GB2120938A - Anti-ulcer pharmaceutical compositions containing salicylic acid or its salts - Google Patents

Abstract

The invention relates to new anti- ulcer and anti-ulcer/antiinflammatory compositions and products, which contain an anti-ulcer agent or a salt thereof and salicylic acid or an alkali metal salt thereof optionally together with a nonsteroidal antiinflammatory agent. As an anti-ulcer agent preferably cimetidine or ranitidine is employed, while the preferred non-steroidal antiinflammatory agent is indomethacin.

Description

SPECIFICATION Anti-ulcer pharmaceutical compositions The invention relates to new anti-ulcer pharmaceutical compositions and a process for their preparation.

More particularly, the invention concerns new pharmaceutical compositions containing two or more active ingredients which compositions are effective against gastrointestinal ulceration and, if desired, may also contain anti-inflammatory agents.

Since the H2-receptor antagonists were first described, [Nature 236,385 (1962)1 this novel group of anti-ulcer agents has been subjected to extensive experimental and clinical investigations. Shortly afterwards, cimetidine (N"-cyano-N'-methly-N-[2-(((5-methyl-1 H-imidazolyl-4-yl)-methyl)-thio)-ethyl]- guanidine) appeared on the market and has been favourably received. In the past few years numerous new H2-receptor antagonists have been prepared and investigated.

During the last few years, since the world-wide introduction of cimetidine, more than 1500 articles have been published concerning this agent. In experiments on rats it has been demonstrated for example by P.

Del Soldato et al [Br. J. Pharmac. 67,33 (1979)] that cimetidine cannot prevent indomethacin-induced intestinal ulceration. Similar observations have recently been published by W.S. Mitchell et al [Brit. Med. J.

284,731(1982)] following human clinical practice. It has been reported that the concurrentadministration of cimetidine and indomethacin has resulted in perforated ulcers in the case of several patients.

It is well known that gastrointestinal ulcers, a typical disease peculiar to civilized communities, are occurring in more and more people. Among ulcerous patients there are numerous people suffering also from inflammatory or degenerative locomotor diseases. In such cases the medical attendant has to face a hitherto practically insoluble situation since until now no pharmaceutical composition was known in the art which could effectively be used under these conditions without serious side-effects. It is highly probable that the concurrent administration of an anti-ulcer agent and a non-steroidal antiinflammatory agent may accelerate the perforation of the ulcer.

It would thus be desirable to be able to provide a pharmaceutical composition which is devoid of these disadvantages and in which the activity of the anti-ulcer active ingredient is favourably increased, i.e.

potentiated.

It is known that a common, undesired side-effect of non-steroidal antiinflammatory agents is their ulcerogenic effect. According to numerous publications 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-ylacetic acid (indomethacin), 4-butyl-1 ,2-diphenylpyrazolidine-3,5-dione (phenylbutazone), d-2-(6-methoxy-2naphthyl)-propionic acid (naproxen), 3-(3-trifluoromethylanilino)-nicotinic acid (niflumic acid) and acetyl salicylic acid show an ulcerogenic side-effect. There are several methods by which the above undesired side-effect of antiinflammatory substances can be reduced.Our own experiments have showed that some reduction of side-effects can be achieved using certain salicylates (British Patent Specification 1,483,165) but there is no suggestion in the literature to combine these agents as anti-ulcer active ingredients; on the contrary, it is generally pointed out that the salicylates have an undesirable effect on the gastrointestinal condition (see for example: Aspirin and Related Drugs: Their Actions and Uses, K.D. Rainsford, K. Brune, M.W. Whitehouse, Birkhäuser Verlag, Basel und Stuttgart 1977). Though different pharmacological investigations, recently carried out, have demonstrated unambiguously that sodium salicyate has a gastrointestinal cytoprotective effect (e.g. J.Pharm. Pharmac. 28,655 1976); Prostaglandins21, Suppl. 139 (1981)), it has also been reported that the gastrointestinal cytoprotective effect of sodium salicylate has no connection with gastric acid secretion (Adv. Physiol. Sci., Vol. 29, Gastrointestinal Defense Mechanisms, Pergamon Press-Akadémiai Kid6, Budapest, Hungary, 1981).

We have found that in a concurrent administration of various antiinflammatory agents, particularly indomethacin, and cimetidine, the latter compound in a certain concentration range does not inhibit the intestinal ulcerogenic effect of the antiinflammatory agents, instead it facilitates this undesired action.

Accordingly, it could not be expected that the administration of a certain dose of salicylic acid or a salicylate as a further component would almost entirely suppress the undesired side-effect.

The present invention is based on the surprising discovery that a combination of known anti-ulcer agents with sodium salicylate has a more significant, i.e. synergistic, anti-ulcer effect than the anti-ulcer agent alone.

We have further found that when a non-steroidal antiinflammatory agent is added to such a combination, the undesired side-effects of the non-steroidal antiinflammatory agent can also be avoided.

According to one feature of the invention there are provided compositions comprising, as active ingredient, 1 part by weight of an anti-ulcer agent or a salt thereof and 0.1 to 10 parts by weight of salicylic acid or an alkali metal salt thereof. In one particular embodiment the active ingredient further includes 0.01 to 1 part by weight of a non-steroidal antiinflammatory agent or a salt thereof. If desired, the compositions may also contain carriers and/or other additives such as are conveniently used in the pharmaceutical industry.

According to a preferred embodiment of the invention there are provided compositions wherein the anti-ulcer agent comprises cimetidine, ranitidine (N-[2-(((5-(dimethylamino)-methyl-2-furanyl)-methyl)-thio)- ethyl]-N'-methyl-2-nitro-1 ,1 -ethylenediamine), propantheline (N,N-diisopropyl-N-methyl-2-(xanthene-9carbonyloxy)-ethylammonium hydroxide), gastrixone (xanthene-9-carboxylic acid tropinester methyl hydrochloride) or zolimidine (2-(p-methylsulfonylphenyl)-imidazo[1 ,2-a]-pyridine).

According to a further preferred embodiment of the invention the pharmaceutical compositions contain, as a non-steroidal antiinflammatory agent, indomethacin, naproxen, phenylbutazone, acetylsalicilic acid or niflumic acid.

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

Also preferred are compositions of 0.01 to 1 part by weight of sodium salicylate and 1 part by weight of cimetidine. The above compositions may additionally contain one or more conventional carriers and/or other additives.

In the compositions according to the invention the total active ingredient concentration preferably constitutes from 10 to 90% by weight of the total weight of the composition, the remainder consisting of carriers and/or other additives.

The invention further relates to a process for the preparation of these pharmaceutical compositions, which comprises mixing 0.1 to 10 parts by weight of salicylic acid or an alkali metal salt thereof with 1 part by weight of an anti-ulcer agent or a salt thereof, optionally together with 0.01 to 1 part by weight of a non-steroidal antiinflammatory agent and/or with carriers and/or with other additives.

According to a preferred embodiment of the process 1 part by weight of cimetidine is mixed with 0.1 to 1 part by weight of sodium salicylate optionally together with one or more conventional carriers and/or additives; or 0.1 to 1 part by weight of sodium salicylate and 0.1 to 1 part by weight of indomethacin are mixed with 1 part by weight of cimetidine optionally together with one or more 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 optionally together with one or more conventional carriers and/or other additives.

According to a further aspect of the present invention there is provided a pharmaceutical product comprising a first container containing salicyclic acid or an alkali metal salt thereof and a second container containing an anti-ulcer agent or a salt thereof in association with written or printed directions to administer the contents of the first and second containers concurrently in an amount of 0.1 to 10 parts by weight of salicyclic acid or salt thereof to 1 part by weight of anti-ulcer agent or salt thereof.If desired the product may further include a non-steroidal antiinflammatory agent such as described hereinabove in which case the directions will further indicate that the non-steroidal antiinflammatory agent be administered concurrently with the contents of the first and second containers in an amount of 0.01 to 1 part by weight of non-steroidal antiinflammatory agent to 1 part by weight of anti-ulcer agent or salt thereof. The anti-ulcer agent or salt thereof and the salicylic acid or alkali metal salt thereof, together with, if present, the antiinflammatory agent and/or any carriers and/or other additives, may either be admixed prior to administration or alternatively they may be administered to the patient immediately concurrently e.g. as tablets taken one after the other.

EXPERIMENTAL METHODS 1 ) Indomethacin-induced intestinal ulceration Non-fasted Hannover-Wistar rats, each weighing 120-150 g., were given a 15 mg./kg. dose of indomethacin in a Tween 80 suspension to induce fatal intestinal ulceration. The test material was administered immediately after the indomethacin treatment, also orally.

To evaluate the development of small intestinal ulcers, the tensile strength of the intestinal wall was determined bytheso-calledinflationtechnique [J. Pharm. Pharmac. 27,867 (1975)], because the erosion caused by ulcerogenesis leads to a weakening of the strength of the intestinal wall. The animals were killed 48 and 72 hours, respectively, after the indomethacin treatment by ether narcosis. The small intestine from pylorus to caecum was carefully removed and one end was ligated, while the other end was connected to a W+W electronic BP Recorder 8005 (Ugo Basile, Italy) through a polyethylene tube. The entire small intestine was placed into a physiological saline solution at 37"C and the pressure increased until air bubbles appeared at the weakened sites in the intestinal wall.This pressure, expressed in mmHg, is defined as the tensile strength (T.S.). Parallel with the progress of the indomethacin-induced intestinal ulceration the tensile strength of the intestinal wall, also called intestinal wall resistancy, gradually decreases as illustrated in Figure 1 of the accompanying drawings.

2) Abs. alcohol-induced gastric necrosis Gastric necrosis was induced by acidic-alcohol, by the modified method of Robert et al. [Gastroenterology 77,433 (1979)]. Female Hannover-Wistar rats, each weighing 120-150 g., were fasted for 24 hours. Water was allowed adllbitum.

Compounds to be tested were administered orally 30 minutes prior to acidic-alcohol administration.

Acidic-alcohol (cc. HCl :abs.ethanol= :50 v/v) was administered orally through a canula in a dose of 0.5 ml.

pro 100 g. of body weight, Two hours later the animals were killed by ether overdose. Stomachs were removed and opened along the major curvature. The lesions induced by ethanol are located at the corpus of the stomach as multiple linear hemorrhagic bands of necrotic tissue. Lengths of the lesions were measured and expressed in mm.-s and the total length of lesions of each stomach was calculated. Degree of lesion severity was expressed as the mean of total lesion-length per stomach. The stomach cytoprotection was expressed in comparison with the control animals.

3) Gastric acid secretion in Shay-rats The tests were carried out according to the method of Shay et al. [Gastroenterology 5,43-46 (1945)].

Female Wistar rats, each weighing 120-150 g., were used. Pyrolic ligation was performed under ether anaesthesia after twenty-four hours' fasting. The animals were treated by the compounds to be tested intraperitoneally, immediately after the surgical intervention. The oral treatments were performed 30 minutes priorto operation. The animals were killed 4 hours after pyrolic ligation. After extension of the stomach the volume of gastric juice was measured and HCI concentration was determined by titration against 0.01 N NaOh in the presence of phenolphtalein as indicator. The amount of acid was expressed in moles per 100 g. of body weight. The statistical evaluation of the results was performed by Student's test.

Evaluation of the experimental results By the above experiments the optimal cimetidine/sodium salicylate ratio, by which the indomethacininduced intestinal ulceration (10 mg./kg.) and the gastric-acid secretion on Shay-rats could be inhibited was determined.

TABLE 1 Inhibition of Indomethacin-induced intestinal ulceration after concurrent administration of combinations of Cimetidine-Sodium-Salicylate in different ratios Tensile strength of Resistance of Dose s.intestine, 48 hours intestinal wall mg.lkg. after treat. in inpercentof Treatment n p.o. mmHg untreated value Untreated 30 - 231 j4 100 Indomethacin(lnd.) 26 10 111 j 10 48xx Cimetidine (Cim.) 9 100 227 + 1 98 Ind. + Cim. 10 10+100 63 + 11 27xx Ind.+Cim.+Na-Salicylate 10 10+/100+10/ 157 + 28 68X Ind.+Cim.+Na-Salicylate 10 10+/100+25/ 158 + 19 68X Ind.+Cim.+Na-Salicylate 10 10+/100+50/ 213 t 7 94X xp < 0.01 compared with Ind.+Cim. group xxp < 0.01 compared with untreated group TABLE 2 Inhibition of gastric acid secretion bycimetidine and various combinations ofcimetidine with Na-Salicylate on Shay-rats HC1/4 hours Inhibition ofHCI- Dose cLmoles/100 g. production in Treatment n mg.lkg. bwt. + S.E.M. percent Control 10 - 457 + 55 Cimetidine (Cimet.) 10 50 163 + 41 65x Cimet. + Na-Salicylate 10 50 + 10 172 + 32 63x Cimet. + Na-Salicylate 10 50 + 25 40 t 28 93XX Cimet. + Na-Salicylate 10 50 + 50 150 + 42 68X < 0.01 compared with the control xxp < 0.01 compared with the cimetidine 50 mg./kg. group TABLE 3 In an abs. alcohol-induced gastric necrosis test Na-Salicylate is cytoprotective even in combination with cimetidine Dose mg.lkg. Cytoprotection in % Treatment n p.o. ofthe combination Remarks Na-Salicylate 10 4 35 ED50 = 7.9 Na-Salicylate 10 8 60X EE50 by A. Robert 15 mg./kg.

Prostaglandins Na-Salicylate 10 16 58x Suppl.21.1981.

Na-Salicylate 10 16 94X p. 139-146 Cimetidine (Cim.) Cim. + Na-Salicylate 10 8 + 4 5 ED50 = 30 Cim. + Na-Salicylate 10 16 + 8 41k this contains Cim. + Na-Salicylate 10 32 + 16 82x 10 mg. of sodium-salicylate Cim. + Na-Saiicylate 10 64 + 32 93X According to the literature cimetidine is not protective in this test (Hagel et al.: Gastroenterology, 82.No.5.

Suppl. 2. 1078, 1982; Soldato P.Del: Boll. Chim. Farm. 120, No.11,631-638. 1981) xp < 0.01 TABLE 4 Intestinal ulceration after repeated treatment (on three consecutive days) with Indomethacin, Cimetidine and combination of Cimetidine and Na-Salicylate (2:1) Tensile strength Resistance of ofs. intestine, intestinal Dose 24 hours after wall in per mg.lkg. last treat in Mortality in cent of un Treatment n p.o. mmHg percent treated value Untreated (normal) 30 - 2314 100 Indomethacin (Ind.) 10 3x10 2010 30 9 Cimetidine (Cim.) 10 3x100 18616 16 0 80 Ind. + Cim. 10 3 x (10+100) 9 + 15 50 4 Ind. + Cim. + Na Salicylate2::1 10 3x (10+100+50) 225 6 0 97X Xp < 0.01 compared with Ind. group TABLE 5 Inhibition of gastric acid secretion in pylorus-ligated rats by Cimetidine and combination of Cimetidine and Na-Salicylate (2:1) treatment Dose Inhibition mg.lkg. HCI output/4 hours of HCI Treatment n i.p. mol 100g. bwt. output% Remark Control 40 - 425 23 Sodium-Salicylate 5 25 420 t 47 0 Sodium-Salicylate 5 50 381 i 75 11 Cimetidine 10 15 37855 12 Cimetidine 10 25 327 50 33 ED50=54.4 Cimetidine 10 50 25962 39 Cimetidine 5 100 140 ~ 38 67 TABLE 6 Inhibition of gastric acid secretion in Shay-rats by treatment with a 2::1 combination of Cimetidine and Na-Salicylate Dose HCl output/4 hours HCl output mg.lkg. moll 100 g. bwt inhibition Treatment n i.p. + S.EM. in% Remark Control 9 - 435 36 Cim. + Na-Salicylate 10 6 + 3 316 j 45 28 Cim. + Na-Salicylate 10 12 + 6 374 + 40 14 ED50 = 35.6, Cim. + Na-Salicylate 10 24 + 12 256 j 36 48x which contains: Cim. + Na-Salicylate 20 50 + 25 156 j 18 64x Cim. = 23.8 mg.

Cim. + Na-Salicylate 5 64 + 32 0 100 Na-Salicylate = = 11.8mg.

Xp < 0.01 compared with the control TABLE 7 Inhibition oflndomethacin-induced fatal intestinal ulceration after concurrent administration of various anti-ulcer compounds Tensile strength Resistance of Dose ofs.intestine, 72 intestinal wall mg.lkg. hours after treat in % of un- Mortality Treatment n p.o. in mmHg treated value in percent Untreated 30 - 231 i4 100 Indomethacin (Ind.) 26 15 66 j 13 28X 20 Ind.+Propantheline 10 15+20 48 + 10 21X 20 lnd.+Gastrixon 10 15+20 57 i 15 25x 10 Ind.+Zolimidine 10 15+100 4515 19X Ind.+Cimetidine 9 15+150 47 +10 20X 10 Ind.+Ranitidine 10 15+50 100 20 43X < 0.01 compared with untreated group TABLE 8 Inhibition oflndomethacin4nduced ulceration after concurrent administration of Ranitidine and Sodium Sallcylate Dose Tensile strength of mg.lkg. s.intestine, 48 hours Treatment n p.o. aftertreat.in mmHg Untreated 30 - 231 i 5 Ranitidine (Ran.) 9 25 225 8 Indomethacin (Ind.) 26 10 111 j 10 Ind. + Ran. 9 10 + 25 145 + 18 Ind. + Ran. + Na-Salicylate 10 10 + 25 + 100 219 Xp < 0.01 compared with Ind. group TABLE 9 Inhibition ofintestinal ulceration induced by a 15 mg.kg. p.o. dose of indomethacin by concurrent administration of sodium-salicylate and various anti-ulcer agents Resistance of Tensile strength intestinal Dose ofs.intestine, wall in % of mg.lkg 72 hours after untreated Mortality Treatment n p.o. treat, in mmHg value in percent untreated (normal) 30 - 231 ~ 5 100 Indomethacin (Ind.) 26 15 66 ~ 10X 28X 20 Ind.+Propantheline (Prop.) 10 15+20 48 ~ 10X 21X 20 Ind.+(Prop.+Na-Salic.) 10 15+(20+100) 211 j6XX 91XX Ind.+Gastrixon (Gas.) 10 15+20 57 t 15X 25X 10 Ind.+(Gas.+Na-Salic.) 10 15+(20+100) 211 j4XX 96XX Ind.+Zolimidine (Zol.) 10 15+100 45 i 13X 19X Ind.+(Zol.+Na-Salic.) 10 15+(100+100) 207 t 11Xx 89M xp 0.01 compared with the untreated group xxp 0.01 compared with indomethacin The data set forth in Tables 1 - 2 show that the optimal ratio between cimetidine and sodium salicylate was 2:1.

In Figure 1 the time course of the intestinal ulceration induced by a 10 mg./kg. dose of indomethacin is illustrated.

Table 3 shows that a 2:1 combination of cimetidine and Na-Salicylate has a dose-dependent cytoprotective effect against abs.alcohol-induced stomach necrosis while cimetidine is not cytoprotective.

As set forth in Table 4 the intestinal toxicity of indomethacin was markedly apparent after repeated treatment on three consecutive days (3x 10 mg./kg. p.o.) and the mortality was found to be 30 percent on the fourth day. Concurrent administration of 3x 100 mg./kg. cimetidine p.o. resulted in a greater intestinal toxicity (mortality 50 %). Concurrent administration of 3x (100+50) mg./kg. of cimetidine and Na-Salicylate (2:1) p.o. results in an absolute blockade of intestinal toxicity.

One of the most important factors, the gastric acid secretion has been investigated in detail by using Shay-rats. The results are summarized in Tables 5 and 6. Both cimetidine and the combination of cimetidine and Na-Salicylate (2:1) have dose dependent inhibitory effect on the gastric acid secretion. The ED50 values for cimetidine and the combination of cimetidine and Na-Salicylate (2:1) were 54.4 mg./kg. i.p. and 35.6 mg./kg. i.p., respectively. The 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 cimetidine 56% less than that of cimetidine alone produced the same (50%) gastric acid secretion. Sodium salicylate alone was actually ineffective as a gastric acid inhibitor. The results were similar in case of intraperitoneal and oral treatment, respectively.The results show that a synergism exists between cimetidine and salicylate, as to the inhibition of gastric acid secretion.

From Table 7 it appears that the concurrent administration of the tested anti-ulcer compounds cannot block the indomethacin-induced fatal intestinal ulceration.

According to the data in Table 8 a combination of ranitidine with sodium salicylate (25+100 mg./kg.) results in a total inhibition of intestinal ulceration induced by a 15 mg./kg. p.o. dose of indomethacin.

The results obtained with combinations of various further anti-ulcer compounds and of sodium salicylate are shown in Table 9. It can be seen that while the anti-ulcer compounds listed in Table 7 alone are ineffective, in a combination with the cytoprotective sodium salicylate they can effectively block the intestinal ulceration induced with indomethacin.

According to a preferred embodiment of the invention a combination of 200 mg. cimetidine and 100 mg.

sodium salicylate is used in one tablet. Instead of sodium salicyiate salicylic acid or lithium salicylate can equally be used.

The pharmaceutical compositions according to the invention can be administered orally, rectally and/or parenterally, in a single daily dose or in several smaller doses. For oral administration the compositions are generally formulated as tablets, preferably coated tablets, dragees or capsules. The oral formulations according to the invention generally do not contain any excipient but, if desired, excipients like lactose or starch can also be employed. As a binding material for example gelatine, sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone or starch gum can be used. As a disintegrating agent preferably potato starch or microcrystalline cellulose are added into the compositions but ultraamylopectin or formaldehyde caseine, etc. can also be employed.As a lubricant and anti-adhesive talc, colloidal silicic acid, stearine, calcium or magnesium stearate, etc. can be used.

Such tablets may be prepared by the conventional techniques of the pharmaceutical industry, e.g. by granulation and subsequent pressing. Thus the mixture of active ingredients and fillers and optionally a part of the disintegrating substances may be granulated with an aqueous, alcoholic or aqueous-alcoholic solution of the binding agents in a suitable apparatus and the granules obtained dried. The dry granulate may then be mixed with the further additives, e.g. disintegrating, anti-adhesive agents and lubricants, and the mixture pressed into tablets. If desired, to facilitate administration the tablets are grooved. The tablets can be coated with a gastric acid resistant film, e.g. shellac, cellulose acetate phthalate or Eudragit-L using an alcoholic, preferably isopropanolic solution of the film-forming materials.The tablets can be prepared from a mixture of the active ingredients and additives directly by pressing, and the tablets obtained can be coated with an intestino-solvent film layer.

Degrees can be prepared by using various protecting, flavouring agents and pigments conventionally used in the preparation of pharmaceuticals, e.g. sugar, cellulose derivatives (methyl or ethyl cellulose, carboxymethyl cellulose sodium, etc.), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food-pigments, food-colour shellacs, iron oxide pigments, aroma substances, etc.

Capsules can for example be prepared by filling a mixture of the active ingredients and additives into a hard gelatine capsule.

For rectal administration suppositories may be prepared. As a carrier vegetable fats, e.g. hardened vegetable oils or triglycerides of fatty acids having 12 to 17 carbon atoms, preferably Witepsol are employed.

The active ingredients are preferably homogeneouslydistributed in the melted mass of the carriers and suppositories are prepared therefrom by moulding.

For parenteral administration injectable preparations are prepared. The active ingredients may be dissolved in water or organic solvents, optionally in the presence of mediators, e.g. polyoxyethylene sorbitan monolaurate, monooleate or monostearate (Tween-20, Tween-60 and Tween-80, respectively,). As an organic solvent for example lower aliphatic alcohols or glycol ethers, preferably ethyleneglycol monoethyl ether, can be employed, optionally in admixture with water. The injectable solutions may contain also various auxiliary agents, such as preservatives, e.g. benzyl alcohol, p-hydroxybenzoic acid methyl and/or propyl ester, phenylmercuriborate or benzalconium chloride, or antioxidants, such as sodium pyrosulfate, ascorbic acid, tocopherol and optionally complexing agents to bind trace metals, e.g.

ethylenediamine tetraacetic acid, and pH-adjusting and buffer materials, and optionally local anaesthetics, e.g. lidocaine.

The injectable solutions according to the invention are preferably filtered prior to filling into ampoules and are then subjected to sterilization.

The invention will further be illustrated by the following specific Examples which are for illustration only and not limitation of our invention.

Example 1 Cimetidine-sodium salicylate tablets cimetidine 200 mg.

sodium salicylate 100 mg.

magnesium stearate 3 mg.

polyvinylpyrrolidone 8 mg.

talc 12 mg.

potato starch 27 mg.

From the materials listed above 350 mg. tablets are prepared by wet granulation and moulding. Essentially the same activity is obtained if in the above composition sodium salicylate is replaced by an equivalent amount of another alkali metal salicylate, e.g. lithium salicylate.

Examples2to 16 In the following Examples 2-16, tablets are prepared as in Example 1 except the active components and ingredients are present in the amounts specified below. The manufacturing procedure is the same as in Example 1. is the same as in Example 1.

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 15mg.

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 12mg.

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.

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.

talc 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 100mg.

niflumic acid 200 mg.

potato starch 40 mg.

tale 20 mg.

polyvinylpyrrolidone 15 mg.

magnesium stearate 5 mg.

Example 11 ranitidine 50 mg.

sodium salicylate 100 mg.

indomethacin 20 mg.

potato starch 15 mg.

polyvinylpyrrolidone 6 mg.

tale 6 mg.

magnesium stearate 3 mg.

Example 12 ranitidine 50 rung.

sodium salicylate 100 mg.

naproxen 150 mg.

potato starch 25 mg.

talc 10 mg.

polyvinylpyrrolidone 10 rng.

magnesium stearate 5 mg.

Example 13 ranitidine 50 mg.

sodium salicylate 100 mg.

phenylbutazone 100 mg.

potato starch 14mg.

talc 6 mg.

polyvinylpyrrolidone 8 mg.

magnesium 2 mg.

Example 14 ranitidine 50 mg.

sodium salicylate 100 mg.

aspirin 200 mg.

potato starch 30 mg.

talc 10 mg.

polyvinylpyrrolidone 8 mug.

magnesium stearate 2 mg.

Example 15 ranitidine 50 mg.

sodium salicylate 100 mg.

niflumic acid 200 mg.

potato starch 30 mg.

talc 10 mg.

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.

polyvinylpryrrolidone 4 mug.

magnesium stearate 1 mg.

Claims (21)

1. Pharmaceutical compositions comprising, as active ingredient, 1 part by weight of an anti-ulcer agent or a salt thereof and 0.1 to 10 parts by weight of salicylic acid or an alkali metal salt thereof.

2. Compositions as claimed in claim 1 further including, as an active ingredient, 0.01 to 1 part by weight of a non-steroidal antiinflammatory agent.

3. A composition as claimed in claim 2 wherein the non-steroidal antiinflammatory agent comprises indomethacin, naproxen, phenylbutazone, acetyl-salicylic acid or niflumic acid.

4. Compositions as claimed in any preceding claim wherein the anti-ulcer agent comprises cimetidine, ranitidine, propantheline, gastrixone or zolimidine.

5. Pharmaceutical compositions comprising 0.1 to 1 part by weight of sodium salicylate and 1 part by weight of cimetidine in combination with one or more carriers and/or other additives.

6. Pharmaceutical compositions comprising 0.1 to 1 parts by weight of sodium salicyate, 0.01 to 1 part by weight of indomethacin and 1 part by weight of cimetidine, in combination with one or more carriers and/or other additives.

7. Pharmaceutical compositions comprising 0.1 to 10 parts byweightofsodium salicylateand 1 part by weight of rantidine, in combination with one or more carriers and/or other additives.

8. Compositions as claimed in any preceding claim in which the total active ingredient concentration constitutes from 10 to 90% by weight of the total weight of the composition, the remainder consisting of one or more carriers and/or other additives.

9. Pharmaceutical compositions as claimed in claim 1 or claim 2 substantially as herein described.

10. Pharmaceutical compositions substantially as herein described in any one of Examples 1 to 16.

11. A process for the preparation of a pharmaceutical composition which comprises mixing 0.1 to 10 parts by weight of salicylic acid or an alkali metal salt thereof with 1 part by weight of an anti-ulcer agent or a salt thereof optionally together with 0.01 to 1 part by weight of a non-steroidal antiinflammatory agent and/or with one or more carriers and/or other additives.

12. A process as claimed in claim 11 wherein the anti-ulcer agent is cimetidine, ranitidine, propantheline, gastrixone or zolimidine and the optional non-steroidal antiinflammatory agent is indomethacin, naproxen, phenylbutazone, acetyl-salicylic acid or niflumic acid or a salt thereof.

13. A process as claimed in claim 12 wherein 0.1 to 1 part by weight of sodium salicylate is mixed with 1 part by weight of cimetidine.

14. A process as claimed in claim 12 wherein 0.1 to 1 part by weight of sodium salicylate is mixed with 0.01 to 1 part by weight of indomethacin and 1 part by weight of cimetidine.

15. A process as claimed in claim 12 wherein 0.1 to 10 parts by weight of sodium salicylate are mixed with 1 part by weight of ranitidine.

16. A process as claimed in claim 11 substantially as herein described.

17. A process as claimed in claim 11 substantially as herein described in any one of Examples 1 to 16.

18. Pharamaceutical compositions whenever prepared by a process as claimed in any one of claims 11 to 17.

19. A pharmaceutical product comprising a first container containing salicylic acid or an alkali metal salt thereof and a second container containing an anti-ulcer agent or a salt thereof in association with written or printed directions to administer the contents of the first and second containers concurrently in an amount of 0.01 to 10 parts by weight of salicylic acid or salt thereof to 1 part by weight of anti-ulcer agent or salt thereof.

20. A product as claimed in claim 19 further including a non-steroidal antiinflammatory agent and wherein the directions indicate that the non-steroidal antiinflammatory agent be administered concurrently with the contents of the first and second containers in an amount of 0.01 to 1 part by weight of non-steroidal antiinflammatory agent to 1 part by weight of anti-ulcer agent or salt thereof.

21. Each and every novel method, process, composition and product herein disclosed.