FR2527078A1 - ANTI-ULCER PHARMACEUTICAL COMPOSITIONS - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS ANTI-ULCER COMPOSITIONS. IT CONCERNS IN PARTICULAR NEW ANTI-ULCER OR ALTI-ULCER AND ANTI-INFLAMMATORY COMPOSITIONS WHICH CONTAIN A COMBINATION OF AN ANTI-ULCERIC AGENT OR OF A SALT OF SUCH AGENT WITH SALICYLIC ACID OR WITH AN ALKALINE METAL AND POSSIBLY A NON-STERANIC ANTI-INFLAMMATORY AGENT OR A SALT OF SUCH AGENT. AS ANTI-ULCER AGENT, CIMETIDINE OR RANITIDINE IS PREFERREDLY USED, WHILE THE PREFERRED NON-STERANIC ANTI-INFLAMMATORY AGENT IS INDOMETHACIN. THE NEW COMPOSITIONS ACCORDING TO THE INVENTION FREE OF KNOWN SIDE EFFECTS OBSERVED AS A RESULT OF THE SIMULTANEOUS ADMINISTRATION OF AN ANTI-ULCER AGENT AND OF A NON-STERANIC ANTI-INFLAMMATORY AGENT; IN ADDITION, THEY HAVE A SYNERGIC ACTIVITY AGAINST ULCERES.

Description

-1-

  The present invention relates to novel compounds

  In particular, it relates to novel pharmaceutical compositions containing two or more active ingredients that are effective against gastrointestinal ulceration and that, if desired,

  it can be used as anti-inflammatory agents.

  Since the description of H 2 receptor antagonists

  / -Nature 236, 385 (1962) 7, this new group of agents

  anti-ulcers has been subjected to experimental investigations

  In just a few years,

  cimetidine (N "-cyano-N'-methyl-N - / - 2 - (((5-methyl-1-H-

  imidazol-4-yl) -methyl) -thio) -ethyl 17-guanidine) has appeared on the market and has achieved unprecedented commercial success. In recent years, many new

  H 2 -receptor antagonists were prepared and studied.

  In recent years, since the introduction of cimetidine anywhere in the world, more than 1500 articles have been published concerning this agent. In experiments on rats, it has been demonstrated for example by P Del Soldato and others. J Pharmac 67, 33

  (1979) 7 that cimetidine can not prevent ulcer

  Indomethacin-induced bowel feeding Similar observations have recently been published by W S Mitchell et al. / Brit Med J 284, 731 (1982) 7 in human clinical practice It has been reported that

  simultaneous administration of cimetidine and

  methacine had resulted in the perforation of the ulcer in

the case of several patients.

  It is well known that gastrointestinal ulcer, which

  is a typical disease peculiar to civil

  more and more people among the

  patients with ulcers, there are many

  also suffering from inflammatory musculoskeletal disorders

  In such cases, the physician -2- must face a situation that is practically insoluble.

  because until now there is no pharmaceutical composition

  It is very likely that the simultaneous administration of an anti-ulcer agent and a non-steroidal anti-inflammatory agent may accelerate the development of the anti-ulcer agent.

perforation of the ulcer.

  The object of the present invention is to provide a

  pharmaceutical position devoid of these disadvantages and in which the activity of the active agent against

  ulcers is favorably increased, potentiated.

  It is known that a common undesirable side effect of non-steroidal anti-inflammatory agents

  is their ulcerogenic effect According to many

  cations, 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-

  indole-3-yl-acetic acid (indomethacin), 4-butyl-l, 2-

  diphenylpyrazolidine-3,5-dione (phenylbutazone), d-2- (6-methoxy-2-naphthyl) -propionic acid (naproxen), 3- (3-trifluoromethylanilino) nicotinic acid (niflumic acid)

  and acetyl salicylic acid have a secondary effect

  There are several methods by which

  The undesirable side effect of the above anti-inflammatory substances can be reduced. The Applicant's own experiments have shown that some reduction in side effects can be provided by some salicylates (British Patent No. 1,483,165), but it does not. there is no suggestion in the published technical literature to combine these agents with active ingredients against ulcers; on the contrary, it is generally indicated that salicylates have an undesirable effect on the gastrointestinal state (see for example: Aspirin and Related Drugs: Their Actions and Uses, KD Rainsford, K Brown, MW Whitehouse, Birckha User Verlag ,

  Basel and Stuggart 1977), although pharma-

  Recent studies have unambiguously demonstrated that sodium salicylate has a gastrointestinal cytoprotective effect (eg J Pharm 28, 655 (1976), Prostaglandins 21, Suppl 139 (1981)), it has also been reported that the gastrointestinal cytoprotective effect of sodium salicylate is unrelated to gastric acid secretion (Adv Physiol Sci, Vol 29, Gastrointestinal Defense Mechanisms,

  Pergamom Press Akademiai Kiad 6, Budapest, Hungary, 1981).

  The applicant has found that in a simultaneous administration of various anti-inflammatory agents, in particular indomethacin and cimetidine, the latter compound in a certain concentration range does not inhibit

  the intestinal ulcerogenic effect of anti-inflammatory agents

  inflammatory conditions, but rather facilitates this

  As a result, it was not foreseeable that the administration of a certain dose of salicylic acid or salicylate as an additional constituent

  completely eliminate this unwanted side effect.

  The present invention is based on the surprising discovery that a combination of anti-ulcer agents

  known with sodium salicylate has an anti-

  ulcers more important, ie synergistic, than cimetidine alone, and at the same time, when using combinations of three types of active ingredients, the

  undesirable side effects of anti-

  non-steroidal inflammatory drugs can also be avoided.

  The invention relates to a pharmaceutical composition which contains 0.1 to 10 parts by weight of salicylic acid

  or an alkali metal salt of this acid and optionally

  0.01 to 1 part by weight of an anti-inflammatory agent

  non-steranic material or a corresponding salt for 1 part by weight of an anti-ulcer active ingredient in admixture with conventional pharmaceutical vehicles

and / or other additives.

  According to a preferred embodiment of the invention, there are provided compositions containing cimetidine or ranitidine as an anti-ulcer agent.

  (N- / 2 - "((5- (dimethylamino) -methyl-2-furanyl) -methyl)

  thio) -ethyl) -N'-methyl-2-nitro-1,1-ethylenediamine) or

  propantheline (N, N-diisopropyl-N-methyl-2-xanthene

  9-carbonyloxy) -ethyl-ammonium-hydroxide) or gastrixone (methyl tropinester acid hydrochloride)

  xanthene-9-carboxylic acid) or zolimidine (2- (p-methyl)

  sulfonylphenyl) imidazo / T, 2-7-pyridine).

  According to a further preferred embodiment of the invention, the pharmaceutical compositions contain

  as a non-steroidal anti-inflammatory agent of

  methacin, naproxen, phenylbutazone, acid

  acetylsalicylic acid or niflumic acid.

  A preferred composition according to the invention may, for example, contain from 0.1 to 1 part by weight of sodium salicylate and optionally from 0.01 to 1 part by weight of indomethacin per 1 part by weight of cimetidine, or from 0, 01 to 1 part by weight of sodium salicylate for 1

  part by weight of cimetidine, mixed with vehicles

  conventional compounds and / or other additives.

  The invention also relates to a method for preparing

  a novel pharmaceutical composition, wherein 0.1 to 10 parts by weight of salicylic acid or an alkali metal salt thereof is mixed and, if desired, 0.01 to 1 part by weight an agent

  non-steroidal anti-inflammatory drug or salt

  laying, preferably indomethacin, naproxen,

  phenylbutazone or acetylsalicylic acid or d-

  niflumic acid or a salt of these compounds with 1 part by weight of an anti-ulcer agent or a salt thereof, preferably cimetidine, ranitidine or propantheline or gastrixone or zolimidine or a salt of these compounds, with also vehicles and / or other additives conventionally used in the

  preparation of pharmaceutical compositions.

  According to a preferred embodiment of the present process, 1 part by weight of cimetidine is mixed with 0.1 to 1 part by weight of sodium salicylate and conventional vehicles and / or additives, or 0.1 mixture is mixed. 1 part by weight of sodium salicylate and 0.1 to 1 part by weight of indomethacin with 1 part by weight of cimetidine and conventional carriers and / or other additives, or 1 part by weight of ranitidine is mixed with 0.1 to 10 parts by weight of sodium salicylate and conventional vehicles and / or other additives. Experimental Methods 1) Indomethacin-induced intestinal ulceration in Hannover-Wistar rats, not deprived of food, each weighing

  -150 g, a dose of 15 mg / kg of

  methacine in a suspension of Tween 80 so as to cause a fatal intestinal ulceration

  tested was administered immediately after treatment.

  indomethacin, also by the oral route.

  To evaluate the development of small intestinal ulcers, the tensile strength of the intestinal wall has been determined by the so-called swelling technique. Pharm Pharmac 27, 867 (1975) 7, because erosion caused by ulcerogenesis leads to The animals were sacrificed 48 and 72 hours, respectively, after treatment with indomethacin by narcosis with ether The small intestine from the pylorus to the caecum was removed with caution , its first end was ligated while the other end was connected to an electronic recorder W + W BP Recorder 8005 (Ugo Basile, Italy) using a polyethylene tube The whole small intestine was placed in a solution saline

252? 078

  The pressure, expressed in millimeters of Hg, is defined as the tensile strength at 370 ° C. and the pressure is increased until air bubbles appear at the weakened areas of the intestinal wall. the progress of intestinal ulceration caused by indomethacin, the tensile strength of the intestinal wall, called

  resistance of the intestinal wall, decreases

  gressively as shown in Figure 1.

  2) Gastric necrosis caused by absolute alcohol Gastric necrosis was caused by alcohol-acid, by the modified method of Robert et al. / Gastroenterology 77, 433 (1979) 7 Female Hannover-Wistar rats , each weighing 120-150 g, were put on a diet for 24 hours.

water ad libitum.

  The compounds to be tested were administered by

  oral 30 minutes before administration of the alcohol-acid.

  The alcohol-acid (HCl ratio: absolute ethanol = 1: 50 v / v) was administered orally by a cannula at a dose of 0.5 ml per 100 g of body weight Two hours later, the animals were killed by a high dose of ether The stomachs were removed and opened along their major curvature ethanol-induced lesions are located on the body of the stomach in the form of multiple linear tissue hemorrhagic bands necrotic The lengths of the lesions were measured and expressed in mm and the total length of the lesions of each stomach was calculated. The severity of the lesions was expressed as the average total length of the lesions per stomach. Cytoprotection of the stomach has been

  expressed by comparison with control animals.

  3) Secretion of gastric acid in Shay rats The tests were carried out according to the method of Shay et al. / Gastroenterology 5, 43-46 (1945) 7 Rats -7-

  Wistar females, each weighing 120-150 g, were used.

  The ligation of the pylorus was carried out under ether anesthesia after diet for 24 hours.

  treated with the compounds to be tested intra-

  peritoneal, immediately after surgical intervention Oral treatments were carried out minutes before the operation Animals were killed 4 days after pylorus ligation After stomach extension, the volume of gastric juice was was measured and the concentration of HCl was determined by titration against 0.01 N NaOH in the presence of phenolphthalein as an indicator The amount of acid was expressed in gmoles per 100 g of body weight Statistical evaluation of the results The first part of the experiments determined the optimal ratio of cimetidine / sodium salicylate by

  intestinal ulceration caused by indometha-

  (10 mg / kg) and the secretion of gastric juice on the

  Shay's rats could be inhibited.

Table 1

  Inhibition of intestinal ulceration caused by indomethacin after simultaneous administration of combinations of cimetidine-sodium salicylate in different ratios Treatment n Dose mg / kg by the mouth Tensile strength Resistance of the wall of the small intestine, 48 intestinal in percent hours after treatment versus animals in mm Hg untreated Indimethacin (Ind) Cimetidine (Cim)

Ind + Cim.

  Ind + Cim + Salicylate of Na Ind + Cim + Salicylate of Na Ind + Cim + Salicylate of Na <0.01 with respect to Xp

+ 100

+ / 100 + 10 /

+ / 100 + 25 /

+ / 100 + 50 /

  group xxp <0.01 compared to the group

Ind + Cim.

untreated

231 + 4

111 + 10

227 + 1

63 + 11

157 + 28

158 + 19

213 + 7

  48 xx 27 xx 68 x 68 x 94 X I lm I P & r ru CD 'N o - ce

Table 2

  Inhibition of gastric acid secretion by cimetidine and various combinations of cimetidine with sodium salicylate in Shay H rats Cl / 4 hours Inhibition of treatment N Dose 4 moles / 100 g HCl mg / kg production bwt SEM in percent Control 10 457 55 Cimetidine (Cimet) 10 50 163 41 65 Cimet + Salicylate of Na 10 50 + 10 172 32 63 x Cimet + Salicylate of Na 10 50 + 25 40 28 93 XX Cimet + Salicylate of Na 10 50 + 50 150 42 68 x xp Xp XX P <0.01 compared to the control <0.01 compared to the cimetidine group 50 mg / kg l% O l tn co

Table 3

  In a test for gastric necrosis caused by absolute alcohol, sodium salicylate is cytoprotective even in combination with cimetidine Treatment Salicylate Na Salicylate Na Salicylate Na Salicylate Na Cimetidine (Cim) Cim + Salicylate Na Cim + Na Cim Salicylate + Na Salicylate Cim + Na Salicylate Dose n mg / kg mouth 4 8 16 32

8 + 4

16 + 8

32 + 16

64 + 32

  Cytoprotection as% combination x 58 x 94 x 41 x 82 x 93 x Observations

ED 50 5.9

  ED 50 by A Robert mg / kg Prostaglandins Suppl 21, 1981, p 139-146

ED 50 30

  this contains: mg sodium salicylate According to the published technical documentation, cimetidine is not protective in this test (Hagel et al: Gastroenterology, 82 N 5 Suppl 2, 1078, 1982; Soldato P Del: Boll Chim Farm 120, No. 11, 631-638, 1981) xp <0.01 o CD ## STR1 ## * ye

Table 4

  Intestinal ulcer after repeated treatment (three consecutive days) with indomethacin, cimetidine and a combination of cimetidine and Na salicylate (2: 1) Treatment n Dose mg / kg by the mouth Tensile strength of the small intestine , 24 h after the last treatment in mm Hg Mortality in

percen-

wall resistance

intestinal

  percent of value without treatment Without treatment (normal) 30 231 + 4 100 Indo & nthacine (Ind) 30 3 x 10 20 + 10 30 9 Cimetidine (Cim) 10 3 x 100 186 + 16 O 80 Ind + Cim 10 3 x (10 + 100) 9 + 15 50 4 Ind + Cim + Na Salicylate 2: 1 10 3 x (10 + 100 + 50) 225 + 6 O 97 x

x <0.01 with respect to the Ind group.

r Jla On r%) -.4 o i T

Table 5

  Inhibition of gastric acid secretion in pylorus ligation rats by treatment with cimetidine and a combination of cimetidine and Na salicylate (2: 1) Treatment N Dose HCl / Inhibition of mg / kg 4 hours production Observations by = moles / 100 g bwt HC 1,% mouth Blank test Sodium salicylate Sodium salicylate Cimetidine Cimetidine Cimetidine Cimetidine

25

50

15

25

50

100

425 23

420 47

381 75

378 55

327 50

259 62

  38 1 1

ED 50 = 54.4

l l l -.4 w

Table 6

  Inhibition of gastric acid secretion in Shay rats by treatment with a 2: 1 combination of cimetidine and Na salicylate Treatment N Dose H Cl / 4 hours production Treatment inhibition N mg / kg moles / 100 g bwt production Observations by + SEM of H Cl in% mouth

Blank test 9,435 + 36 -

  Cim + Salicylate of Na 10 6 + 3 316 + 45 28 Cim + Salicylate of Na 10 12 + 6 374 + 40 14 ED 50 = 35.6, Cim + Salicylate of Na 10 24 + 12 256 + 36 48 x which contains : Cim + Na salicylate 50 + 25 156 + 18 64 Cim = 23.8 mg Cim + Na salicylate 64 + 32 O 100 Salicylate of Na = 11.8 mg wx <0.1 with respect to blank test PN 0 i ra 1% .1 Co

Table 7

  Inhibition of indomethacin-induced fatal bowel ulceration after simultaneous administration of various antiulcer compounds Treatment Dose n mg / kg by the mouth Tensile strength of the small intestine, 72 hours after treatment, in mm Hg Resistance of the intestinal wall as% of value without treatment Percent mortality

No treatment 30 231 + 4 100 -

  Indomethacin (Ind) 26 15 66 + 13 28 x 20 Ind + Propantheline 10 15 + 20 48 + 10 21 x 20 Ind + Gastrixone 10 15 + 20 57 + 15 25 x '10

  Ind + Z Qlimidine 10 15 + 100 45 15 19 x -

  Ind + Cimetidine 9 15 + 150 47 + 10 20 x 10

  Ind + Ranitidine 10 15 + 50 100 20 43 x -

  xp <0.01 relative to the untreated group ra U r o o oe l ab l

Table 8

  Inhibition of intestinal ulceration caused by indomethacin after simultaneous administration of ranitidine and sodium salicylate Treatment N Dose Tensile strength of mg / kg small intestine 48 hours after treatment, mouth in mm Hg Pas of treatment 231 + 5 Ranitidine (Ran) 9 25 225 + 8 Indomethacin (Ind) 26 10 111 + 10 Ind + Ran 9 10 + 25 145 + 18 Lnd + Ran + Salicylate of Na 10 10 + 25 + 100 219 + 5 x vn I

x <0.01 with respect to the Ind group.

P Nr 0 A d) -4 o C_

Table 9

  Inhibition of intestinal ulceration caused by a dose of 15 mg / kg of indole

  oral methacine by simultaneous administration of sodium salicylate and various anti-ulcer agents Treatment Dose n mg / kg oral Tensile strength of the small intestine, 72 hours after treatment, in mm Hg Resistance of the intestinal wall in% of value without treatment No treatment (normal) Indomethacin (Ind) Ind + Propantheline (Prop) Ind + (Prop + Salic of Na) Ind + Gastrixone (Gas) Ind + (Gas + Salic of Na) Ind + Zilimidine (Zol) Ind + (Zol + Salic Na) x P xxp + 20

+ (20 + 100)

+ 20

+ (20 + 100)

+ 100

+ (100 + 100)

231 + 5

  66 + 1 OX 48 + 10 x O 211 + 6 xx 57 15 x 211 + 4 xx + 13 x 207 + 11 x 0.01 compared to untreated group 0.01 compared to indomethacin Mortality in

percen-

  size 28 x 21 x 91: xx X 96: xx 19 x 89 xx l 01% I "N tn

O -

  The results presented in Tables 1 and 2 show that the optimal ratio of cimetidine to

sodium salicylate was 2: 1.

  In Figure 1, there is shown over time intestinal ulceration caused by a dose of

mg / kg indomethacin.

  Table 3 shows that a 2: 1 combination of cimetidine and Na salicylate has a cytoprotective effect

  dose dependent against necrosis of the stomach

  evoked by absolute alcohol while cimetidine is not

not cytoprotective.

  As shown in Table 4, the intestinal toxicity of indomethacin was clearly apparent after repeated treatment for three consecutive days (3 x 10 mg / kg orally) and it was found that

  was 30% on the fourth day Simultaneous administration

  3 x 100 mg / kg oral cimetidine resulted in increased intestinal toxicity (% mortality) Simultaneous administration of 3 x (100 + 50) mg / kg of cimetidine and Na salicylate (2: 1) causes a blockage

absolute intestinal toxicity.

  One of the most important factors, gastric acid secretion, has been studied in detail by the use of Shay rats. The results are summarized in Tables 5 and 6 Both cimetidine and the combination of cimetidine and Na salicylate (2) : 1) have a dose-dependent inhibitory effect on acid secretion

  The ED 50 values for cimetidine and the combination

  doses of cimetidine and Na salicylate (2: 1) were 54.4 mg / kg intraperitoneally and 35.6 mg / kg intraperitoneally, respectively 35.6 mg of the combination of cimetidine and Na salicylate (2: 1) contained 23.8 mg of cimetidine and 11.8 mg of

  Sodium salicylate In combination, a dose of

  56% lower than cimetidine alone -18-

  produced the same secretion of gastric acid (50% 1.

  Sodium salicylate alone was in fact ineffective as a gastric acid inhibitor. The results were similar in the case of intraperitoneal and oral treatment, respectively. The results show that synergism exists between cimetidine and sodium salicylate, with relates to the inhibition of gastric acid secretion. From Table 7 it can be seen that the simultaneous administration of the anti-ulcer compounds tested can not block the fatal intestinal ulceration caused by indomethacin. According to the results presented in Table 8, a combination of ranitidine and sodium salicylate

  (25 + 100 mg / kg) results in complete inhibition of the ulcer

  intestinal diet caused by a dose of 15 mg / kg of indomethacin. The results obtained with combinations of various other anti-ulcer compounds and sodium salicylate are shown in Table 9. It can be seen that although the anti-ulcer compounds indicated in FIG.

  Table 7 are ineffective in isolation, in a combination

  with cytoprotective sodium salicylate can effectively block intestinal ulceration

caused by indomethacin.

  According to a preferred embodiment of the invention, a combination of 200 mg cimetidine and mg sodium salicylate in a tablet is used instead of sodium salicylate.

  salicylic acid or lithium salicylate.

  The pharmaceutical compositions according to the invention can be administered orally, rectally and / or parenterally, in a single daily dose or in several lower doses. For oral administration, the compositions are generally presented in the form of compressed tablets, preferably coated tablets, dragees or capsules The compositions for oral administration according to the invention generally do not contain an excipient, but, if desired, excipients such as lactose or starch can also be used. Examples of binders which may be used are gelatin, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or dextrin. As a disintegrating agent, mainly apple starch is added.

  earth or microcrystalline cellulose in the

  but it is also possible to use ultraamylopectin

  or formaldehyde-casein As a lubricant and

  Adhesive can be talc, colloidal silicic acid, calcium or magnesium stearate, etc.

  Tablets are prepared by conventional techniques.

  in the pharmaceutical industry, for example by granulation and subsequent compression The mixture of active ingredients and fillers and possibly a part of the disintegrating substances is granulated with aqueous, alcoholic or alcoholic aqueous binders in a suitable apparatus and the granules obtained are dried The dry granulate is then mixed with the other additives, for example disintegrating agents, anti-adhesives and lubricants, and the mixture is pressed

  tablets If desired, to facilitate the administration of

  Tablets may be coated with a gastric acid-resistant film, eg shellac, cellulose acetate phthalate or Eudragit-L (a registered trademark) using an alcoholic solution. The tablets may be prepared from a mixture of the active ingredients and the additives directly by compression and the tablets obtained may be coated with a film layer.

dissolving in the intestine.

  Drags can be prepared using various protective agents, flavoring agents and pigments used in

  conventional way in the preparation of pharma-

  such as sugar, cellulose derivatives (methyl or ethyl cellulose, sodium carboxymethylcellulose, etc.), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food pigments, food coloring shellacs, pigments of iron oxide, aromas, etc. Capsules can be prepared for example by filling a hard gelatin capsule with a mixture

  active ingredients and additives.

  For rectal administration, suppositories are prepared

  As a vehicle, vegetable fats are used

  such as hardened vegetable oils or triglycerides of fatty acids having 12 to 17 carbon atoms, preferably Witepsol (a registered trademark). The active ingredients are homogeneously distributed in

  the melt of vehicles and prepare the suppositions

by casting.

  For parenteral administration, injectable compositions are prepared. The active ingredients are

  dissolved in water or in organic solvents, possibly

  in the presence of mediators, for example from mono-

  polyoxyethylene laurate, monooleate or monostearate

  sorbitan (Tween-20, Tween-60 and Tween-80, respectively).

  As the organic solvent, it is possible to use, for example, lower aliphatic alcohols or glycol ethers, preferably ethylene glycol monoethyl ether, optionally in admixture with water.

  injectables may also contain various

  such as preservatives, for example benzyl alcohol, methyl ester and / or propyl of p-oxybenzoic acid, phenyl mercuriborate or benzalkonium chloride, or antioxidants, such as sodium pyrosulphate, ascorbic acid, tocopherol and optionally complexing agents for fixing traces of metals, for example ethylenediamine acid;

  tetracetic agents, and pH-control agents and buffer

  swimming, and possibly local anesthetics, by

example of lidocaine.

  The injectable solutions according to the invention are filtered before being used for filling ampoules and

  they are then subjected to sterilization.

  The invention will be further illustrated by the following examples, which are presented as an illustration,

  but not for limitation of the present invention.

* Example 1

  Cimetidine-sodium salicylate cimetidine tablets 200 mg sodium salicylate 100 mg magnesium stearate 3 mg polyvinylpyrrolidone 8 mg talc 12 mg potato starch 27 mg From the above materials, 350 mg tablets are prepared per tablet. The same activity is essentially obtained if, in the above composition, sodium salicylate is replaced by an equivalent quantity of another alkali metal salicylate, for example

lithium salicylate.

  Examples 2 to 16 In the following examples, the quantity and the quality of the additives are identical to those indicated in Example 1, with the exception of the active constituents and

  ingredients that are specified below.

  the preparation is the same as in Example 1.

-22-

Example 2

  ranitidine 50 mg sodium salicylate 100 mg potato starch 8 mg magnesium stearate 1 mg polyvinylpyrrolidone 3 mg talc 3 mg

Example 3

  propantheline 15 mg sodium salicylate 75 mg magnesium stearate 2 mg potato starch 8 mg polyvinylpyrrolidone 2.5 mg talc 2.5 mg

Example 4

  gastrixone 2 mg sodium salicylate 25 mg magnesium stearate 1 mg potato starch 1 mg polyvinylpyrrolidone 0.5 mg talc 0.5 mg

Example 5

  zolimidine 200 mg sodium salicylate 100 mg magnesium stearate 3 mg polyvinylpyrrolidone 8 mg talc 12 mg potato starch 27 mg

Example 6

  cimetidine 200 mg sodium salicylate 100 mg indomethacin 20 mg magnesium stearate 3 mg polyvinylpyrrolidone 8 mg talc 12 mg potato starch 27 mg -23-

Example 7

  cimetidine 200 mg sodium salicylate 100 mg naproxen 200 mg magnesium stearate 5 mg polyvinylpyrrolidone 3 mg potato starch 37 mg talc 15 mg

Example 8

  cimetidine 200 mg sodium salicylate 100 mg phenylbutazone 100 mg potato starch 40 mg talcum 12 mg polyvinylpyrrolidone 12 mg magnesium stearate 4 mg

Example 9

  cimetidine 200 mg sodium salicylate 100 mg aspirin 200 mg potato starch 40 mg talc 20 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg

Example 10

  cimetidine 200 mg sodium salicylate 100 mg niflumic acid 200 mg potato starch 40 mg talc 20 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg

Example 11

  ranitidine 50 mg sodium salicylate 100 mg -24- indomethacin 20 mg potato starch 15 mg polyvinylpyrrolidone 6 mg talc 6 mg magnesium stearate 3 mg

Example 12

  ranitidine 50 mg sodium salicylate 100 mg naproxen 150 mg potato starch 25 mg talcum 10 mg polyvinylpyrrolidone 10 mg magnesium stearate 5 mg

Example 13

  ranitidine 50 mg sodium salicylate 100 mg phenylbutazone 100 mg potato starch 14 mg talcum 6 mg polyvinylpyrrolidone 8 mg magnesium stearate 2 mg

Example 14

  ranitidine 50 mg sodium salicylate 100 mg aspirin 200 mg potato starch 30 mg talcum 10 mg polyvinylpyrrolidone 8 mg magnesium stearate 2 mg

Example 15

  ranitidine 50 mg sodium salicylate 100 mg niflumic acid 200 mg potato starch 30 mg 3 E talc 10 mg -25- polyvinylpyrrolidone 8 mg magnesium stearate 2 mg

Example 16

  propantheline 15 mg sodium salicylate 150 mg indomethacin 20 mg potato starch 15 mg talc 5 mg polyvinylpyrrolidone 4 mg magnesium stearate 1 mg

Claims (7)

  Pharmaceutical composition characterized in that it comprises from 0.1 to 10 parts by weight of salicylic acid or of a salt of this acid and optionally from 0.01 to 1 part by weight of a non-inflammatory anti-inflammatory agent. -steranic for one part by weight of an anti-   ulcers or a salt of such an agent.   2 A composition according to claim 1, characterized in that the total content of active ingredients is between 10 and 90% by weight relative to the total weight of the composition, mixed with vehicles and / or other additives used in a manner conventional in the preparation of pharmaceutical compositions. A composition according to claim 1,   characterized in that it comprises as an anti-   ulcers of cimetidine or ranitidine or   propantheline or gastrixone or zolimidine.   A composition according to claim 1,   characterized in that it comprises as an anti-   non-steroidal inflammatory nature of indomethacin or   naproxen or phenylbutazone or acetyl-   salicylic acid or niflumic acid.   Anti-ulcer pharmaceutical composition, characterized in that it comprises from 0.1 to 1 part by weight of sodium salicylate per 1 part by weight of cimetidine in combination with vehicles and or other additives known in the art.   Pharmaceutical composition, characterized in that it comprises from 0.1 to 1 part by weight of sodium salicylate and from 0.01 to 1 part by weight of indomethacin per 1 part by weight of cimetidine, in combination with vehicles and or other additives known in the art. Pharmaceutical anti-ulcer composition, characterized in that it comprises from 0.1 to 10 parts by weight of sodium salicylate per 1 part by weight of ranitidine, mixed with vehicles and / or other additives known in the art. Process for the preparation of a pharmaceutical composition, characterized in that a mixture of 0.1 to 10 parts by weight of salicylic acid or of an alkali metal salt of such an acid is prepared and optionally 0 , 01 to 1 part by weight of an anti-inflammatory agent   non-steroid for 1 part by weight of an anti-   ulcers or a salt of such an agent with vehicles conventional and / or other additives.   A process according to claim 8, characterized   in that as an anti-ulcer agent   tidine, ranitidine, propantheline, gastrixone or zolomidine or a salt thereof and as an optional non-steroidal anti-inflammatory agent indomethacin, naproxen, phenylbutazone, acetylsalicylic acid or niflumic acid or a salt of these compounds.   A method according to claim 8, characterized   in that from 0.1 to 1 part by weight of salicy-   sodium for 1 part by weight of cimetidine.   A process according to claim 8, characterized   in that from 0.1 to 1 part by weight of salicy-   sodium and 0.01 to 1 part by weight of indometha   for 1 part by weight of cimetidine.   A process according to claim 8, characterized   in that from 0.1 to 10 parts by weight of salicy-   sodium per 1 part by weight of ranitidine.