged at + 4° C. The plasmas are stored at 20° C. The determination are carried out by a radio-immunological test using a rabbit anti-Prolactin antibody., according to classical techniques.

In the man, the normal level of prolactin ranges from 5 to 15 ng per ml and in the women from 10 to 25 ng/ml.

Results aj Controls before administration 6, 8 + 3,5 ng/ml 8,4 + 7,0 /ml B) Volunteers before administration (TO at JO) Men : 6,8 ng/ml +3,5 Women :10,4 ng/ml + 6,5 c) Volunteers after a single dose of sulpiride Men : 36,6 + 16,3 (+ 440 %) Women : 78,7 + 35,5 (+ 657 %) 1900 28 These considerable increases are highly statistically significative for both sexes.

D) Volunteers after one week of administration of sulpiride Men : 42,25 ng/ml + 16,2 (+ 521 %) Women : 80 ,75 ng/ml + 32,9 (+ 676 %) p < .001 E) Volunteers after a single dose of sulpiride after 7 days of treatment (J ?T0 / J? T 120) Men : 42,25 + 16,2 v.s 38.1 + 16,0 Women : 80,75 + 32,9 v.s 83.7 + 14.1 An extra administration of sulpiride after one week of treatment does not further increase the blood level of prolactin; F) Blood level of Prolactin 120 m, after administration of sulpiride the first day (Jo) and after a week of treatment (J ?) is : Men : 36.7 + 16.3 (JO) 38.1 + 16,0 (J ) Women : 78.7 + 35.5 (JO) 83.7 + 14.1 (J?) It appears that the blood level of Prolactin reachs a plateau after the first administration of sulpiride.Thus, according to previous author^ sulpiride increases steeply Prolactin.

G) Blood levels after administration of 7 - £ (3-chloro 6-methyl 6.11-dihydro dibenzo (c,f) thiazepin. 1,2 -11 yl) amino} heptanoic acid. 1) after a single dose (Jo To vs. Jo T ) Men : 7.4 + 10.2 120 mn after administration (- 12 %-) Women : 3.9 +3.0 (120 mn after administration) ( - 52 %) 1 900 2 2) after one week of treatment (JyTo vs Oo To) before absorption of the drug 6 Men : 5,8 + 4.5 (8.4 + 7.0 ) i.e. - 31 % 6 Women : 6.8 + 2.7 (8.2 + 6.2) i.e. - 17 % Prolactin is still low." 3) After absorption (120 mn later) ^7^ 120VS ^ 7^®) Men : 4.1 + 5.8 (5.8+4.6) i.e. - 29 % -Women : 2.2 + 0.9 ( 6.8 + 2.7) i.e. - 68 % p <0.005 The decrease in the blood levels becomes statistically -significative (in the female volunteers at least) 4) The Prolactin increase Ratio between the 7th and 1st day is (J Tj2q) Men : 4.1 + 5.8 (vs 7.4 + 10.2 ) i. e. - 45 % Women : 2.2 + . 9 (vs 3.9 + 3.0 ) i..e. - 44 % Cone!usion Whilst sulpiride as many neurotropic drugs increases the Prolactinhemia , the pharmaceutical compositions according to the invention induce only a slight decrease of the blood levels of Prolactin , and this effect is of short duration without any cumulative effect when tne administrations are renewed for 7 days. 190023

Claims (8)

WHAT WE CLAIM IS:

1. Pharmaceutical compositions which restore the normal gastro-intestinal motility, containing as active ingredient a compound selected from the group consisting of 7-/T3-chloro 6-methyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepine 1,2" 11-yl) amino/ heptanoic acid in the racemic form or in an optically-active form, and a salt thereof, in admixture or conjunction with an inert non-toxic pharmaceutically-acceptable carrier or vehicle.

2. A pharmaceutical composition according to claim 1 wherein the active ingredient is dl 7-/T3-chloro 6-methyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepine 1,2-11 yl) amino/ heptanoic acid.

3. A pharmaceutical composition according to claim 1 wherein the active ingredient is an inorganic or organic base addition salt of 7-/T3-chloro 6-methyl 5,5-dioxo 6,11 dihydro dibenzo (c,f) thiazepine 1,2 - llyl) amino/ heptanoic acid.

4. A pharmaceutical composition according to claim 1 wherein the active ingredient is the sodium salt of 7-/T3-chloro 6-methyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepine 1,2 -11 yl) amino/ heptanoic acid.

5. A pharmaceutical composition according to claim 1 wherein the active ingredient is an inorganic or organic acid addition salt of 7-/T3-chloro 6-methyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiazepine 1,2-11 yl) amino/ heptanoic acid.

6. A pharmaceutical composition according to claim 1 wherein the content in active ingredient ranges from 12 to 50 mg per unit dosage expressed as free acid.

7. A pharmaceutical composition according to claim. .1 wherein the carrier or vehicle is one of those adapted for parenteral, buccal or rectal ways of administration.

8. A method for treating gastro-intestinal disturbances resulting from abnormal motility of the stomach or upper part of the small intestine which consists in adminstering to patients excluding humans suffering from said disturbances a said but effective amount of a compound selected from the group consisting of 7—^3-chloro 6—methyl 5,5-dioxo 6,11-dihydro dibenzo (c,f) thiaze-pine 1,2 - 11 yl) amino/ heptanoic acid and a base or acid addition salt thereof. v By ^ps/cheir authorised tE.a *•' \r^V!t>V A* «!• & SON.