CA1211374A - Pharmaceutical compositions containing more active ingredients - Google Patents

Abstract

A b s t r a c t The invention relates to new anti-ulcer or anti-ulcer and antiinflammatory compositions, which contain a combination of an anti-ulcer agent or a salt thereof with salicylic acid or an alkali metal salt thereof and optionally a non-steroidal antiinflammatory agent or a salt thereof. As an anti-ulcer agent prefer-ably cimetidine or ranitidine is employed, while the preferred non-steroidal antiinflammatory agent is indomethacin.
The new compositions according to the invention are devoid of the known side-effects observed as a result of concurrent administration of an anti-ulcer agent and a non-steroidal antiinflammatory agent, moreover they possess a synergistic anti-ulcer activity.

Description

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The presen-t invention relates to new anti-ulcer pharmaceu-tical compositions and a process for their pre-para-tion. More par-ticularly, the present inven-tion pro-vides new pharmaceutical compositions con-taining two or more active ingredien-ts which are effec-tive against gas-troin-tes-tinal ulceration and, iE desired, may be employecl as anti-inflammatory agents.

Since the description of H2-recep-tor an-tagonis-ts [Nature 236, 385 (1962)] this novel group of anti-ulcer agents has been subjec-tecl to extensive experimental and clinical inves-tigations. In a few years cimetidine (N"-cyano-N'-methyl-N-[2-(((5-methyl-1-H-imidazol-~-yl)-methyl)-thio)-ethyl]-guanidine) appeared on the market and achieved unprecedented commercial success. In -the past few year 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 coneerning this agent. In experiments on rats it has been demonstrated for example by P. Del Soldato et al [Br. J. Pharmae. 67, 33 (1979)] that cimetidine could not prevent the indomethaein-induced intestinal ulcera-tion.
Similar observations have recently q~

3~

been published by W~ ~. Mitchell et al /Brit. Med. J.
~, 731 (198217 in human clinical prac-tice~ I-t wa~
reported that the concurren-t adminigtra~tion of' cimetidin~
and indomethacin had resulted in the perforation o~ ulcer in ca~e of several patien-ts.
It i~ well known that the ga~trointe~tinal ulcer, which i3 a typical di~ease peculiar to civilized communitie~, rack~ more and more people~ Alnong the ulcerous patients there are numerous people suffering also from inflammatory or degenerative locomotor di~eases, In such cases the medical attendant ha~ to face a practically insoluble situation since un-til now there i~
no pharmaceutical composition known in the art which could effectively be used under the~e conditions without serious side-effect~. It i9 highly probable that the concurrent admini~tration o~ an anti-ulcer agent and a non-~teroidal antiinflamma-tory agent may accelerate th~ perforation of the ulcer, The present invention provides a pharmaceu-tical composition which i~ devoid of these di~adva~tages and in which the activity of ~he anti-ulcer active ingredient is ~avourably increased, potentiatedO
It i~ known that a common, undesired side-effect of non-s-teroidal antiin~lammatory agent~ is their ulcerogenic effect. According to numerou~ publications l~ chloro-benzoyl)~5-methoxy-2-methylindole-3-yl-acetic acid (indomethacin~, 4~butyl-1,2-diphenylpyrazolidine-3S5-dione ~ '.
. :, .~' , ~ .

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(phenylbutazone)~ d~2-(6 methoxy-2-naph-thyl)-propionic acid (naproxen) 9 3-(3--trif`luorome-thylanilino~-nicotinic acid (niflumic acid) and acetyl ~alicylic acid sh~w ~n ulcerogenic ~ide-eP~`ect. ~here are ~everal mc--thod~
by which the above undesired side-effect of` anti~
inflammatory substances can be reduced~ Our ovJn experiments showed that a certain reduction o:f ~ide-e~fects can ~e achieved by certain salicylatej (Britîsh Pa-~ent Speci~ication 1,483,165) but there i~ no suggestion in the literature to combine these agent~ by anti-ulcer active ingxedients; on the contrary, it i~ generally pointed ou-t that the salicylate~ have an undesirable effect on the gastrointe~tinal condition (see for example: Aspirin and Related Drugs: Their Action~ and Uses, K~ D. Rainsford, K. Brune, M. W Whitehouse, Birk-hau~er Verlag, Basel und Stuttgart 1977). q'hough different pharmacological investigation~, recently carried out, demonstrated unambiguously that sodium sallcyate has a gastrointe~tinal oytoprotective effect (e. g. J, Pharm~ Pharmac~ 28, 655 (1976), Pro3taglandin~
219 Suppl~ 139 (1981~), it has also been reported that the ~astrointesti~al cytoprotective e~fect o~ sodium ~alicylate has no connection with the ~astric acid secre~ion (Adv. Physiol. Sci. t Vol~ 29; Ga~trointe~tinal Defen~e Mechanism~, Pergamon Press - Akadémiai Kiado,~:
Budapest 9 Hungary, 1981).
: We have found that in a concurrent admini~tration ~L23L3~3~7 o~ variou~ antiinflammatory agen-ts,particularly indomethacin and cimetidine, the latter cornpound in a certain concentration range doe~ not ~nhiblt the i~te~tinal ulcerogenic effect o~ the antiinflammatory agent~, in~tead facilitate~ thi~ undesired action~ Accordingly, it could not be expected that the admi.ni~tration o~ a certain do~e of ~alicylic acid or a salicylate a3 a ~urther component entirely ~u~resæeæ the unde~ired ~ide~effect.
The pre~ent invention i9 ba~ed on the ~urprising recognition that a combination of known anti~ulcer agent3 with ~odium salicylate has a more signi~icant, i~ e~ synergistic,anti-ulcer e~fect than cimetidine alone, and at the same time, when combinations with three types of active ingredient are employedg the undesired ~ide-effects of non-steroidal antiinflamma-tory agents can also be avoided.
The present invention provides a phal~naceutical compo~itions which contain~ 0~1 -to 10 parts by weight of aalicylic acid or an alkali metal salt thereof and optionally 0,01 to 1 parts by weight of a non-steroidal antiinflammatory agent or a salt thereof related to 1 part by weight of an anti-ulcer active ingredient in admixture with conventional pharmaceutical carriers and/or further additive~.
According to a pre~erred embodiment o~ the in~ention there are provided compositions containi.ng aæ an anti-ulcer agent cimetidine o~ ranitidine 3`
.....

, ~ 5 ( N~2~ ! ~ f5-(dimethylamino)-me~hyl-2-furanyl~-methyl)-thio)-e-thyl)-N~-methyl~2-ni-tro~ ethylenedlc:lmirle ) o~
propantheline ( N,N-dii~opropyl-N methyl-2~(xarl-then~9-carbonyloxy)-ethyl-ammoni.um-hydroxide ) or ga~tri~on~
( xanthene-9~carboxylic acid tropi~.ester methyl hydrochlo~ide ) or zolimidine ( 2~ me-thyl~ulfonylpherlyl i.midazo~I,2~a7-pyridine ).
According to a further pre~erred embodimerlt of the invention the pharmaceutical composition~ contain as a non-stero.idal antiinflammatory agen-t indomethacin, nap.roxen9 phenylbutazone, acetyl~alicilic acid or niflumic acid.
A preferred composition according to the invention may for example contain 0.1 to 1 part~ by weight o~
sodium salicylate and optionally 0.01 to 1 par-t~ by wei~ht of indomethacin related to 1 part by weight of cimetidine9 or 0.01 to 1 parts by weight of ~odium salicylate related to l part by weight of cimetidine, in admi~ture with conventional carriers and/or further additive~
The invention further relate~ to a process for the preparation o~ new pharmaceutical compositions, which comprises admixing 0.1 to 10 parts by weight of ~alicylic acid or an alkali me-tal salt thereof and9 if de~ixed, O.Ql to 1 parts by weight of a non-steroidal antiinflammatory agent or a salt thereof, preferably indomethacin, naproxen, phenylbutazone or acetylsalicyllc :
\

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aci.d or nif`lumic acid or a ~alt thereof with 1 part by weigllt of an anti-ulcer agent or a ~al-t thereo~', pre~er-ably cime-tidine, ranitidine or pro~antheline or ga~trixone or zolimidine or a ~alt thereof3 ~ur-ther with carriers and/or further additives con-Yentionally ur-~ed in the preparation of pharmaceutical corll~ositions.
Accordin~ to a preferred embodiment o~ the in~-tant process 1 part by weight o~ cimetidine i~
admixed Wit~l 0.1 to 1 part~ by wei~ht of sodium ~alicylate and conventional carriers and/or additives, or 0.1 t,o 1 part~ by weight of ~odium ~alicylate and 0.1 to 1 part~
by weight of indGmethaGin are admixed with 1 part by weight of cimetidine and conventional carriers a~d/or further additives, or 1 part by weight of ranitidine is admixed with 0.1 to 10 parts by weight o~ sodium salicylate and conventional carriers and/or further additive~.
Ex~_rimental methods __ ___.________ _ _ 1) Indomethacin-induced intestinal ulceration Non-~a~tened Hannover-Wistar rats, each wei~h1ng 120~150 g1 were administered a 15 mgO /kg. dose o~
indomethacin in a Tween 80 (a trademark) suspension to induce fatal intestinal ulceration. The test material was admini~-tered immediately a~ter the indomethacin treatment, al~o orally.
To evaluate the development of small intestinal ulcer~, the ten~ile!~treneth of inte~tinal wall was ~2~37~

de-termined by the so-called inflation technique - ~J. Pharmn Pharmac. 27~ 867 (1975~7, because the ero~io~
caused b~ ulcerogene~i~ lead~ to -the weakening o~ the strength o~ the inte~tinal wall. The animal~ were kill~d 48 and 72 houra, re~pec-tively9 a~ter the indomethacin treatment by ether narcosi~. The ~mall inte,stine ~rom pyloru~ to caecum wa~ carefully removed, its one end wa~ ligated, while the other end was connected with a W+W electronic BP Recorder 8005 (Ugo Ba~ile, Italy) -t~ough a polyethylene tubeO The entire ~mall inte3tine waa placed into a physiological saline ~olution at ~ 37 C and the pres~ur~ increased until air bubbles appeared at the weakened sites in the intestinal wall.
Thi3 pre~sure~ expre~sed in mmHg, is defined a~ the -tensile strength ~T~So )o Parallel with the progress of the indomethacin-induced intestinal ulceration the ten~ile ~trength o~ the inte~tinal wall, al~o called intestinal wall resistancy, gradually decreases as illu~trated by Fig~ lo

2) Ab_. alcohol-~nduced ~a~tric necrosis Gastric necro~is wag induced by acidic-alcohol, by the modified method o~ Robert et al. /Ga~tro enterology 77, 433 ~1979)7. Female Hannover-Wi~tar rats, each weighing 120-150 g., were fasted for 24 hours, ~5 Water was allowed ad libit _ .
Compound~ to be tested were administered orally 30 mlnute~ prior to acidic-a:Lcohol admini~t;ration.

.

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Acidic-alcohol (cc. HCl:abs~ethanol-1:50 Y/~1 wag admini~tered orally through a canul~ irl a do~e of' 0~5 rnlt pro 100 g. o~ body weight. Two hour~ late~ t~e animal~
were killed by overdo~lng ~therO Stomach~ were removed and opened along -the major curvature. ~he l~ion~
induced by ethanol are located at the corpu~ o~ the stomach as multiple linear hemorrhagic band3 of' necrotic ti~sue. Lengths of the le~ion~ were mea~ured and expres~ed in mm.~s and the total length of lesions o~ each stomach '' wa~ calculated. Degree of lesion~ severity was expre~sed as the mean of total lesion-length per stomach. ~he ~tomach cytoprotection was expre~sed in comparison with the cont,rol animals.

3) Gastric acid secretion in Sha~rats The tests were carried out according to the method o~ Shay et alO /Gastroenterology ~, 43-46 (1945)7.
Female Wistar rats, each weighing 120-150 g., were used.
Pyrolic ligation was performed under aether anaesthe~ia a~ter twent~-f`our hours~ fastingO The animal~ were treated by the cornpounds -to be tested intraperitoneally, ir~mediately after the surgical intervention. ~he oral treatments were performed 30 minutes prior to operation~
'llhe animals were killed 4 hours after pyrolic iigation.
After the extension of stomach the volume of ga~tric juice wa~ mea~ured and HCl concentration was determ1ned ' by titration against 0.01 n NaOH in the pre~ence of ~' phenol~talein as indicator~ The amount o~ the acid was .
..; . .

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_ g _ e~pres~ed in /umole~ related to 100 g. of body weight,.
The ~-ta-tistical evaluation of r~ults wa~ performed by Student~ 9 te~-t.
Evaluation of the experim ntal re~ults ~y the ~irst part of experimen~ the optimal cimetidine/~odium salicylate ratio,by which the indomethacin-~
-induced in-te~tinal ulceration tlO mg./kg.) and the ga~tric-acid secretion on Shay-rat~ could be inhibi-ted wa~ determined, . .

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~.. ~ 19 --The da~a ~et ~orth in ~able~ 1 ~ 2 ~how tha-t tho optimal ra-tio between cimetldine arld sodlwn ~alicyl~te wa~ 2.1.
In ~ig~ 1 the time course of the in-teFJtinal ulceration induced by a 10 mg./kg. do~e o~ indomethacin i.s illustratedO
~able 3 3hows tha~ a 2:1 combination o~ cimetidine and Na-Salicylate ha~ a do3e-dependent cy-toprotective effect against abs.alcohol-induced ~tomach necrosis ~hile cimetidine i~ not cytoprotective~
A~ aet forth in Table ~ the inte~ti~t~l toxicit~
of indomethacin was markedly apparent after re~eated treatment on three consecu~ive days (3xlO mg./kg. pDO~ ) and the mortality was ~ound to be 30 percent on the :~ourth day~ Concurrent administration of 3xlOO mg./kg. cimetidine p.o. resulted in a greater intestinal toxicity (mortality 50 %~. Concurrent admini~tration o~ 3x(100~50) mg~/kjgD
of cimetidineand Na-Salicylate ~'201) pØ re~ult~ in an absolu-te blockade of intestinal toxicityO
One of the mo~t importan-t factors, the gastric acid secretion has been investigated in detall by using~
; Shay~rat~. The result~ are summarized in Tables 5 and 60 Both cimetidine and the combination of cimetidine and Na~Salicylate (2:1) have ~ose dependent inhibitory ~5 ef`fect on the gastric acid ~ecretion~ The ED50 values for cimetidine and the combination of cimetid~le and Na-Salicylate (2:1~ were 5404 mg./kgO i~p~ and 35~6 .
; i' ' ~ ., J `

37~
~ 20 ~

mgl /kg~ iop~ ~ re~pectively. The 35.6 mg~ of the combination o~ cimetid~ne and Na-Salicylate (2:1) con~aille~
23~8 mg~ o~ cime-tidine and 11.8 mgq o~ sodium ~alicylate~
In combination a do~e o~ cimetidine 56 ~ le~ ~han tha~
o~ cirnetidine alone produced the same (50 ~0) ga~tric acid secretion. Sodium salicylate alone wa~ actual~y ine~fective a~ a ga~tric acid inhibitor, The re~ult~ were ~imilar in ca~e of intraperitoneal and oral treatmerlt, respectively~
The re~ults ~how tha-t a ~ r~ism e~ists between cimetidine and sodium salicylate, as to the inhibi-tion of` gastric acid secretion.
~rom Table 7 it appears that the concurren-t administration o~ the te~ted anti-ulcer compounds cannot block -the indomethacin-induced ~atal intestinal ulceration.
According to the data in Table 8 a combination o~ ranitidine with ~odium salicylate (25~100 mg~/kg~) result~ in a total lnhibition of intestinal ulceration induced by a 15 mg./kg. p.o~ dose o~ indomethacin.
The results obtained with combinations of ;~ variou~ further anti-ulcer compounds and of sodium salicylate are shown in Table 9. It can be ~een that while the anti-ulcer compounds listed in Table 7 alone are ine~fective, in a combination with the cytoprotective sodium salicylate they can e~ectively block the intestinal ulceration induced wi-th indomethacin.
According to a pref`erred embodiment of the . j , ~
, . .

... .

3~
~ 21 inventlon a comblna-tion of 200 mg. cimetidine an~
100 mg. ~odium salicylate i~ u~ed in one ta~let~ In~teac1 o~ 30dium ~alicylate salicylic acid or li~hium ~alicylate can equally be used.
The pharmaceutical cornpo~ition~ ~cco~ding to the inven-tion can be administered orally, rectally and/or paren-terally, in a ~ingle daily ~o~e ox in more smaller doses~ ~or oral adminis-tration the compo~itions are generally formulated a~ tablet~, preferably coated tablets, dragées or capsule~. q`he oral formula-tions according -to the invention generally do not contain any excipient but, if de~ired, exclpients like lactose or starch can also be employed. As a binding material ~or example gela-tine, ~odium carboxyme-thyl cellulose, methyl cellulo~e, polyvinylpyrrolidone o.r starch gum can be used. A~ a disintegrating agent fir~t of all po-tato starch or microcrystalline cellulose are added into the compositions but ultraamylopectine or form-aldehyde caseine~ etc. can al~o be employed A~ a 20 lubricant and antl-adhesive talc, colloidal silicic :
acid, ~tearine, calcium or magnesium stearate~ etcO
can be u~ed.
The tablets are prepared by the conven-tional techniques of pharmaceutical industry, e. g. by granulation and a subsequent pre~slng. The ~ix-ture o~
ac-tive ingredients and filler~ and optionally a par-t of the disintegxating ~ubstance~ is granulated with , , .

- 22 ~

an aqueous, alcoholic or aqueou~-alcoholic ~olution of the binding agents in a ~uitable apparatu~ and ~he granules obtained are dried~ The dry granulate i~ then . admixed with -the ~ur-ther addi-tives, e. gO di.~integrating7 anti-adhe~ive agents and lubricant~, and the mixture is pressed to tablet~ desired, to facilitate ad-ministration the tablets are grooved. '~he tablets can ~e coated with a gastric acid re~istànt film, e. g.
shellac, cellulose acetate phthalate o.r Eudragit-L
(a registered trade mark) using an alcoholic, preferably isopropanolic solution of the film forming materials~.
The tablet~ can be prepared from a mixture of -the active ingredient~ and addi-tives direc-tly by pressing, and the tablets obtained can be coated with an in-tes-tino-solvent film layer.
Dragées can be prepared by using various protecting~
flavouring agents and pigmen-ts conventionally used in the preparation of pharmaceutical~, e. gO ~ugar, cellulose derivatives (methyl or ethyl cellulose, carboxymethyl cellulose sodium, etc.), polyvinylpyrro-lidone, calcium phosphate, calcium carbonate, food-pigments, food~colour ~hellacs, iron oxide pigment~, aroma substances 9 etc.
Gapsules can for example be prepared by filling a mixture of the active ingredients and additive~ into a hard gelatine capsule.
E`or xectal administration supl:ositori.es are '~; , \ ' ,i~ ~p~ ~ ~ '1 ~4 - 23 ~

prepaI'ed D A~ a carrier vegetable ~t~, e. g. hardened vegetable oil~ or triglyc0ride~ of fatty acids havirl~
12 to 17 carbon atome 9 preferably Wi-tepsol (a regi~-tered trade markJ are employed~ The active ingredierlts ~re hornogenously distributed in -the melted mas~ o~ carriers and suppositories are prepared by ca~ting.
E'or parenteral administration injectable prepara-tions are prepared. The active ingredients are dissolved in water or organic ~olvent~, optionally in the presence of mediators, e. g~ polyoxyethylene sorbitane monolaurate, monooleate or monostearate (Tween-20, Tween-60 and ~ween-~0, respectivelyplAs an organic solvent for example lower aliphatic alcohols or glycol ethers, preferably ethyleneglycol monoethyl ether, can be employed, optionally in admixture with wa-ter. The injectable solutions may contain also various auxiliary agents, ~uch a9 preservatives, eO g. benzyl alcohol~
~-oxybenzoic acid methyl and/or propyl e~-ter, phenyl~
mercuribo~ate or benzalconlum chloride~ or antioxidants, such a~ sodium pyrosulfate, ascorbic acid, tocopherol and optionally complexing agent~ to bind the metal traces, e. g. ethylenediamine tetraacetic acid, and pH-adju~ting and bu~fer materials, and optionally local anaesthe-tic~, e. g. lidocaine.
The injectable solutions according to -the invention are filtered prior to filling into -the amL~oule~ and are t~len ~ubjected to ~terili~ation~

i ~ ~ , ~u ., .

t ~ 3~
. ~ 24 The invention will f'urther be illu~trated by the following specific Example~ which are f'or i.llu~tration buk not limitation of our inventionO
Exam~le 1 Cirnetidine-sod,ium sali_~late tablet~
cimetldine 200 mg.
~odium salicylate 100 mg.
magne~ium stearate 3 mg~
polyvinylpyrrolidone 8 mg~
-talc 12 mg.
potato ~tarch 27 mg.
l~rom the materials listed above 350 m~. tablet~
are prepared by we~ granulation and mouldingO E~sentially -the same activ.ity is obtained if in the above compo~ition sodium ~alicylate i~ replaced by an equivalent amount of another alkali metal salicylate, e. gO lithium salicylate.
Examples 2 to 16i , In the following Examples the amount and quality of the additives are identical with that given in Example 1 except the active components and ingredient~ ' which are a~ specified belo~!. The manufacturing procedure is the same as in Example 1.
Exam~le 2 ranitidine , 50 mg.
~odium salicylate 100 mg~
potato starch ~ 8 mg~

, ~ .

- 25 ~-Z~ 37~

magne~ium s-tearate 1 mg r polyvinylpyrrolidone 3 mg.
talc 3 ~ng, ~X_~IP~le-~
propantheline 15 mg.
sodium ~alicylate 75 mg.
magne~ n stearate 2 mg.
pota-to starch 8 mg.
polyvinylpyrrolidone 2.5 rng.
talc 2.5 mg.
Ex_mPle_4 gastrixone 2 mg.
sodium salicyla-te 25 mg.
magne 9 ium 9 tearate 1 mg.
potato ~tarch 1 mgO
polyvinylpyrrolidone 0.5 mg.
talc 0.5 rng.
Example 5 . zolimidine . 200 mg.
sodiurn ~alicylate 100 mg.
magnesium stearate 3 mg.
polyvinylpyrrolidone 8 mg~
-talc ~ 12 mg.
potato s-tarch 27 mg~
Ex_~le 6 .
cimetidine . 200 mg.
sodium ~alicylate 100 mg~

indomethacin 20 mg.
magne~ium ~tearate 3 rng~
polyvinylpyrrolidone 8 m~,.
talc 12 mg.
potato ~tarch 27 rng.
Exam~le 7 cimetidine 200 mg.
~odium salicylate 100 mg.
naproxen 200 mg.
magnesium s-tearate 5 mg.
polyvinylpyrrolidone 3 mg.
potato starch 37 mg.
talc 15 mg.
~xam~le 8 -- 15 cimetidine ~ 200 mg.
~odium ~alicylate 100 Ing, phenylbutazone 100 mg~
potato starch 40 mg.
talc 12 mgD
polyvinylpyrrolidone 12 mg magne~ium ~tearate 4 mg~
Exam~e ~ -cimetidine 200 mg.
~odium salicylate 100 mg, Aspirin (a ~ademark) 200 mg.
potato ~tarch 40 mg.
talc 20 mg~
;

.~,. ~ ' .
'''``

2~L~37 polyvi.nylp;yrrolidone 15 mg.
magnesium ~-tearate 5 m~
Exar~le 10 cimetidine 200 mg.
sodium ~alicylate 100 mg.
niflumic acid 200 rng.
po-tato starch 40 mg.
talc 20 mg~
polyvinylpyrrolidone 15 mg.
rnagne~ium ~tearate 5 mg, Exa ~e 11 ranitidine 50 mg.
~odium ~alicylate 100 mg.
indomethacin .20 mgO
potato ~tarch 15 mg.
polyvinylpyrrolidone 6 rng.
talc 6 mg~
magne~ium ~tearate 3 mg.
Exam~le 12 ranitidine . 50 mg.
~odium salicylate - 100 rng.
naproxen 150 mg~
potato r~tarch 25 mg~
talc 10 mg.
polyvinylpyrrolidone . 10 mg.
magnesium ~-tearate 5 mg.

.
. . ,. ~ .

3~7~
. 28 -Exarn~e 1~
_._ _ __ ranitidi.ne 50 mgO
~odium ~alicyla-te 100 mg.
phenylbutazorle 100 m~O
potato ~tarch 14 mg.
talc 6 rng.
polyvinylpyrrolidone 8 mg.
magne3ium ~tearate 2 mg.
Example 14 ___ _ __ ranitidine 50 mg~
~odium salicylate . 100 mg.
a~pirin 200 mg.
potato ~tarch 30 me.
talc 10 mgr polyvinylpyrrolidone 8 mg.
magne~ium stearate 2 mgO
ExamPle_a~
ranitidine 50 nlg.
~odium ~alicylate 100 mg.
niflumic acid 200 mg.
potato starch 30 mg.
talc 10 mg.
polyviny.lpyrrolidone ~ Ing.
magne~ium stearate 2 mg.
Example 16 ~_ _ propantheline 15 mg.
~odium ~ali¢ylate - 150 mg.
, ~ .

... . .

indome-thacin 20 mg~
po-ta-to ~tarch 15 In~
talc 5 rng.
polyvinylpyrrolidone 4 m~
magne~ium steara-te 1 mg~

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLU-SIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition which comprises an anti-ulcer agent and 0.1 to 10 parts by weight of salicylic acid or an alkali metal salt thereof per part by weight of anti-ulcer agent.

2. A composition according to claim 1, which con-tains 0.01 to 1 part by weight of a non-steroidal anti infla-matory agent.

3. A composition according to claim 1, in which the anti-ulcer agent is in the form of a salt.

4. A composition according to claim 1, 2 or 3, in which the total active ingredient concentration is 10 to 90%
by weight related to the total weight of the composition, in admixture with at least one carrier and further additives con-ventionally used in the preparation of pharmaceutical composi-tions.

5. A composition according to claim 1 or 2, in which the anti-ulcer agent is cimetidine, ranitidine, prop-antheline, gastrixone or zolimidine.

6. A composition according to claim 2, in which the non-steroidal anti-inflammatory agent is indomethacin, naproxen, phenylbutazone, acetylsalicylic acid or niflumic acid.

7. Anti-ulcer pharmaceutical composition which comprises cimetidine and 0.1 to 1 parts by weight of sodium salicylate per part by weight of cimetidine in combination with at least one of carriers and/or further additives con-ventionally used in the preparation of pharmaceutical composi-tions.

8. A pharmaceutical composition which comprises cimetidine, 0.1 to 1 parts by weight of sodium salicylate and 0.01 to 1 parts by weight of indomethacin per part by weight of cimetidine, in combination with at least one of carriers and/or further additives conventionally used in the prepara-tion of pharmaceutical compositions.

9. An anti-ulcer pharmaceutical composition which comprises ranitidine and 0.1 to 10 parts by weight of sodium salicylate per part by weight or ranitidine, in admixture with at least one of carriers and/or further additives con-ventionally used in the preparation of pharmaceutical composi-tions.

10. A process for the preparation of a pharmaceutical composition which comprises mixing an anti-ulcer agent and 0.1 to 10 parts by weight of salicylic acid or an alkali metal salt thereof per part by weight of an anti-ulcer agent with at least one of conventional carriers and/or further additives.

11. A process as claimed in claim 10 in which the anti-ulcer agent is cimetidine, ranitidine, propantheline, gastrixone or zolimidine or a salt thereof.

12. A process according to claim 10 in which 0.01 to 1 part by weight of a non-steroidal anti-inflammatory agent is admixed.

13. A process according to claim 12 in which the non-steroidal anti-inflammatory agent is indomethacin, naproxen, phenylbutazone, acetylsalicylic acid or niflumic acid or a salt thereof.

14. A process according to claim 10 which comprises admixing 0.1 to l parts by weight of sodium salicylate per l part by weight of cimetidine.

15. A process according to claim 13 which comprises admixing 0.1 to 1 parts by weight of sodium salicylate and 0.01 to l parts by weight of indomethacin per park by weight of cimetidine.

16. A process according to claim 10 which comprises admixing 0.1 to 10 parts by weight of sodium salicylate per part by weight of ranitidine.