DD209735A5 - METHOD FOR THE PRODUCTION OF A NEW MEDICAMENT PREPARATION - Google Patents

Abstract

The invention relates to a process for the preparation of a new drug composition. The new drug composition is suitable for the healing of ulcers in the gastrointestinal tract and can also be used as an antiperspirant. The aim of the invention is to provide a new composition which compensates for the ulcer-producing effect of known antiperspirant substances. It is characteristic of the new composition of the medicament that it contains an anti-ulcer substance or its salt in an amount of 1 part by weight, salicylic acid or its alkali salt in an amount of 0.1-10 parts by weight, and that for the preparation of As an anti-ulcer substance, the drug composition preferably contains cimetidine or ratinidine or propantheline or gatrixone or zolimidine, as a non-steroidal antiperspirant substance preferably indomethacin or naproxen or phenylbutazone or aspirin or niflumic acid.

Description

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Process for the preparation of a novel pharmaceutical preparation Field of application of the invention

The invention relates to a process for the preparation of a novel pharmaceutical preparation. The novel pharmaceutical composition is suitable for the healing of peels in the gastrointestinal tract and can also be used as an anti-inflammatory agent.

Characteristic of the known technical solutions

With the discovery of ^ receptors in the stomach (Nature 236, 385 (1962)), a new chapter in the research and therapeutic application of compounds suitable for the control of ulcers began. "A few years later, the oimetidine (uf-Oyano-H ') appeared. methyl-N- {2 - (/ 75-methyl-1-H-imidazol-4-yl / -methyl7- "^ b- ⁱ -o) -ethyl} -guanidine), which has enjoyed unprecedented market success to date · Numerous new Hg receptor antagonists have been produced and tested in clinical trials ·

With the Oimetidin deal wide-ranging research. For example, P · Del Soldato u. a * that small bowel ulcers induced with indomethacin on batten can not be cured by treatment with oimetidine (Br. J. Pharmac., 6, _9, 33 (1979)). Di® animal studies have recently also been obtained by clinical data (W, S. Mitchell et al.: Brit. Med. J. 284, 731 (1982)) * The authors report that when cimetidine and indomethacin are given concomitantly, ulcer perforation occurred in several patients.

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It is well-known that the new disease of civilization, the gastro-intestinal ulcer, torments more and more people. Among the patients, whose number is increasing, there are numerous cases in which the patient is simultaneously affected by inflammatory diseases of the locomotor system or such degenerative origin suffers. The attending physician faces a practically unsolvable problem because there is currently no drug combination known which is effective for the condition in question, but does not have the undesirable side effects. The patient is treated with a combination therapy consisting of an anti-ulcer and a non-steroid anti-inflammatory agent. With this double treatment there is a serious risk that the anti-inflammatory substance will accelerate the perforation of the ulcer.

It is known that the non-steroidal anti-inflammatory substances have a common lifting effect if they produce ulcers. "According to numerous references, the 1- (p-chloro-benzoyl) -5-metho-2-methyl-indol-3 ~ yl ~ acetic acid (hereinafter indomethacin), 4-butyl-1,2-diphenyl-pyrazolidine-3-dione (hereinafter phenylbutazone), d-2- (6-methoxy-2-naphthyl) -propionic acid ( in the following naproxen), the 2- (3-trifluoro-methyl-anilino) -nicotinic acid (hereinafter »niflumic acid) and the acetylsalicylic acid a side-effect causing ulcer · Various methods are used to reduce this unpleasant side effect of the anti-inflammatory substances · So from own researches (British Patent No. 1,483,165) that the undesirable side effect is reduced by certain salicylates. However, the possibility of a combination with anti-ulcer substances has hitherto not been considered; on the contrary, in

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Most monographs emphasize that certain salicylates undesirably alter the proportions of the gastrointestinal system (see, for example, Aspirin and Related Drugs ι Their Actions and Uses, KD Rainsford, Κ · Brune, MW Whitehouse, Birkhäuser Verlag, Basel and Stuttgart 1977) Although the cytosensitive activity of the sodium salicylate in the gastric tract has been clearly demonstrated in recent years (for example, J. Pharm. Pharmao., 28, 655 (1976), Prostaglandins 21, Suppl (1981)), but publications are also known that the gastrointestinal oytoprotective effect of Natriumsalicylates is unrelated to the acid secretion (Adv. Physiol * Sei, Vol. 29 · Gastrointestinal Defense Mechanisms · Pergamon Press - Akademiai Eiad6 , Budapest 1981).

In its own experiments with simultaneous administration of indomethacin and cimetidine, it has been found that in certain concentrations the cortical effect of indomethacins is not only not inhibited by cimetidine but even facilitated.

Object of the invention

A further object of the invention is to effectively potentiate the basic action of the currently known active ingredients against ulcers. A further object of the invention is to provide a drug combination with which the aforementioned harmful effect can be eliminated.

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Explanation of the essence of the invention

The invention has for its object to find suitable components and suitable amounts for a drug composition with the desired properties »

According to the invention, unpleasant side effects are completely suppressed by salicylic acid or salicylate used as a second component in a specific dose.

The invention is therefore based on the surprising finding that the combination of known anti-ulcer substances with sodium azoylate shows an unexpected synergistic effect in the inhibition of acid secretion, or that in the case of a combination of three components, the unpleasant side effect of non-steroidal anti-inflammatory substances can be suppressed ·

The invention therefore relates to a drug combination comprising an anti-ulcer substance or its salt in an amount of 1 part by weight, salicylic acid or its alkali metal salt in an amount of 0.1-10 parts by weight for the preparation of pharmaceutical preparations commonly used excipients, excipients and adjuvants and desirably contains a non-steroidal anti-inflammatory substance or its salt

As an anti-ulcer drug, the combination of drugs of the invention preferably contains oimetidine or kanitidine (N- {2- (Z "*" / "" 5 - "" / dimethylamino / -methyl-2-furanyl)

-methyl-.2 ~ nitro- * 1,1-ethylenediamine)

2 5 O 9 t 3

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or propanteline (N, N-diisopropyl-N-methyl-2 -> (xanthene-9-carbonyl oxy) -äthylamiixmiumhydroxyd) or gastrixone (xanthene-9-carboxylic acid-tropinester-methyl-hydroxyd) or zolimidine ( 2- (p "methylsulfonylphenyl) imidazo ^ T ^ .a / pyridine)

As a non-steroidal anti-inflammatory agent, the drug combination according to the invention preferably contains indomethacin or naproxen or phenylbutazone or acetylsalicylic acid or niflumic acid *

The erf indungsgemäße drug combination may, for example 1 part by weight iPeil Gimetidin, 0.1 to 1 part by weight of sodium salicylate and the customary extenders ~ and / or excipients or 1 wt --a _e) eil cimetidine, O _S 1 - 1 wt Part of sodium salicylate, 0.01 to 1 part by weight of indomethacin and the usual extenders and / or auxiliaries or 1 GeW ₀ -EeU ranitidine, 0.1 to 10 parts by weight of sodium salicylate and the usual extenders and / or auxiliaries contain.

The invention also relates to a process for the preparation of the novel drug combination. The process is characterized in that one part by weight of an anti-ulcer agent or its salt, preferably oimetidine or ranitidine or propanteline or gastrixone or zolimidine or the salt of one of compounds listed, 0 ₉ 1 - 10 parts by weight of salicylic acid or its alkali metal salt, di © customary for the preparation of pharmaceutical preparations, extenders, carriers and / or auxiliary substance and, if desired © 0.01 to 1 G © w ~ _e part of a non- steroids of antiinflammatory substance or its salt, preferably indomethacin or naproxen or phenylbutazone or acetylsalicylic acid or niflumic acid or the salt of one of the listed compounds mixed together

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According to a preferred embodiment of the erfiadungsgemä Ben-process are 1 wt _e ~ eil ever tried g cimetidine ₉ 0.1 - 1 part by weight sodium al icy 1 at and the customary extenders ",, carriers and / or Hllfsstoffβ, or

1 Geviu part cimetidine * 0 ₉ 1 - 1 weight part of sodium _e ~ al toyl at from 0.1 to 1 wt * -part indomethacin and the customary extenders · »* excipients and / or adjuvants ₉ or

_S 1> Part Raaltidin "0 - - 10 wt _s parts by sodium salicylate and the usual extenders, carriers and / or excipients mixed with each 1 percent _e

1 · Examination of the small intestine triggered by Indom@tb.acin. gesGhwürs

Noxious .Hannover-Wistar rats (wieibl ") were administered in the form of a suspension with Tw 30 in order to form a intestinal ulcer-5 sig / g of indomethacin. The substances to be tested were also administered orally immediately after the indomethacin. the visual assessment of .Darmgeschwüren. · 'holds .zahlreiche possible errors in it, so was aur quantitative evaluation of ulcers the so-called. inflation method (J "Pharm" Pharmao · 2 _£? 867 (1975)) applied "the evaluation is done as dermaßens the animals are killed by Ithernartosis _f the small intestine is carefully removed »The one Efode is tied off, and the other end connected via a polyethylene cannula to a device that inflates the intestine and registers the pressure (eg BaSiIe ₉ W + W 'electronic BP Hecorder 8.005) "V® £ bowel is placed warm saline in 37 O ⁰ and the pressure increased allmählioJi" When tensile strength of the intestinal

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wall is that pressure considered (Torr), wherein the Darruwand breaks or will appear in the physiological saline bubbles "With the progress of the induced by indomethacin Gesohwürbildung the tensile strength of the Darmwandj d _e decreases fcu the intestinal" andresistena (s _e Fig * 1) » the animals were 48 _s or 72 hours after treatment with indomethacin killed. "

2 » Examination of by. Alcohol-induced gastric necrosis

The term gastrointestinal cytoprotectin has been described by Bobert et al. e. (Gastroenterology 21 $ ^ 33 (1979)) Introduced in the Preparation of Alcohol Necrosis Test. Female Honnover-Wistar rats of 120-150 gm g / ioht were cultured for 24 hours and watered only. To induce gastric necrosis, the animals were decontaminated with 0.5 ml / 100 g of body weight, $ ® alcohol was administered by gavage * The substances to be tested were orally administered 30 minutes before the alcohol killed "the stomach entferntj was cut along the greater curvature and stretched after gently washing" the length of the longitudinal n@krotiscb.en strip was measured and the length of the attributable to ea'jien stomach average lesion in mm ₀ is calculated relative to the value of Control animals gives the value of ifiagencytoprotection.

3 * Study of gastric acid secretion on Shay-Katten

The investigations were carried out according to the method of Shay et al. (Gasteroenterology, 43-46 (194-5)) "Female rats weighing 120-150 g were exposed for 24 hours.

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hungry and then ligature under mild thyroid © her pylorus ligated · Immediately thereafter, the substances to be tested were administered intraperitoneally The oral treatment was performed 30 minutes prior to the procedure. Four hours after the pylorus had set, the animals were killed. The volume and pH of the gastric secretion were measured after removal of the stomach. The HGl content was titrated with 0 _s 01 η NaOH against phenolphthalein. The amount of the acid is given in yUMol / 100 g body weight For the statistical evaluation of the results, the t * * sample after student consulted «ν:: ''. , ,

The evaluation of the examination results

In the first part of the investigations it was clarified which ratio between gimetidine and ITa-SaIiCyI at at least 10 mg / 3cg indomethacin-induced ulceration in the small intestine was prevented. The data of Table 2 show that the ratio between .Ceflefldin and Ha-salicylate at 2 ι 1 has its optimal value »For the following experiments, this mixing ratio was applied«

Figure 1 shows the time course of the ulcer disease of the small intestine triggered by a dose of 10 mg / kg indomethacin.

It can be seen from the data in Table 3 that the mixture of cimetidine and Na-salicylate applied at a ratio of 2 $ 1 has a clearly dose-dependent gastrointoprotective action against abscess-induced gastric necrosis, whereas gimetidine does not have such an effect.

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When the animals were given cimetidine at a dose of 100 mg / kg together with indomethacin at a dose of 10 kg / kg (both active substances po) (on three consecutive days), as shown in Table 4, a 50th % mortality due to bowel perforation · This means that treatment with oimetidine does not abolish but even potentiates the gastrointestinal toxicity of indomethacin. By administering 100 mg of ciidinol-t-50-ing sodium salicylate per 100 kg of body weight, on the other hand • the gastrointestinal toxicity of indomethacin was fully compensated for> the tensile strength of the intestinal wall (225 torr) is close to normal ·

Tables 5 and 6% show very important experimental data. They show how the gastric acid secretion of so-called shay rats is influenced by cimetidine, by sodium salicylate or by the mixture applied in the ratio of 2 s -1.

The inhibitory effect of Na salicylate is insignificant at the dose tested. »Oimetidine and salimetidine inhibit acid secretion dose-dependent The calculated BDcQ values for cimetidine were 5 ^, 4 mg / kg i * pa _S ^ Ur salimetidine 35.6 mg / kg In the combination administered in a dose of 35-6 »s, the gimetidine content was $ 23 8 mg, the estest consisted of Ca-salicylate, and a 50% inhibition of acid secretion is in the combination 56 % less oimetidine required «This proves that the .2. ι 1 combination of cimetidine and ITa-salicylate in the inhibition of acid cerebral «; syn: syn@rgj.smus Similar results were obtained when the animals were orally treated with cimetidine or salimetidine 30 minutes before the procedure *

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Table 7 shows that the compounds tested against ulcers could not eliminate the intestinal ulcer-inducing effect of indomethacin. In Table 8, the 15 mg / kg P * o. Indomethacin-induced intestinal ulceration completely suppressed by the combination of eanitidine and Ha-salicylate (25 + 100 mg / kg). Table 9 shows in summary the effect of treatments combined with Ha salicylate. It is evident that the anti-ulcer compounds in Table I? indomethacin-induced ulceration in the intestine is not capable of inhibiting it, but its combination with the cytoprotective ÜTa ^ Säücylat this Hernmwirkung has *

According to a preferred Ausfübjcungsform of the method according to the invention is made as an anti-ulcer © tablets containing 200 mg of oimetidine and 100 mg Ha "salicylate. The salicylate component can also be added in the form of salicylic acid or lithium salicylate «

The veterinary combination according to the invention can be administered orally, rectally and / or parenterally once a day or divided into several smaller divided doses. Werden.Tabletten for oral administration ,, expediently with a felt cover ₉ tablets provided dragees or capsules prepared * The orally administrable erfindungsgemäßen.Arzneimittelpräparate generally do not contain fillers, however, may optionally be used as fillers lactose or starch. " _S are used as binders or granulating can ζ ", B ₉ gelatine., Oarbpxymethyloellulose-Natriiim, methylcellulose, polyvinylpyrrolidone or starch paste used as disintegrants are primarily potato

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starch or microcrystalline cellulose in question, however, can auob. Ultra amylopectin, formaldehyde casein, etc. are used. As anti-adhesive substances and GMtmittel talc, colloidal silica, stearin ₉ calcium and magnesium stearate, etc., are used.

The tablets can z. B. be prepared by wet granulation and subsequent pre-pressing. The active substances and fillers mixed together and optionally a part of the disintegrating agent are granulated with the aqueous, alcoholic or aqueous-alcoholic solution of the binders in a suitable granulating device. The granules are dried and then mixed with the disintegrating agent, the lubricant and the antiadhesive auxiliaries. The mixture is compressed into tablets. "To facilitate the dosage, the tablets may be provided with a graduation mark. Optionally, the tablets may be coated with a gastric acid-resistant film which comprises, for example, the alcoholic solution of shellac, preferably the solution of shellac prepared with isopropanol. Cellulose acetate phthalate or Eudragit L (protected trademark of a film former) is also formed. The tablets may also be prepared by directly pre-pressing the mixture of the active ingredients and suitable excipients, and optionally with an intestino-olived Film coating be provided ·

The tablets may, if desired, with the usual in the pharmaceutical industry substances such as protective, Aromabzw ,, dyes z, B * sugar, cellulose derivatives (methyl or ethyl cellulose, carboxymethyl cellulose, etc.), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food colorants, food color lacquers , Iron oxide pigments, flavors etc. ", to be coated with sugar"

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For the production of capsules, the mixture of active ingredients and auxiliaries is filled into hard gelatine capsules.

For rectal administration suppositories are produced. As a carrier used vegetable fats, z. B. Hardened vegetable oils or triglycerides of fatty acids having 12- 18 carbon atoms, preferably protected under the name Witepsol (Erägerstof f e · The active ingredients are homogeneously distributed in the molten carrier mass and poured into molds to suppositories.

For parenteral administration, the drug combination according to the invention is formulated into injection solutions. For their preparation, the active ingredients optionally together with solubilizers, eg. B ₀ Plyoxyäthylensorbitanmonolaurat, monooleate or monostearate (Tween 20, Tween 60, Tween 80) in distilled water and / or organic solvents, z ₉ B "lower aliphatic alcohols or glycol ethers, preferably in Äthylenglycolmonoäthyläther, dissolved · The injection solutions can also different auxiliary agents, such · B _e - preservatives such as benzyl alcohol, p-Oxybenzoesäuremethyl- or propyl, or benzalkonium chloride PhenylmerGuriborat | Furthermore, antioxidants such. B # ITatriumpyrosulphate, ascorbic acid, tocopherol and optionally complexing substances such as ethylenediaminetetraacetic acid, substances for adjusting the pH, buffer substances and optionally local anesthetics such as lidocaine, for binding metal traces.

The injection solutions containing the active compound combination according to the invention are filtered into ampoules before being filled and sterilized after filling.

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embodiment

The preparation of the medicament preparations according to the invention is explained in more detail by the following examples. The examples do not limit the scope of protection.

Example 1 Cimetidine sodium salicylate tablets

Oimetidin 200 mg Natrum alioy 1 at 100 mg magnesium stearate 3 mg Polyvinylpyrrο1idon 8 mg talc 12 mg potato starch 27 mg

From the above substances, by wet granulation and subsequent pressing, the drug is prepared in the form of tablets of 350 mg weight. In the manner described, tablets can also be prepared using another alkali metal salicylate, eg, lithium salicylate.

Examples 2 to 16 Other combinations

The procedure is as described in Example 1, but using the substance combinations given below,

Example 2 50 mg Kanitidin 100 mg Na-salicylate 1 mg Mg stearate 8 mg Strength 3 mg PVP 3 mg talc

165

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Example 3

Propanteline 15 mg

Na salioylate 75 mg

Mg stearate 2 mg

Starch 8 mg

PVP 2.5 mg

Talc 2.5 mg

100 mg Example 4 Gastrixon 2 mg Na Salioylat 25 mg Mg stearate 1 mg Strength 1 mg PVP 0.5 mg talc 0.5 mg 30.0 mg Example 5 zolimidine 200 mg Na Salioylat 100 mg Mg stearate 3 mg PVP 8 mg talc 12 mg Strength 27 mg

350 mg

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Example 6

Oimetidine 200 mg

Na salicylate 100 mg

Indomethacin 20 mg

Mg-Stöarat 3 mg

PVP 8 mg

Talcum 12 mg

Starch 27 mg

370 mg Example 7 cimetidine 200 mg Na-salicylate 100 mg naproxen 200 mg Mg stearate 5 mg PVP 3 mg Strength 37 mg talc 15 mg 560 mg Example 8 cimetidine 200 mg Na-salicylate 100 mg phenylbutazone 100 mg Strength 40 mg talc 12 mg PVP 12 mg Mg-St ear at 4 mg

470 mg

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Example 9

Cimetidine 200 mg

Ha salicylate 100 mg

Aspirin 200 mg

Starch 40 mg

Talc - 20 mg

PVP 15 mg

Mg stearate 5 mg

5BO mg Example 10 Gimetidin 200 mg Ha-Salloylat 100 mg Hifluminsäure 200 mg Strength 40 mg talc 20 mg PVP 15 mg Mg stearate 5 mg 580 mg Example 11 ranitidine 50 mg Na-SaI ioyl at 100 mg Indbmethaoin 20 mg Strength 15 mg PVP 6 mg talc 6 mg Mg-St © arat 3 mg

200 mg

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Example 12

Ranitidine 50

Na salicylate 100 mg

Naproxen 150 mg

Starch 25 mg

Talcum 10 mg

FVP 10 mg

Mg-otearate 5 mg

350 mg Example 13 ranitidine 50 mg Na-salicylate 100 mg phenylbutazone 100 mg Strength 14 mg talc 6 mg FVP 8 mg Mg stearate 2 mg 280 mg Example 14 ranitidine 50 mg Na SaI icy 1 at 100 mg aspirin 200 mg Strength 30 mg talc 10 mg PVP 8 mg Mg stearate 2 mg

400 mg

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Example 15

 Raaitldin. 50 mg

Na salioylate 100 mg

Niflumic acid 200 mg

Starch 30 mg

Talcum 10 mg

PTP 8 mg

Mg stearate 2 mg

400 mg Example 16 Propontelin 15 mg Na salioylate f 150 mg indomethacin 20 mg Strength 15 mg Talc ^ VJ! PVP 4 mg Mg stearate 1 mg

350 mg

Table 1s

Inhibition of intestinal ulcer indexing effect when treated with combinations of cimetidine and salicylate Na in differentiated ratio

treatment

η dose tensile strength of the

mg / kg p »o · Small intestine 48 hours after treatment (Sforr + S _a Resistance of the intestinal wall in % of the hormonal value

untreated

indomethacin

Oimetidin

Indometh · + Oimetidine

30 26

9 10

Indometh.sup. + (O.sub.i.sup. + L.sup.Ta.sup.-Sal) 10 Ind.sup. + (O.sub.Met. + K.sup.a-Salicylate) 10 Ind. + (Cimetate + Ua-Salicylate) 10

10

100

10 +

10 + (100 H-10)

10 + (100 + 25)

10 + (100 + 50)

231 ± 111 + 227 + 63 +

157 +

158 + 218 +100 48 98 27 68 68 94

^x p <0.01, based on the untreated group? ^X2C ρ < 0.01

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Table 2: Inhibition of gastric acid secretion on Shay-Hatten by treatment with oimetidine and sodium salicylate in different ratios

Treatment η dose of HCl production in 4 hours Inhibition of the <

1 · ρ · per 100 g body weight, in H'Cl production *

control + Ha salicylate 10 50 50 457 + 55 cimetidine + Na-salicylate 10 50 + 10 163 + 41 cimetidine + tta-salicylate 10 50 + 25 172 + 32 Oimetidin 10 + 50 4P + 28 Oimetidin 10 150 +42

ρ < 0.01 based on the control © P <0 »01 based on the cimetidine-treated group

65 ^. G

^x - I

93 68

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Table 3 s

The cytoprotective effect of B "a-salicylate in combination with cimetidine in absolute alcohol-induced gastric necrosis

treatment

η dose of cytoprotection in % mg / kg p " _e (total Eomp = 100 %)

comment

Ha saliylate Ha-SaI icy lab

Na-Saicylate IT a ~ salicylate

Oimet * + Na-Salioylate Cimet * + Ha-Salicylate Cimet ₉ + Na-Salicylate Cimet * + Ua-SaI icylate

10 4 ν Α 10 8th + 8 10 16 + 16 10 32 + 32 10 8 H 10 16 10 32 10 64

_Λ by A. Rober 15 ibs / ^ p

prostaglandins

Suppl. 21, 1981 p. 139 -

SD ₅₀ =

(containing 10 mg of Ha salicylate)

Cimetidine is not cytoprotective according to references in this article (Hagel and Gastroenterology, 82, Ho. 5, Suppl. 2, 1078 (1982). Soldatos Boll. Chim. Form. 120, Ho. 11, 631-638 (1981)

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Table 4:

treatment

Intestinal ulceration on treatment with indomethacin and various combinations (treatment on three consecutive episodes, evaluation 24 hours after the last treatment)

ώ dose mg / kg

Tensile strength of intestinal wallj Torr

Resistance of the Morta-Dannwancl in % of the normal *%

untreated (normal) 30 ca ^ V 10 231 ± 4 indomethacin 10 j s iodo 20 + 10 Gimetidin 10 3 x (10 ^: + 100) 186 16 Indo + Clmetidine 10 3 x (10 + 100 + 50) 9 15 Ind * ' ¹ + Gimet * + Ha ~ Salic « 10 225 + 6

100

9 80

30

'S.

ρ <0.01 relative to the indomethacin-treated group

Table 5?

treatment

The inhibitory effect of Oimetidine and Ha-Salioylate on the gastric acid secretion of Shay Eatten under intraperitoneal treatment

Control Ka-Salicylate Na-Salioylate Gimetidine Oimetidine Gimetidine Oimetidine

η dose

mg / kg i.p.

40 5 5

10

10

10

25 50

15

25

50

100 HCl production in inhibition of the remark 4 hours, μmol / 100 g HGl production body weight %

425 + 23 420 + 47 381 + 75 378 + 55 327 + 50 259 + 62 140 + 38

O 11 12 33 39 67

ED ₅₀ * 54 _S 4

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Table 6:

The Hemnra "ir of the 2 % 1-Koinbination of Oimetidin and Na salicylate in different doses on the gastric acid secretion of Shay-Batten

treatment η dose HGl production in Inhibition of comment ι N (J mg / kg i.p · 4 hours yumol / 100 g. HCl production SD__ - 35.6 ro C body weight production, % containing _s M control 9 - 435 + 36 _ 23.8 mg Cim * u. O Cimet. + Ha-Salic. 10 6 + 3 316 + 45 28 11> 8 mg Na SaIi, Cimet. + Ua-Salio. 10 12 + 6 374 + 40 14 Cimet · + Ha-SaIic » 10 24 + 12 256 + 36 48 ^x Cimet. + Na-Salic. 20 50 + 25 156 +18 64 * Cimet · + Na-Salio · 5 64 + 32 0 100

ρ <O ₉ OI relative to the control

(X) CO

Table? S

The course of intestinal ulcer disease provoked by 15 mg / kg p.o.indomethacin with concomitant treatment with various ulcer-active compounds

treatment

η dose mg / kg Tear resistance of small intestinal wall resistance 72 hours Small intestinal wall after treatment in % of (torr) control

mortality

untreated control Indomethacin (Ind ·) Inde + Propantheline Ind * + Gastrixon Ind. + Zolimidine Ind. + Oimetidine Ind · + Banitidine

ρ <0.01 based on the control

30 »Β 15 231 + n- 26 15 η 66 + 13 10 15 - 48 + 10 10 15 ι 57 + 15 10 15 - 45 + 13 9 15 - 47 + 10 10 100 + 20 l · 20 l · 20 h 100 h 150 h 50

100

28 ^x 21 ^x 25 ^X

19 ^X

20 ^X

43 ^x

20 20 10

10

Table 3: Indomethacin inhibition of intestinal ulcer-producing activity by treatment with a combination of eanitidine and efatrium salicylate

treatment

η dose

mg / kg ρ _β θβ

Tensile strength of the small intestine 48 hours after treatment (Torr)

untreated control 30

Ranitidine (Ran «) 9

Indomethacin (Ind.) 26

Ind · + Kan »9

Ind + Ban + Ha-Salic # 10

25

10

10 +

10 + 25 + 100

231 ± 5 225 ± 8 111 + 10 145 + 18 219 + 5 ³

ro

ρ <0.01 relative to the indomethacin-treated group

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Table 9ί

The course of the intestinal ulcer disease provoked by 15 mg / kg ρ · ο · indomethacin with concomitant treatment with combinations of Na salicylate and various anti-ulcer compounds

treatment

Dose Tensile strength of mg / kg po · Small intestine 72 hours after treatment (ODorr) Resistance of mortar wall% in% of % control

untreated control 30

Indomethacin (Ind.) 26

Ind. + Propantheline 10

Ind. + (Prop. + Ha-3alicO 10

Ind. + Gastrixon 10

Ind. + (Gas. + Na-salic.) 10

Ind. + Zolimidine 10

Ind. + (ZoI. + Na-Salic.) 10

15

15 +

15+ (20 + 10O)

15 +

15+ (20 + 10O)

15 + 100

231 ± 66 ± 10 ^x 48 + 10 ^X

211 +

37 + +

221

+

15+ (100 + 10O) 207 ±

xx

100 - ^28x 20 ^21x 20 25 * 10 ₉₆ xx MM " 19 ^x - 89 ² ^

χ ρ <0.01 based on the untreated control xx ρ <0.01 relative to the indomethacin-treated group

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Claims (4)

Erfindungsanspruoh Characterized in that 1 part by weight of an active substance or its salt, preferably gimetidine or ranitidine or propantheline or gastrixone or zolimidine or the salt of one of the compounds listed, 10 wt -iEeile _a salicylic acid or its alkali metal salt, the customary for the preparation of pharmaceutical preparations, extenders, carriers and / or auxiliaries and, if desired, 0.01 to 1 wt "part of a non-steroidal anti-inflammatory substance or its salt, preferably ₉ indomethacin or naproxen or phenylbutazone or acetylsalicylic acid or niflumic acid or the salt of one of the listed compounds mixed together » 2 »Method according to item 1, characterized in that one part by weight of gimetidine, 0.1 to 1 part by weight of sodium salicylate and known stretchers, carriers and / or auxiliaries are mixed together. 3 "Process according to item 1, characterized in that 1 part by weight of oimetidine, 0 ₉ 1 - 1 part by weight of sodium salioylate, 0.1-1 Ge? J _s portion indomethacin and known stretching, carrier and / or excipients mixed together » 4. The method according to item 1 _9, characterized in that one part by weight of ranitidine, 0 ₉ 1 - 10 parts by weight, sodium salicylate and known excipients, carriers and excipients mixed together «