PHARMACEUTICAL COMPOSITIONS OF ANTI-PANCREATIC INFLAMMATORY EFFECT

Abstract: Pharmaceutical compositions comprising 3-dimethylamino-7-methyl-1,2-(n-propylmalonyl)-1,2-dihydro-1,2,4-benzotriazine and at least one of a factor of Vitamine P and/or (+)-2-(3,4-dihydroxyphenyl)-3,5,7-cromanetriole as active ingredients, a process for preparing the same and a method for treating pancreatic inflammations with the said composition. The pharmaceutical compositions according to the invention are useful for the treatment of pancreatic inflammations.

Description: PHARMACEUTICAL COMPOSITIONS OP AUTI-P CREATIC I3STPT.AM A ORY EPPECT Technical field The present invention relates to synergistic pharmaceutical compositions of anti-pancreatic inflammatory effect, a process for preparing the same and a method for treating pancreatic inflammations. In particular, the invention is directed to pharmaceutical compositions comprising one or more active ingredients of antiphlogystic and vascular effect, a process for preparing the same and a method for treating pancreatic inflammations with the said compo¬ sitions. Background art In the last two decades the chronic inflammatory diseases of pancreas appeared to cause increased clinical problems. This phenomenon is accompanied on one hand by the increased number of patients, on the other hand by the increased number of diagnostic methods. These facts are referred to in the following publication: Marks, J.2T., Bank, S., louw, I.H.: Leber, Magen, Darm. 6 257, 1976. It is known in the art that the pancreatic inflammatory processes show specific features (Papp, M.: Congress of the Hungarian Gastroent. Society, Keszthely, Hungary, 1981} . The inflammation is of either ductalic or paren- chimic feature, the deterioration of parenchyma, pro- gressive histolysis, fibrotizing processes and cicatriza¬ tion occur soon. The constant presence of the free digestive enzymes assuring the autoperpetuation is induced by the inflammatory mechanism, the oedematic processes and the trophyc disorders to a high degree. Besides the inflammed oedema the compression of the subcapsular limphatics also diminishes the microcircula- tion. G. Kaiser's and G. Hommel's observation is also of great importance. According to their report the de¬ creasing demand for blood supply of the pancreas mass under deterioration induces adaptive intimafibrosis in the small blood-vessels. This process further reduces the blood amount rushing to the gland and it can be the basis of further athropy. /^Raiser, G., Hommel, G.: Morphometrisch-statistische Analyse der Pankreasarterien bei chronischer Pankreatitis. Virchows Arch fPathol. Δnat * ) 26£ 103 (1975i7. In spite of the above theoretical considerations there are no available pharmaceutical compositions of satisfactory efficiency for the treatment of pancreatic inflammations till now. In order to relieve the patients of the unpleasant effect of the chronic inflammations the medical treatment is delimited to administering enzyme as substitution with simultaneous diet. Such enzyme preparations are e. g. Dipankrine, Cotasym Porte or Panpur. Disclosure of the invention The aim of our research work was to elaborate a pharmaceutical composition which ±B suitable for the • efficient treatment of patients suffering from pancreatic inflammations and for the cure of pan- creatitis. According to ou observation from the group of antiinflammatory agents the steroids would rather induce recidiva while the prostaglandine antagonists are powerless. Surprisingly we have found that the pharmaceutical compositions containing 3-dimethylamino-7-methyl-l,2- (n-propylmalonyl)-l,2-dihydro-l,2,4-benzo riazine and at least one of the Vitamine P factors and/or (+)-2- f3,4-dihydro_∑yphenyl)-3 » 5 > 7-cromanetriole as active ingredients are effective against pancreatic inflamma- tions. As a factor of Vitamine P a water soluble rutine derivative, preferably 3',4',7-tris (β-hydroxyethyl)- rutoside, can be used. The weight ratio of 3-dimethylamino-7-methyl- 1,2-(n-propylmalonyl)-l,2-dihydro-l,2,4-benzotriazine and a factor of Vitamine P is between 2 : 1 to 1 : 1 OMPI in the compositions of the invention. The weight ratio of 3-dimethylamino-7-methyl- 1,2-(n-propylmalonyl)-l, -dihydro-l,2,4-benzotriazine and (+)-2-(3,4-dihydro3yphenyl)-3, ,7-cromanetriole varies within the range of 2 : 1 to 1 : 1 in the composi¬ tions of the invention. The compositions according to the invention contain suitably 60 to 300 mg. of 3-dimethylamino-7- meth 1-1,2-(n-propylmalonyl)-l,2-dihydro-l,2,4-benzo- triazine and altogether 60 to 300 mg. of a factor of Vitamine P and/or (+)-2-(3,4-dihydro:xyphenyl)-3,5,7- cromanetriole per dosage unit * The pharmaceutical compositions according to the invention contain optionally one or more known anti- biotics and/or trace elements and/or vitamines in association with carrier(s), excipient(s) and diluent(s) conventionally used in the preparation of pharmaceutical compositions. As antibiotics Penicillin V or Tobra ycin are preferred. The compositions of the invention contain option¬ ally as vitamines e. g. magnesium ascorbinate, ascorbinic acid or other conventionally used vitamines. As carriers or diluents those conventionally used, e.g. talc, calcium carbonate, magnesium stearate, starch, dextrine, water, physiological saline solution or poly- ethylene glycols can be used. The compositions according to the invention contain as excipients conventional excipients, for example emulsifying agents, disintegrating agents or sweeteners. Preferred pharmaceutical forms of the present invention are solid forms such as tablets, pills, cap¬ sules, dragees, granules, or liquid forms, such as solu¬ tions, suspensions, emulsion, syrups, injections, infusion solutions. These compositions are administered orally, by intravenous or subcutane injections or by infusions. Clinical results obtained by the administration of 3-dimethylamino-7-methyl-l t 2-fn-propylmalonyl )-l.2- dihydro-1,2.4-benzot iazine fAzapropazonum) As it is well known from pharmacological and pharmaco-kinetical experiments, Azapropazonum can be well absorbed from the duodenum and well spreads in the extra¬ cellular space. In infla med tissues it enriches to 3 to 8-fold amound calculated for the oedemic liquids. It does not get decomposed in the organismus, it is not. metabolised in liver and it evacuates with the urine. The ulcerogenic effect of the compound can be neglected, liver and medulla damaging effect is not observed, and it does not possess teratogenic and carcinogenic effect. It does not influence detectably the function of the organs, does not effect the increase in the body weight, the composition of the urine and the blood. It has a slight influence on the anabolic function of the cells, does not change either the cell production or the specific synthesis thereof, thus it does not embarrass the mucopolysaccharide production and therefore does not interfere with the reparation process. However, it restrains the " catabolic anabolic processes by its effect on the mediators of the inflammation. It blocks the course of the inflammatory process on the level of the deliberation or the function of the lysosomalic enzymes. The results of the treatments with Azapropazonum as active ingredients are enclosed by Table 1 # Table 1 Number of patienta P a t o g r a p h y from 20 patienta cholecya o- cholangiopancr. Chol.pancr. Pane. Pane. pancreatitis (st.p.cholecyat- + chr. chr. (with atonea) ectomiam) diabetes ale. ale. + pa.cyata men: 7 1 1 4 women: 13 4 1 1 I clinical effect I inaignificant 5 4 2 medium 2 1 3 excellent Daily 3 x 300 mg. of Azapropazonum were adminiatered orally. The treatment was carried out for 12 weeks. Clinical results obtained by the administration of Hydroxyrutosidea or Catechin alone and combinations according to the invention In order to increase the antiinflammatory effect, compounds of vascular effect were simultaneously tested. Two compounds were choosen: 3*,4',7-tris (β- hydroxyethyl)rutoside (referred to as Hydroxyrutosidea) and (+)-2-(3,4-dihydroxyphenyl)-3,5,7-cromanetriole (referred to as Catechin). Having demonstrated that the acut toxicity of Azapropazonum is not increased in the presence of Hydroxyrutosidea or Catechin, further experiments were carried out. In the first step of these experiments Hydroxy¬ rutosidea or Catechin were administered to the patients alone. The results are shown in Tables 2 and 3« Table 2 Number of patienta P a t h o g r a p h y from 20 cholecyato- cholangiopancr. chol.pancr. chol. Pane, Pane, patienta pancreati*- (at.p. chole- + pancr. chr. chr. tia (with cyatectomiam) diabetes + ale. + atones ) pa.cyata pa.cyata men: 5 1 3 women: 15 5 2 I clinical effect I inaignificant 6 2 Daily 3 x 300 mg. of Hydroxyrutosidea were adminiatered orally. The treatment was carried out for 12 weeka. Table ? Number of patienta P a t h o g r a p h y from 20 patients cholecyato- cholangiopancr. chol.pancr. chol. Pane, Pane, pancreati- (st.p.cholecyst- + pancr. chr. chr. + tis (with ectomiam) diabetes + ale. pa.cyata atonea ) pa.cyata men: 7 2 1 3 1 women: 13 5 4 2 1 clinical effect insignificant 6 1 Dally 3 x 300 rag. of Catechin were adminiatered orally to the patients. The treatment was carried out for 12 weeka. As it is ahown by the tables, the administra¬ tion of Hydroxyrutosidea or Catechin alone resulted in an insignificant effect. Surprisingly, the simultaneous administration of Azapropazonum and Hydroxyrutosidea or Azapropazonum and Catechin resulted in an unexpected effect. The anti-pancreatic inflammatory effect of Azapropazonum was highly synergyzed by the compounds of vascular effect employed in the experiments. The results are included into Table 4. Table 4 Number of Combination of patients co pounda applied P a t h o g r a p h y from 50 Azapropa¬ Chole- Choi. Choi. Chol- Pane Panc . Panc . patienta zonum + cyato pancr. angio angio chr. chron. chron. Hydroxy- pancr. (at.p. pancr. pancr. ale. ale. + ale. + rutoaidea (with chole- + dia- + pa. diabe¬ pa. atones) cyateco- betea cyata tes cyata miam) men: 16 2 2 1 2 2 3 women: 34 10 10 6 2 5 1 clinical effect insufficient - - - _. - - _ medium 18 7 3 4 1 - 2 1 excellent 32 5 9 4 3 7 1 3 men: 16 Azapropa- 1 2 1 2 1 3 4 woman: 36 zonum + 10 11 6 3 5 1 - Catechin clinical effect insufficient - - - - - - - medium 15 6 3 3 1 1 - 1 excellent 35 6 8 5 3 8 3 2 Abbreviations applied in Tables 1 to.4: cholangiopancr. = cholangiopancreatitis st.p.cholecyatectomiam = status post cholecyatectomiam chol.pancr.+diabetes = ■ cholangipancreatitis + diabetes pane.chr.ale. = pancreatitis chronica alcoholica pane.chr.ale.+ps.cysta = pancreatitis chronica alcoho¬ lica + pancreas cysta Modes of Carrying out the Invention The invention is illustrated by the following, non-limiting examples. Example 1 Composition of a tablet: Azapropazonum 300 mg. Hydroxyrutosidea 300 mg. Carrier q.s. for a tablet Example 2 Composition of a tablet: Azapropazonum 300 mg. Hydroxyrutosidea 150 mg. Catechin 150 mg. Carrier q.s. for a tablet Example 3 Composition of a tablet: Azapropazonum 300 mg. Hydroxyrutosidea 150 mg. Ascorbinic acid 100 mg. Carrier q.s. for a tablet Example 4 Composition for a tablet: Azapropazonum 150 mg. Catechin 150 mg. Carrier q.s. for a tablet Example 5 Composition of a dragee: Azapropazonum 150 mg. Hydroxyru osidea 150 mg. Magnesium ascorbinate 150 mg. Penicillin V 30 mg. Tobramycin 40 mg. Carrier q.s. for a dragee Example 6 Composition of a capsule Azapropazonum 150 mg. Hydroxyrutosidea 150 mg. Carrier q.s. for a capsule Example 7 Composition of a capsule Azapropazonum 150 mg. Catechin 150 mg. Sodium ascorbinate 30 mg. Carrier q.s. for a capsule Example 8 Composition of a drinkable liquid (drops): Azapropazonum 300 mg. Hydroxyrutosidea 300 mg. Vitamine C 3 mg. Diluent q.s. 100 ml. Example 9 Composition of an infusion solution: Azapropazonum 3 g. Polescutol 3 g. Vitamine C 3 g. Solved in physiological saline solution, filled into infusion glasses of 0.5 or 1.0 1. volume after filtration to steryle q.a. 1000 ml. Example 10 Composition of an injectable preparation: Azapropazonum 3 g. Hydroxyrutosidea 3 g. Penicillin V 30 mg. Solved in physiological saline solution, filled into 2.0 to 5-0 ml. ampoulles after filtration to steryle q.s. 1000 ml.

Claims: What we claim is: 1. Pharmaceutical compositions comprising 3- dimethylamino-7-methyl-l,2-(n-propylmalonyl)-l,2- dihydro-1,2,4-benzotriazine and at least one of a fac- tor of Vitamine P and/or (+)-2-(3,4-dihydroxyphenyl)- 3,5,7-cromanetriole as active ingredient. 2. Pharmaceutical compositions as claimed in Claim 1 comprising one or more antibiotics and/or trace elements and/or vitamines and carrier(s), diluent(s), excipient(s) generally used in the prep¬ aration of pharmaceutical compositions. 3. Pharmaceutical compositions as claimed in Claim 1 or 2 comprising a water soluble rutine deriv- ative, preferably 3' ,4',7-tris(/i-hydroxyethyl)rutoside, as a factor of Vitamine P. 4. Pharmaceutical compositions as claimed in Claims 1 to 3 comprising 60 to 300 mg. of 3-dimethyl- amino-7-methyl-l,2-(n-propylmalonyl)-l,2-dihydro- 1,2,4-benzotriazine per dosage unit. 5. Pharmaceutical compositions as claimed in Claims 1 to 4 comprising 60 to 300 mg. of a factor of Vitamine P and/or (+)-2-(3,4-dihydroxyphenyl)-3,5,7- cromanetriole per dosage unit. 6. Pharmaceutical compositions as claimed in Claims 1 to 4 comprising 3-dimethylamino-7-methyl- 1,2-(n-propylmalonyl)-l,2-dihydro-l,2,4-benzotriazine and a factor of Vitamine P in a weight ratio of 2 : 1 to 1 : 1. 7. Pharmaceutical compositions as claimed in any of Claims 1 to 4 comprising 3-dimethylamino-7-methyl- -1,2-(n-propylmalonyl)-l,2-dihydro-1,2,4-benzotriazine and (+)-2-(3,4-dihydroxyphenyl)-3,5-7-cromanetriole in a weight ratio of 2 : 1 to 1 : 1. 8. A process for the preparation of pharmaceu- tical compositions which comprises admixing 3-dimethyl- amino-7-methyl-l,2-(n-propylmalonyl)-l,2-dihydro- 1,2,4-benzotriazine and at least one of a factor of Vitamine P and/or (+)-2-(3,4-dihydroxyphenyl)-3,5,7- chromanetriole and optionally one or more antibiotics and/or trace elements and/or vitamines to excipient (s), carrier(s), diluent(s) conventionally used in the preparation of pharmaceutical compositions and transfor- ing the obtained mixture into a pharmaceutical composi¬ tion in a known manner. 9» A process as claimed in Claim 8 which comprises applying a water soluble rutine derivative, preferably 3' »4*,7-tris (ji-hydroxyethyl)rutoside, as a factor of Vitamine P. 10. A process as claimed in Claims 8 or 9 which comprises applying 60 to 300 mg. of 3-dimethylamino-7- methyl-1,2-(n-propylmalonyl)-l,2-dihydro-l,2,4-benzo- triazine per dosage unit. 11. A process as claimed in any of Claims 8 to 10 which comprises applying 60 to 300 mg. of a factor of Vitamine P and/or (+)-2-(3,4-dihydroxyphenyl)- 3,5,7-cromanetriole per dosage unit. 12. A process as claimed in any of Claims 8 to 11 which comprises applying 3-dimethylamino-7-methyl- 1,2-(n-propylmalonyl)-l,2-dihydro-1,2,4-benzotriazine and a factor of Vitamine P in a weight ratio of 2 : 1 to 1 : 1. 13. A process as claimed in any of claims 8 to 12 which comprises applying 3-dimethylamino-7- methyl-1,2-(n-propylmalonyl)-l,2-dihydro-l,2,4-benzo- triazine in a weight ratio of 2 : 1 to 1 : 1. 14• Method for treating pancreatic inflamma¬ tions which comprises administering an effective amount of a pharmaceutical composition according to any of Claims 1 to 7.

Inventors: BACSA GYOERGY, BENE MAGDOLNA NEE HORVATH, HORVATH EVA, JANCSO SANDOR, KISS ILONA MARIA NEE LOOS, KOVACS ISTVAN, KUBALA MARIA NEE PAPP, MADI-SZABO LASZLO, MORVAI MARGIT, TAMASI PIROSKA, BACSA, GYOERGY, BENE, MAGDOLNA NEE HORVATH, HORVATH, EVA, JANCSO, SANDOR, KISS, ILONA, MARIA NEE LOOS, KOVACS, ISTVAN, KUBALA, MARIA NEE PAPP, MADI-SZABO, LASZLO, MORVAI, MARGIT, TAMASI, PIROSKA
Applicants: ALKALOIDA VEGYESZETI GYAR, BIOGAL GYOGYSZERGYAR, ALKALOIDA, VEGYESZETI, GYAR, BIOGAL, GYOGYSZERGYAR
Application year: 1984
Main classification: A61K31
IPC codes: A61K31