IL101739A - Pharmaceutical compositions comprising alginic acid and a metal compound for use in the treatment of gastroenteritic diseases wounds and burns as well as a hemostatic agent - Google Patents

Description

1017.39/2 i πα rn^nm ia>U3 vnwvi ΠΏΠΏ nmDirn ΓΡΓ^Ν nsnin π^ 3ηπ ηιηρπ n yan mn 7 ΙΥΙΡ πτκα i nvnai π^α ,o"ym Pharmaceutical compositions comprising alginic acid and a metal compound for use in the treatment of gastroenteritic diseases, wounds and burns as well as a hemostatic agent VSESOJUZNY NAUCHNO-ISSLEDOVATELSKY INSTITUT MEDITSINSKIKH POLIMEROV, The present invention relates to medicine, more specifically, to the preventive treatment and cure of diseases of the gas ro.enteritxc tract, surface skin injuries and burns and also as a hemostatic.

Factors which influence the function of the upper and lower sections of the gastroe.nteritic tract are rather wide. Λ number of reasons of a genetic, physiological, ecological and psychogenic nature cause a great number of various diseases: gastritis, duodenitis, eso-phagitis, colitis, ulcer etc.

The causes of pathology of the gastroenteritic tract are disturbance of the nerve, hormone and local mechanisms of digestion. The general mechanisms of origin and development of a disease finally close up on the local mechanisms and the formation of a defect of mucous membrane is realized along the lines of dynamic relationship of two opposite factors: aggressiveness and protection. Aggressive forces are muriatic acid, pepsin, pathogenic microorganisms, biliary acids and certain medicaments (for example, corticosteroids, ace-tylsalicylic acid etc.); protective forces are represented by the resistance of mucosa; a layer of surface mucus, cell regeneration, a normal state of local blood flow, the protective action of some hormones and also by the alkaline reaction of saliva and pancreas juice. The disturbance of dynamic balance between these forces induces pathology. Therefore conservative treatment is directed to the removal of disbalance.

The pharmaceutical compounds used for treatment are as follows: the antagonists of histamine ^-receptors blocking liberation of an acid (popular cymetidi- 101739/2 - 2 - ne and ranitidine and also a retarded form of cymetidi- ne-neutronotn retard); antacids neutralizing a gastric juice excess acid; anticholinergics reducing acid secretion; prostaglandins which increase mucosa resistance and inhibit acid secretion; prokinet c agents whic increase mobility of the gastroenteritic tract.

Said agents pursue in the main the aim of suppressing the increased secretion. However, in many manifestations of erosive-ulcerative pathology a decisive factor is not increased secretion, but an inadequate protective function of a mucosa wall from the effect of aggressive factors.

A desire to isolate mucosa defects from the action of aggressive factors and a further development of pathology and also to promote restoration of the disturbed normal functions of the muc'ous membrane necessitates the emergence of cytoprotective agents.

Cytoprotective properties are intrinsic in the salts of iron, bismuth, aluminum and calcium, which salts demonstrate a binding effect causing, on application, colloids, extra-cell liquid, mucus, exudates and cell membranes to thicken due to dehydration and formation of the insoluble compounds of proteins, and along with this, the surface of defect is coated with a thin protective layer. Effective cytoprotective agents are the coordination compounds of bismuth and aluminum.

Howevnr, many cytoprotective agents have no bactericidal activity in relation to pyloric Campylobacters (PC) which are known to be one of -the aggressive factors influencing the origin and progress of erosive-ulcerative pathology. Experiments in vitro show 101739/2 - 3 -that PC produce mucolytic ferments and an urease ferment in a great amount that promotes separation of the appreciable amounts of ammonia on the cell surface, a factor that results in damaging the epithelial section of the stomach. Possibly the PC-caused inflammation of the mucus renders it vulnerable to the action of other aggressive factors which promote the progress of pathology. It is very difficult to destory PC, they can exist on the stomach mucosa for a long time.

The most effective cytoprotective agent having bactericidal activity with respect to PC in vitro and in vivo is a pharmaceutical composition in the form of a colloidal solution of tripotassiumdicytratobismuthate in an ammonia buffer at pH 10 that is known as a de-nol preparation (the prospectus of the firm "Cist-brocades", the Netherlands, 1985); in literature the preparation is often called a bismuth colloidal subcitrate.

Under the effect of gastric acid, bismuth precipitates in the form of a thin inorganic film consisting of basic chloride and bismuth citrate. A high affinity of these presipitates has been established with respect to the granulation and cicatricial tissues of the surface of defect on account of the chelate-forma-tion of bismuth with proteins. This being so, the damaged section of the mucous membrane is reliably protected from aggressive factors.

However, the specificity of the preparation is 3uch that the insoluble bismuth chelate with proteins forms only in an ulcer crater in close proximity to it, i.e., there occurs selective chelate-formation. Localization of FC is in the main the antral section of the stomach; PCs are absent in the ulcer crater and near it. Therefore, a de-nol preparation is effective only during intake with the subsequent quick restoration of infection, upon stopping taking the preparation, i.e. PCs are not completely killed. To all appearances this explains the use of the preparation in great doses; a general dose for a course of treatment is 13,5 g. Besides this, de-nol is used in combination with antibiotics for purposes of increasing efficiency of the killing of PCs, Employment of antibiotics causes known complications: adaptation (getting accostomed) , disturbance of microflora, side reactions and the like.

The erosive-ulcerative affections of the mucosa are not infrequently accompained by hemorrhage of different intensity. More often than not, the stopping of hemorrhages poses most serious problem and threatens the patient's life. Sometimes even a reduction of intensity of hemorrhage or temporary heraostasis (in case of impossibility of full hemostasis) helps to save a patient and replace the urgent operation, unfavourable to him, with an ordinary one.

Despite evident progress in the diagnostics and treatment of hemorrhages , a number of problems such as the determination of a degree of hemorrhage, the best time for therapy and option of adequate treatment remain unsolved.

Widely used are alginates in the capacity of a local, protective, medicinal and hemostatic agent, which reduce the time of coagulation of blood in vitro and in vivo, prevent hemorrhage from surgically operated wounds and promote the development of epithelium and formation of collagen fibres.

Known in the art is the use of a pharmaceutical composition as an aqueous solution of the sodium, potassium, ammonium and/or amine salt of alginic acid in the capacity of a local, protective, medicinal & hemostatic agent as applicable to the erosive-ulcerative diseases of the gastric-enteritic tract (Jp, A, 57-46920). This composition form an insoluble alginic acid at the place of hemorrhage or erosion under the action of gastric juice, thus covering the defect of mucosa and protecting it from aggressive factors, stopping a flux of painful impulses to the central nerve system, inhibiting the disintegration of tissues' and creating comfort conditions for the speediest healing of the defect.

However, such a protective coat forms only in acid media (pH 1 - 4) is not strong enough, as being formed on account of weak hydrogen bonds playing the role of a cross-linking agent and is not coupled with the defect surface of the mucous membrane. And as this is so, the composition is taken 3-5 times a day, and it is effective only in case of weak hemorrhages.

A bismuth alginate is used in the form of suspension (Pr, B, 1728M) for the treatment of ulcer, colitis, enterocolitis, dyspepsia and other gastrologic disturbances. However, the effectiveness of therapy-is manifest in case of the considerable doses of preparation.

Also known is the use of alginates as the healing stimulants of surface wounds and burns, for instance mixed Ca-Na-salt of alginic acid.

On the basis of a sodium alginate with the addition of ant septic there has been created a hemostatic aerosol preparation of the type used for the treatment of wounds (G.B, B, 1254534). However, this preparation makes it possible to stop weak and capillary hemorrhages.

The process described in Israel Patent No. 90513 is directed for preparing calcium alginate gel for food products and used for structurizing meat products by releasing said calcium salts encapsulated in gel.

In Israel Patent No. 69706 the pharmaceutical composition described is used in the treatment of prophylaxis of kidney diseases and is administered orally.

EP Application No. 48123 discloses a composition comprising, as opposed to the composition of the present application, an emulsifier and an oil apart from the alginic acid salts and di- or trivalent metal ions.

In the Japan laid-open Application No. 62-230731, a mixture of calcium salts and alginic acid salts is used for capsulating soluble drugs, bears no relevancy to our application.

As for the scientific papers, J. of Food Science, 54:5, 1336-1340 (1989) deals with binding of calcium ions by an alginate of microbe nature, whereas Arzneim-Forsch. 40:7, 754-760 (1990) is concerned with an interaction study of iron salts and complexes with food products and medications.

The composition described in FRG Application No. 3,601,132 is based on polysaccharides and calcium salts and is characterized by a good adhesion to the mucous membrane but without any indication of retention time thereon.

- - It is the principal object of the present invention to obtain a pharmaceutical composition by qualitatively and quantitatively selecting components, which would possess simultaneously bactericidal activity with respect to pyloric campilobacters and the properties of a hemostatic agent, ensuring with small doses and short- time effect the formation on the surface of mucosa defects, skin wounds and burns of a reliable protective coating from the action of aggressive factors for a long period of time and high efficiency in treating the erosive-ulcerative affections of the gastro-enteritic tract, stopping hemorrhages and healing the surface wounds and burns.

The set task is solved owi-ng to the fact that proposed is a pharmaceutical composition for use in medicine which, according to the invention, contains algi- nic acid and/or its pharmaceutically acceptable salt and a metal compound selected from the group consisting of iron ammonium alum, iron glycerophosphate, iron lactate., reduced iron, basic bismuth nitrate, potassium alum, aluminum hydroxide, kaolin, barium sulfate, calcium gluconate, calcium carbonate and calcium chloride or a mixture thereof with the following ratio of components (wt. ): alginic acid and/or its pharmaceutically acceptable salt 5 - 91 metal compound The p-oposed pharmaceutical composition is intended for topical use on the defects of a mucous membrane and integuments. 101739/3 - Ί - : The composition assures a quick and stable effect of antiulcer therapy (curtails ^ime periods by 1,5- 3.5 times) that is accompanied by analgesic, spasmolytic and normalizing effects.

It displays a local hemostatic effect and is especially efficient in emergency cases with hemorrhages of different etiology, stable pain syndrome, stress and prolonged injuries.

The study of reaction of animal organisms and also pre-clinic tests testify to harmlensness of the composition. The pharmaceutical composition permits reducing the time of stay in hospital, considerably facilitating the pre-operation preparation of patients having acute gastroenteritic hemorrhages and avoiding hospitalization.

The composition is characterized by a synergistic effect of its ingredients which provides it with protective, bactericidal and hemostatic properties.

Unlike conventional antiulcer preparations, the proposed composition exhibits a pronounced prophylactic effect for the prevention of origination of stress ulcerative diseases.

The pharmaceutical composition of the invention forms at the place of the mucosa defect or integument a protective coat in the form of a gel v/ith prolonged action.

An excessive ratio of components in the proposed pharmaceutical composition changes its medicinal effect. An excess of alginates is going to violate a gel-forming process and deteriorate the quality of the obtainable protective coating. It quickly disintegrates, is low effective, requires a considerab- - 8 - le increase in the frequency of application, hence a marked increase in both single and general doses.

An excess of metal compound causes the composition to show only antacid and binding properties. Departure from the limits of any of the components sharply reduces the pronounced hemostatic effect.

The pharmaceutically acceptable salts of alginic acid in a pharmaceutical composition are represented by harmless sodium/potasaium/ammonium alginates.

In order to destroy pyloric campilobacters to the disinfection of a mucous membrane as effec ively as possible, it is advisable to use a pharmaceutical composition of the invention which comprises additionally methyl cellulose and/or carboxymethyl cellulose and having the following structure (wt. ): basic bismuth nitrate 30 - 70, sodium alginate 5 - 50, methyl cellulose and/or carboxymethyl cellulose 5 - 50.

Such a composition makes it possible to completely kill PC in case of the erosive-ulcerafcive affection of the mucosa with a simultaneous reduction of a dose of bismuth salt and a course of treatment, the improvement of the state of mucosa and also assurance of the minimum of possible therapeutic complications owing to the use of small doses of said bismuth salt and elimination of other antibacterial agents.

Said cellulose derivatives in the proposed composition serve the function of a hydrophylic addition and contribute to a quick and easy penetration underneath the mucus in the places of settlement of PCs.

Thus, one can manage to obtain, over a long period - 9 - of time, a high local concentration of the bismuth salt in said places* It is preferable that the proposed composition simultaneously with basic bismuth nitrate contain, for purposes of increasing a disinfecting effect, a metal compound - potassium alum* in an amount of from 20 "to 33 , 3% by weight.

Departure from the limits of the component ratio in the proposed pharmaceutical composition alters its disinfecting effect. An excess of sodium alginate and also the excess and lack of cellulose derivatives cause disappearance of said disinfecting effect , a ^ the excess of said basic bismuth nitrate contributes to efficiency with respect to PC only in case of use of the considerable doses of bismuth salt and a obligatory combination with antibiotics for a long period of time.

A composition of the invention is prepared by mixing powder-like alginic acid and/or its salt and a metal compound taken in a mass ratio of from 5-91 to 95-9. The powder is put in a can and sterilized.

On using the composition for eliminating PCs, the basic components of the mixture are added with methyl cellulose and/or carboxymethyl cellulose in an amount of from 5 to 50% by weight.

The composition of different formations were tested for hemostatic properties in the conditions of an experimental model and in a clinic and for retention of a protective gel coating on the stomach mucosa and on other organs. The composition containing the basic bismuth nitrate was tested on the "pure" PC cultures and in clinics in treating the erosive-ulcerative pathology and sanitation of the stomach mucosa.

The experimental investigations of the hemosta- - 10 -tic properties of a composition were performed on dogs , rabbits, rats and mice.

The main experimental study was carried out in acute and chronic tests on dogs, 3, 4 k . Premedication consisted in administering a promedol solution (1 -4 ml). Hexenal narcosis was used to perform laparotomy and then gastrotomy with the aid of a laser scalpel and laser clamps. To intesify bleeding, the dogs were administrated intravenously with 350 mg of heparin each. By using an ulcer-former on the stomach mucosa of each dog were applied 20 acute ulcers having a diameter of up to 0,5 cm: weak hemorrhage - 6 ulcers, average hemorrhage - 6 ulcers, heavy hemorrhage - also 6 ulcers; two control ulcers - heavy hemorrhage. For purposes of experimental study, use was made of application of a powder pharmaceutical composition of different formations. The time of stopping the bleeding was fixed by a stopwatch.

In a chronic experiment on dogs, use was on the mouth of the animals of the pincers, scissors or scalpel to apply small wounds of various sizes with compositions of different structure applied thereon Por modelling the hemorrhages of different intensity, the animals were subjected to starvation, immobilization and cooling.

The stability of a gel formed from a pharmaceutical composi ion of different structure was determined in a chemical laboratory. Model media imitating the acidity and ionic force of the physiological liquids of the gastroenteritic tract v/ere distilled water, an isotonic solution of sodium chloride (0,15 M aqueous solution of sodium chloride) and 0.1 N muriatic acid - 11 - (against the 0,15 M background of sodium chloride). These three liquid media cover the entire possible pH range.

The experiment was conducted in the following manner.

On polyethylene cups (the diameter and height of a cup are 15 and 1-2 mm, respectively, - the average size of an ulcerative defect) was applied a powder layer of the pharmaceutical composition of various formations in an amount of about 170 mg. The powder was wetted with 10 drops of acetone and pasted in even layers over the surface of the cup. Upon evaporation of acetone ( and as a result the thickening of the powder layer), the cup was lowered into a conic flask with a capacity of 100 ml that had preliminarily been filled with 25 ml of this or that model medium. The cups were maintained for about 1 hr and the conic flasks were then shaken by means of a shaker at a frequency of 600 min"1. The stability of a gel in model media was evaluated visually according to the time of preservation of the integrity of said gel in the absence of fragmentation.

The time of retention of the composition in the form of a gel in accordance with the invention on the mucous membrane of the stomach was determined according to the data of endoscopic examination.

The strength of adherence of said gel with the stomach mucosa was evaluated in an experiment on dogs (acute experiment) visually according to a 10 - point system with the gel mechanically removed by scraping off.

Table 1 shows the indices of properties of a gellike formed composition of different make-ups which were obtained in clinics, experiments on animals and in the model media. - 12 Table 1 Pharmaceutical composition Retent- Gel stabili- structure content, ion time ty in a mo- t.55 of a gel del medium, on sto- hr Sodium alginate 67,5 Iron ammonium > 5 days 120 120 120 alum 32,5 Sodium alginate 45,0 Iron ammonium > 5 days 120 120 120 alum 55,0 Sodium alginate 80,5 Iron ammonium > 5 days 120 120 120 alum 19,5 Sodium alginate 55,85 Glycerophosphate < 5 days 5-15 5-15 5-15 of Pe 44,15 Sodium alginate 87,3 2-4 5 5 Fe lactate 12,7 days Sodium alginate 25,64 Basic bismuth 2-3 1 1 10-12 nitrate 74,36 days Sodium alginate 40,0 Bismuth basic 1,5-2 1,5 1 24 nitrate 60,0 days - 13 - 2 3 4 5 6 7 Alginic acid 20,0 Bismuth basic - 5 2-3 nitrate 80,0 Alginic acid 26,6 Sodium alginate 26,9 1 ,5-2 8-10 8-10 8-10 Basic nitrate days (bismuth) 43 ·' Potassium algi- 40,0 nate Bismuth basic - 2,0 1 ,5 24 ' nitrate 60,0 Ammonium alginate 40,0 Bismuth basic " 1 1 24 nitrate 60,0 Sodium alginate 79,25 Aluminum hydro- 1-1,5 2,5 2,5 24 xide 20,75 dayS Sodium alginate 82,5 up to ^ -\ 5 Kaolin 17,5 1 day Sodium alginate 33,3 Bismuth basic nitrate 33,3 2-3 24 24 24 Potassium alum 33,3 days Sodium alginate 50,4 up to 3_ 3_4 5 Barium sulfate 49,6 2 days Sodium alginate 21,3 Bismuth basic nitrate 30,7 1-1,5 5 0 0 Calcium gluconate 48,0 days - 14 - 2 3 4 5 6 7 Sodium alginate 30,6 up to 6-8 0 6-8 Calcium gluconate 69,4 1 day Sodium alginate 12,7 up to 6-8 0 0 Calcium gluconate 87,3 1 day Sodium alginate 81,3 up to 2-2,5 2-2,5 5 Calcium carbonate 18,7 1 day Sodium alginate 78,3 up to 8-10 1-5 8-10 Calcium chloride 21,7 1 day Sodium alginate 2 hours 2 - 5,6 Sodium alginate 24,0 Bismuth basic nitrate 34,75 1,5-2 5 5 3 Calcium gluconate 27,0 days Barium sulfate 14,25 Sodium alginate 77,9 1,5 5 5 5 Reduced Pe 22,1 days Table 1 , continued Hemostatic properties Gel bond bleeding time of stopping strength with intensity the bleeding, sec. stomach mucosa, points 8 9 10 aver. 1 -35 10 aver. 15-35 7 aver. 15-35 7 - 15 - 1 8 9 10 4 aver. with multiple application 6-7 5 aver. with multiple application 5-6 6 aver. 10-20 5-6 7 aver 8 5-6 8 aver. with multiple application - 9 aver. with multiple application 5-6 10 aver. 10-15 5-6 1 1 aver. 10-15 5 12 aver. with multiple application 4-5 1 3 aver. with multiple application 4-5 14 aver. with multiple application 4-5 15 weak 10-30 4 16 aver. with multiple application 4 strong with multiple application ( 1 10 sec) 17 weak 20-30 2 18 weak 30-40 2 19 weak 20-40 2 20 weak 30-50 1 -2 21 weak 50-70 1 22 aver. 30-40 4-5 23 2-3 .

From the inspection of Table 1 , preservation of the gel on the stomach mucosa and in model media as well as its bond strength with the mucosa increase in a series of the cited formations of the pharmaceutical composition (with respect to metal compounds) in the following manner: Ca Experimental investigations show that the composition of said make-ups as proposed stops, in the experiment conducted on a preheparrized dog, weak and capilla- 101739/2 - 16 -ry hemorrhages with a single application. In case of mul tiple application, all formations lower bleeding intensity by 90%, transforming weak hemorrhages into average ones and the latter into weak hemorrhages. It has been found out that the best hemostatic properties belong to a composition consisting of a sodium alginate and bismuth basic nitrate (formation 7, Table 1). It stops the average bleeding on the pre-heparinized dog with a single application for 8 sec /as is the case with a laser beam. The time of residence of coating on the mucosa defect of varied in the range of 1 to 5 days.

The best adhesion of the formed coating to the mucosa was observed in the composition of formation 1 (Table 1). Such coating formed on the liver mucosa of a dog in the acute experiment was removed with great difficulty.

The pharmaceutical composition, in accordance with the invention, of formation 14 (Table 1) was used on upwards of 200 patients having the erosive-ulcerative affection of the gastroenteritic tract.

Through a catheter introduced into the biopsic channel of an endoscope, a composition is applied to the mucosa in aerosol form under visual control. Application: 1 g of a powder mixture in a session.

Already after the first application, there disappears generally a painful syndrome not relieved by other drugs. Under the protective cover, the defect is cleaned to create comfort conditions for healing-stimulation of metabolic - trophic processes, absence of rough cicatrization.

The composition is effective in protecting the mucosa of. the gastroenteritic tract and in preventing hemorrhage therein. 101739/2 - 17 - The composition of the invention, formulation 7 (Table 1 ) was used on 20 patients having nasal hemorrhages of different etiology. The results obtained show a high hemostatic effect: in all cases stable hemostasis set in the first minutes which did not require retreatment of the bleeding places.

The composition of formulation 7 (Table 1) was applied in the form of powder to the bleeding burn wounds (burns ShA - ShB degree over an area of 5 to 50 of the body surface), without causing any side reactions and complications. A burning sensation appearing in the patient's wounds is short-lived and is over for 20-40 sec, and the bleeding from the wound surface is stopped during 30-60 sec. During the subsequent bandaging, hemophilia of burn wounds drastically diminished and/or did not resume at all. No disturbance of the progress of a wound process was observed. There remained activity in the injuries and the independent restoration of integument.

The check-up of the composition on PC "pure" cultures was performed in the following manner.

PC cultures were separated on Belo-Horizonte media according to the generally accepted methods. To determine sensitivity of said PC cultures to the proposed pharmaceutical composition containing a bismuth basic nitrate, the material of 72-hour strains was washed off with a sterile phosphate buffer at pH 7,4 and diluted by it to an optical density corresponding to standard cloudiness per 10 units. The resulting suspension was applied to the surface of a control medium Belo-Hori-zonte and then gradually to the surface of samples of the same medium comprising 1, 10, 20, 40, 80 and 160 mg of the pharmaceutical composition in accordance 101739/3 - 18 - with the present invention and poured as a control sample ex tempore. Seeds were incubated at 37°G under an atmosphere of a conventional composition for .96 hours 'and the results were taken into consideration- 100% of the isolated cultures demonstrated sensitivity to 4· mg/ml of the proposed composition; 95% to 2 mg/ml; 95% to 1 mg/ml; 55% to 0,05 mg/ml. Also, 100% of the isolated cultures had resistance to a concentration of bismuth of 0,01 mg/ml.

For purposes of the clinical study of a possibility of said PC being; eliminated in case of erosive-ulcerative pathology and the therapeutic capability of a pharmaceutical composition containing a basic bismuth nitrate, it was diffused in the antral section of the patient's stomach.

And the composition is applied (0,6-0,8 g) having 0,2 g of the bismuth salt. A course of treatment is 4-8 sessions every other day. The total dose of bismuth salt was about 2 g and never exceeded 3 g« On endoscopic examination that is obligatory for the objective appraisal of effectiveness of therapy and for the confirmation of diagnosis, the degree of infection of the mucosa bioptate of the PC infected patient (field of vision, 630-multiple enlargement) and is characterized in the following fashion: "weak" or "+" with the presence of up to 20 micro-bic bodies; "moderate" or "++" - 20-50-' microbic bodies; "pronounced" or "+++" - over 50 microbic bodies.

A conclusion about the effectiveness of the composition and its therapeutic capability was made on the basis of an inflammatory degree of the mucous membrane biopatate before and after the course of treatment.

The therapeutic capability of the pharmaceutical composition in vitro was characterized by: - the presence of such an ability ("Yes") - suppre sion of initial infection in over 50 of the cases; - the absence of such an ability ("No") - suppression of initial infection in less than 20% of the cases Given below (Table 2) are the test results of a pharmaceutical composition comprising the different amounts of a bismuth basic nitrate, i.e. different formulations and efficiency, for the therapeutic capability and the inflammatory degree of the mucous membrane biopatate.

Table 2 Pharmaceutical composition Initi- Final Therap- structure content , eutic cap- al in- infect- t . ¾ ability feet, ion of biopatate 1 Bismuth basic nitrate 33, Yes +++ Sodium alginate 22,2 Methyl cellulose 11,1 Potassium alum 33,3 Bismuth basic 33,4 Yes +++ 0 nitrate Sodium alginate 11,1 Carb oxy e t hyl 22,2 cellulose Potassium alum 22,2 Bismuth basic 33,3 Yes +++ nitrate Sodium alginate 16,7 Carboxyme L"hyl 16,7 cellulose Potassium alum 33,3 1 2 3 .4 5 6 Bismuth basic 40,0 Yes +++ 0 nitrate Sodium alginate 20,0 Carboxyme thyl 20,0 cellulose Potassium alum 20,0 Bismuth basic 33,4 Yes +-(· 0 nitrate Sodium alginate 33,3 Methyl cellulose 33,3 Bismuth basic 50,0 Yes ++ 0 nitrate Sodium alginate 25,0 Methyl cellulose 25,0 Bismuth basic 30,0 Y&s + 0 nitrate Sodium alginate 40,0 Carboxymethyl 40,0 cellulose The concrete examples illustrating the treatment of patients having the erosive-ulcerative pathology of the gastroenteritic . tract with the use of the composition of formulation 5 (Table 2).

Example 1.

Patient S. , 17* Ulcerative disease with localization in the duodenum bulb, exacerbation of the disease at least twice a year. The size of ulcer defect 0,6 x 0,6 cm* The examination of the mucosa bioptate of the antral section reveals the pronounced degree of infection (PC) 101739/2 - 21 - (+++), 6 sessions of aerosol application were performed v/ith a single dose and a general dose of a bismuth basic nitrate (0,2 and 1,2 g, respectively). With control endoscopy carried out in the stomach mucosa bioptate no PC were found.

Example 2, Patient G. , 40. Ulcerative disease v/ith localization in the duodenum bulb. The 'size of ulcer defect is 1 ,0 x 1 , 0 cm, 8 sessions of aerosol application were performed with the single and general doses of a bismuth basic nitrate - 0,2 and 1,6 g, respectively. The initial infection of said bioptate was moderate (++), after a course of treatment no PC were found in the bioptate.

Example 3· Patient P. , 48. Ulcerative disease with localization in the duodenum bulb during 10 years, exacerbating twice a year. On endoscopic examination it had been established that the ulcer defect had a size of 1,0 x 1,0 cm, the degree of infection is v/eak (+). 5 sessions of aerosol application were performed on the mucosa of the antral section of the stomach. On control inspection no PC v/ere discovered.

The pharmaceutical composition as proposed comprises a bismuth basic nitrate, effectively kills PC in all places of colonization thereof, and reduces the time required for the ulcer scarring. It further permits reducing the therapeutic doses of bismuth salt by 4,5 times and eliminating antibiotics from treatment. The composition contributes to improvement of the state of the mucous membrane and drastic reduction of relapses. 101739/2 - 22 - The pharmaceutical composition for which patent protection is being sought exhibits a clearly pronounced universal nature of action - protective, prophylactic, medicinal , hemostatic and disinfective. It will find a wide variety of application in the different areas of medicine, in production and in every day life for treatment and disinfecting of the mucosa of the gastroenteri-tic tract and other defects of the mucous membranes and the surface of the skin, in gynecology and otolaryngology as well as in general surgery as a local hemostatic agent. 101739/3 - 23 -

Claims (8)

1. A pharmaceutical composition for use in the treatment of gastroen-teritic diseases, wounds and burns, as well as a hemostatic agent, characterized in that it comprises alginic acid and/or its pharmaceutically acceptable salt and a metal compound, selected from the group consisting of Fe ammonium alum, Fe glycerophosphate, Fe lactate, reduced Fe, bismuth basic nitrate, potassium alum, aluminum hydroxide, kaolin, barium sulfate, calcium gluconate, calcium chloride, calcium carbonate or a mixture thereof with the following ratio of components (wt. ) : alginic acid and/or its pharmaceutically acceptable salt 5 - 91 , metal compound the rest.

2. A pharmaceutical composition as claimed in Claim 1, c h a r a c t e r i z e d in that the pharmaceutically acceptable salt of alginic acid contained is represented by a sodium alginate, potassium alginate, and ammonium alginate.

3. A pharmaceutical composition as claimed in Claims 1 , 2, c h a r a c t e r i z e d in that it further comprises methyl cellulose and/or carboxymethyl cellulose and has a content (wt. ): bismuth basic nitrate 30 - 70, sodium alginate 5 - 50, methyl cellulose and/or carboxymethyl cellulose 5 - 50.

4. - A pharmaceutical composition as claimed in Claim 2, characterized in that the metal compound contained therein is potassium alum taken in an amount of 20 to 33.3% by weight. - 24 - 101739/3 1

5. A pharmaceutical composition according to any one of claims 1 to 4 for the preventive treatment and curing of gastroenteritic diseases.

6. A pharmaceutical composition according to any one of claims i to 4 for use as a hemostatic agent.

7. A pharmaceutical composition according to any one of claims 1 to 4 for the treatment of surface wounds and burns.

8. A pharmaceutical composition according to any one of claims 3 and 4 for killing PC (pyloric campilobacters) and therapy of the mucous membrane. For the Applicants,