PHARMACEUTICAL COMPOSITIONS HAVING APPETITE REDUCING ACTIVITY AND A PROCESS FOR THEIR PREPARATION

Abstract: Pharmaceutical compositions having appetite reducing activity. The compositions contain (5 alpha ,6 alpha )-7,8-didehydro-4,5-epoxy-17-(2-propanyl)-morphinane-3,6-diol.

Description: Pharmaceutical compositions having appetite reducing activity and a process for their preparation Background of the invention One of the basic phenomenon of life is that the living creatures take food from their environment. As a basic phenomenon is concerned, it has been risen simultaneously with the rise of life. Considering that for the living creatures both overfeeding and under eeding are dangerous, simultaneously with the rise of the food intake also a system for controlling the food intake has been risen. Together with the development of life also this system became more and more developed and today it operates as a very complicated system "having several regulating circles^*» (A summary of some presumed and proved regulating mechanisms is given in The Lancet of February 19, 1983 on pages 398 to 401.) One of these regulating mechanisms is based on the so called opioid endogenic peptides. This is supported by.the observation that if a special opiate antagonist, naloxone [(5o)- - ,5-epo_t_y-3,14-dihydro3 * y-17-(2-propenyl)-morphiπaτ.e-6- -one] . is administered to animals it is absorbed by the opiafe receptors and thereby the food intake, the appetite and also the fluid intake of the animal is hindered. The observation that by the administration of endogenic (and exogenic) opiates the appetite of animals and humans can be increased shows that these compounds exert an influence on the nutrition (Am. J. Olin. Hutr. , _2≥, 757-761, 1982 and Appetite, £, 193-208, 1981). While ±n case of non-domesticated animals the regulating mechanisms f nction more or less properly and ensure the appropriate food intake of the animals, in case of humans of ten lesions deriving from overfeed emerge. This can be readily understood as on the one hand in case of humans food intake is caused not only by the sensation of hunger and, on the other hand the degree of the ood intake does not follow the demands of the organism, the demands are often many time surpassed. It is true that by proposeful food intake obesity can be avoided but in many instances the decision in itself is not sufficient for changing the alimentary habits, for carrying out the decision a medical support is necessary as well. The best known slimming agents are desopi one (4— -chloro-oc ,o^-d_Lmethyl-phenethylamine), gracidine (3- -methyl-2-phenyl-morpholine) and teronac -phenyl)-2,5-dihydro-3S-imida_5θ " 2,l-a7isoindole-5-ol). Un ortunately the known slimming agents have several contraindications and side effects, so in case of a great part of the patients requiring treatment these agents cannot be used. The side effects of desopimone are the dilatation of the pupil, increase of the inner pressure of the erjes, vomiting, diarrhoea, abdominal pains, difficulty at the beginning of urination, headache, allergic exanthema, vertigo; and insomnia and nervosity as well as somnolence and sedative ef ect appear in about equal proportions. Gracidine only with increased care can be administered in case of obesity associated with heart diseases, cardio¬ vascular troubles and hypertension. At the intake of gracidine and when it is administered continuously during the cure driving of vehicles, working above ground and on dangerous machines are prohibited. During its use. and influence, respectively, also the take of alcoholic drinks is prohibited. According to new informations the compositions containing gracidine are forbidden. Teronac may cause mouth dryness, headache, nervosity, nausea, constipation, impairment of sleep, dizziness, tachycardia, reversible trouble of sexual functions, sweating, eczema, dilatation of the pupil, allergy. Also in case of glaucoma, heart-rhythm troubles, serious cardiac failure, renal insufficiencies, liver troubles, hypertensions, cerebral processes, psychiatric diseases, gastric and intestinal ulcers it is contraindicated. On the basis of the aforesaid an appetite reducing composition is needed which does not show the side effects of the known compositions and which can be widely used without side effects. As the active ingredient of a composition like this primarily those substances can be taken into consideration which exert their influence on the field of the central nervous system. Substances of this type are also the opiate antagonists mentioned above. It is known that on obese people the food intake is reduced by naloxone ( . Glin. Endocrin. Metab., .55, 196-198, 1982). It has the similar activity in Prader- Willi syndrome (The lancet, 1980, 876-877)* traumatic hypothalamic hyperphagia (Am. J. Olin. Nutr. , _2_2, 757-761, 1982) and also in case of healthy patients rendered hungry by 2-desoxy-glucose infusion. The use of naloxone as active ingredient in appetite reducing compositions is unavoidable hindered by the fact that when administered per os it should be --ξi REAl OMPI given in extremely high doses. But in case of a widely used appetite reducing composition only the peroral administration can come into consideration. The object of the present invention is to provide an appetite reducing composition which can be widely used without side 'ef ects and contraindications. Brief descTvL-ption of the invention The object of the present invention is attained by an appetite reducing composition cintaining as active ingredient nalorph e /~(5oc, 6oc)-7,8-didehydro- ,5-epoxy- -17-(2-propenyl)-morph ane-5,6-diol7« This composition can be administered perorally and rectally Detailed deg gript- oa of frfae inY irtiQB According to the present invention nalorphine, preferably in the form of its salt prepared with a strong acid, such as a mineral acid, e.g. hydrochloric acid, hydrobro ic acid is formulated into pharmaceutical compositions with carriers, diluents, flavouring, aromatizing, colouring agents and other auxiliary materials normally used for the preparation of oral or rectal pharmaceutical compositions. The pharmaceutical compositions of the present invention are prepared in the form of tablets, dragees, pilules, capsulated or chartulated powder compositions and various solutions, suspensions (such as liquid medicines, drops etc.), suppositories. According to a preferred embodiment of the invention one dosage unit or a low number of the dosage units (tablet, dragee, chartula, capsule, suppository, drop or spoonful amount) of the pharmaceutical composition contain the single dose. A dosage unit may contain of course more doses, in this case for example the tablets may be provided with dividing cuts in order to facilitate their break into pieces. The daily dose of the active ingredient is 15 to 30 mg. As the active ingredient is long since used as an _mtinsureotic, the actual dose can be easily determined by the physician on the basis of his skill, considering the individual reactivity and tolerance of the patient and the effect intended to be achieved. These doses may exceed the doses mentioned above or may be less than in¬ dicated. The daily dose may be divided into more single doses containing equal or different amounts of the active ingredient. Thus the constant active ingredient level can be easily ensured. The invention relates to a process for reducing the appetite of humans or animals as well, wherein the effective dose of the composition of the present invention, e.g. the amount containing 15 to 30 mg of the active ingredient is administered to the person or to the animal to be treated * It has been surprisingly found that during or after the treatment carried out with the pharmaceutical composition of the presentinvention side effect (mouth dryness) attributable to the composition only very rarely and in a very mild form was observed. Bo side effect was observed which could have been connected to the narcotic effect of the opium derivatives. No dependence on the medicine has been risen, no habituation or withdrawal symptom was observed after the treatment. The invention is illustrated by the ollowing non limiting examples. OMPI YΛ. BWffl lg I Tablet containing 5 "ag of active ingredient . A powder mixture of the following composition is prepared: nalorphine hydrobromide 5»0 δ colloidal silica 1.0 g magnesium stearate 3.0 g talc 9.0 g microcrystalline cellulose fi2.O y 100.0 g Prom the powder mixture thus obtained after ho ogenisation tablets each weighing 100.00 mg are compressed under a pressure of 4-9-785 &P* (500-8000 kp/cm ). Bsfflple 2 Tablet containing 10 mg of active ingredient A powder mixture of the following composition is prepared.? nalorphine hydrobromide 10.0 g colloidal silica 1.0 g magnesium stearate 3 * 0 g talc 9.0 g microcrystalline cellulose 77.Q g 100.0 g From the powder mixture thus obtained after homogenisation tablets each weighing 100.00 mg are compressed under a pressure of 4-9-785 MPa (500-8000 kp/cm ). Tablet containing 20 mg of active ingredient A powder mixture of the following composition is prepared: nalorphine hydrobromide 20.0 g talc 3.0 g magnesium stearate 4-.0 g annitol Iflfi.Q g 135.0 g From 15.0 g of starch and water a 3-5 # granulating liquid is prepared. The powder mixture is granulated with the starch solution thus obtained. Granules having a diameter of about 1 mm are prepared. The granules are dried at a temperature of 50°0, then they are compressed under a pressure of 49-785 MPa (500-8000 kp/cm 2 ) into tablets each weighing 150.00 mg. fgrampl* 4 Suppository containing 20 mg of active ingredient A suppository mass of the following composition is prepared: nalorphine hydrobromide 2o.0 g suppository base (cocoa butter) 1-380.0 g 2000.0 g The suppository base is melted at 37-38°0, the active ingredient is uniformly distributed therein, then the mass is filled into suppository forms suitable for preparing suppositories of 2 g and it is cooled. Clinical tests were carried out on obesed voluntary patients with the tablets containing 5 &g of active ingredient prepared according to Example 1. The body weight was measured at the beginning and at the end of the test, the number of the tablets administered daily was also registered and at the end of the treatment the weight loss was calculated in the dimension of kg/week. The following Table contains the data thus obtained together with the occasional side effects. Table Number Body weight Weight Number of at ad- at dis¬ loss of Side effect patient mission charge (kg/week) tablets per day- 1. 103.5 kg 100.5 k 0.75 2 mouth dryness 2. 92.0 kg 84.5 kg 1.07 1 0 3. 82.0 kg 76.0 kg 0.50 3 0 4. 80.0 kg 78.0 kg 0.66 3 0 5. 123.0 kg 122.0 kg 0.50 5 0 6. 87.0 kg 85.0 kg 1.0 3 0 7. 80.0 kg 77.0 kg 0.75 2 ø 8. 84.0 kg 79.0 kg 0.83 2 ø 9. 114.0 kg 103.0 kg 0.75 3 obstipation 10. 78.0 kg 72.0 kg 1.0 4 thirst 11. 100.0 kg 87.0 kg 2.1 3 obstipation 12. 90.0 kg 82.0 kg 0.5 4 obstipation 13. 114.0 kg 98.0 kg 0.7 3 obstipation 14. 92.0 kg 81.53εg 0.7 4 obstipation 15. 124.0 kg 108.0 kg 0.8 3 0 16. 97.0 kg 88.0 kg 0.4 5 0 17. 75.0 kg 68.0 kg 0.7 6 transitorial vertigo 18. 103.0 kg 99.0 kg 0.5 5 0 19. 83.0 kg 75.0 kg 1.0 4 transitorial nausea Number Body weight Weight Number of s of Side effect patient at ad- at dis¬ los mission charge (kg/week) tablets per day 20. 96.0 kg 77.0 kg 1.1 3 obstipation 21. 91.0 kg 87.0 kg 0.5 4 0 22. 86.0 kg 75.0 kg 1.5 5. obstipation 23. 104.0 kg 93.0 kg 0.5 4 0 24. 78.0 kg 72.0 kg 0.7 4 0 25. 109.0 kg 100.0 kg 0.9 4 obstipation 26. 119.0 kg 106.0 kg 1.0 4 0 27. 97.3 kg 87.3 *δ 1.0 4 0 28. .82.5 kg 76.0 kg 0.6 3 0 29. 126.2 kg 115.0 kg 1.3 3 obstipation 30. 81.5 kg 73.8 kg 1.1 3 0 31. 83.0 kg 75.0 kg 0.8 3 obstipation 32. 103.6 kg 101.3 kg 0.8 3 transitorial vertigo sleepiness 33. 119.8 kg 112.0 kg 0.8 4 obstipation 34. 115.0 kg 110.5 kg 0.9 4 obstipation 35. 98.0 kg 87.0 kg 1.2 3 0 36. 97.0 kg 90.0 kg 1.1 3 0 37. 115.5 leg 100.3 kg 2.1 3 0 38. 125.0 kg 102.5 kg 1.3 3 0 39. 132.0 kg 121.0 kg 0.7 4 0

Claims: Claims: 1, Pharmaceutical compositions having appetite reducing activity characterized in that they contain 5 to 30 mg of (5oc, 6o )-7,8-didehydro-4,5-epoxy-17-(2-propenyl) -morphinane-3,6-diol per dosage unit or a salt thereof formed with a strong acid together with a carrier, diluent, flavouring, aromatizing, colouring agent and other auxiliary material normally used for the preparatign of oral or rectal pharmaceutical compositions. 2. The pharmaceutical compositions of claim 1 characterized in that they are formulated into solid compositions suitable for oral administration. 3. The pharmaceutical compositions of claim 1 characterized in that they are formulated into suppository compositions suitable for rectal administration. 4. Process for the preparation of pharmaceutical compositions having appetite reducing activity characterizs in that 5 to 30 mg of (5c ,6oc )-7,8-didehydro-4,5-epoxy- -17-(2-propenyl)-morphinane-5,6-diol per dosage unit or a salt thereof formed with a strong acid is formulated into a pharmaceutical composition together with a carrier, diluent, flavouring, aromatiz ng, colouring agent and other auxiliary material normally used for the preparation of oral or rectal pharmaceutical compositions. 5. The process of claim 4 characterized in that solid pharmaceutical compositions, preferably tablets are prepared using solid auxiliary materials. 6. The process of claim 4 characterized in that suppository compositions are prepared using serai-liquid auxiliary materials. --gUREA O PI 7. Process for treating mammals, such as humans in order to reduce their appetite and thereby their body weight characterized in that a pharmaceutical composition containing 5 to 30 g of (5c ,6oO-7 > 8- -didehydro-4,5-epoa_y-17-(2-propenyl)-morphinane-3,6-diol is administered daily to mammals, such as humans preferably in the form of its salt formed with a strong acid.

Inventors: BALKANYI IVAN, HADI FERENC, KERI EVA, KOESZEGI BELA, MARSO MIKLOS, SZEBENI RUDOLF, BALKANYI, IVAN, HADI, FERENC, KERI, EVA, KOESZEGI, BELA, MARSO, MIKLOS, SZEBENI, RUDOLF
Applicants: BALKANYI IVAN, HADI FERENC, KERI EVA, KOESZEGI BELA, MARSO MIKLOS, SZEBENI RUDOLF, BALKANYI, IVAN, HADI, FERENC, KERI, EVA, KOESZEGI, BELA, MARSO, MIKLOS, SZEBENI, RUDOLF
Application year: 1984
Main classification: A61K31
IPC codes: A61K31, A61P3, C07D489