United States Patent (19) 11) 4,198,402 Ezer et al. 45) Apr. 15, 1980

54 ANTIPHLOGISTIC COMPOSITION OF 58) Field of Search ...... 424/230, 231, 232 PHENYLBUTOZONE AND ALKALI 56) References Cited SALICYLATE AND METHOD OF TREATMENT PUBLICATIONS 75 Inventors: Elemer Ezer; Laszio Szporny; Lilla Gietka et al.-Chem. Abst., vol. 82, (1975), p. 291 p. Forgach; Eva Palosi; Eszter Trinus et al.-Chem. Abst., vol. 77, (1972), p. 135,081n. Cholnoky; Egon Karpati; György Kirichek-Chem. Abst. vol., 76, (1972), p. 121,798u. Hajos; Gyozo Hortobagyi; Katalin Mhirden et al.-Chem. Abst., vol. 82, (1975), p. 38,749g. Gidai, all of Budapest, Hungary Zathurecky et al.-Chem. Abst., vol. 82, (1975), p. 164,817r. 73) Assignee: Richter Gedeon Vegyeszeti Gyar Rt., Budapest, Hungary Primary Examiner-Sam Rosen Attorney, Agent, or Firm-Karl F. Ross Appl. No.: 892,918 (21) 57 ABSTRACT 22 Filed: Apr. 3, 1978 Ulcer production in animals is prevented during pro longed antiphlogistic treatment with ulcerogenic quan Related U.S. Application Data tities of phenylbutazone by using it in a composition of 62 Division of Ser. No. 641,771, Dec. 17, 1975, aban 1 part of antiphlogistic to 0.2 to 50 parts by weight of doned. alkali metal salicylate. (51) Int. Cl...... A61K 31/62 52) U.S. Cl...... 424/232; 424/273 P 4 Claims, No Drawings 4,198,402 1. 2 tube immediately before injecting the carrageenine so ANTIPHLOGISTIC COMPOSITION OF lution. 4 hours after this treatment the animals were PHENY LIBUTOZONE AND ALKALSALCYLATE sacrified, and both hind paws were amputated above AND METHOD OF TREATMENT the ankles. The paws were weighed, and the oedema weight was calculated from the weight difference of the This is a division of application Ser. No. 641,771, filed treated and untreated paws. . Dec. 17, 1975, now abandoned. The gastrointestinal ulcerogenic side-effects of the This invention relates to new pharmaceutical compo individual active agents and their combinations were sitions and to a process for the preparation thereof. also examined on Wistar rats weighing 100 to 150 g. More particularly, the invention relates to new pharma 10 The animals were starved for 24 hours, and the sub ceutical compositions possessing antiphlogistic effects. stances to be tested were administered to them via a As known, all of the hitherto applied antiphlogistic stomach tube. 4 hours after the treatment the animals agents have the common disadvantage of causing gas were sacrified, the stomach was removed, incised along trointestinal haemorrhages or ulcers. The ulcerogenic the greater curvature, washed, and the haemorrhages side-effects of 1-(p-chlorobenzoyl)-5-methoxy-2-meth 5 (brown spots) appearing on the glandular part were yl-indole-3-yl-acetic acid (indomethacin), 4-butyl-1,2- counted. The results were subjected to Student's "t'- diphenyl-pyrazolidine-3,5-dione (phenylbutazone) and test. acetylsalicylic acid have been reported in numerous The ulcerogenic side-effects of the individual anti publications (Bonfils et al.: Bull. Mem. Soc. Med. Hosp. phlogistic agents were examined first by these tests. The Paris, 5, 114 (1955); Somogyi et al.: J. Pharm. Phar 20 macol. 21, 122 (1969); R. Nath: Studies on the Pharma results are summarized in Table 1. As it appears from cology of Inflammation, M.D. Thesis Lucknow Univer the data of the Table, all the compounds examined pos sity, Lucknow, India (1970); Lee et al.: Arch. Int. Phar sess more or less pronounced ulcerogenic side-effects. macodyn. 19, 370 (1971); Bhargava et al.: European J. Table 1 of Pharmacol. 22, 191 (1973); Katz et al.: Clin. Pharm. 25 Ther. 6, 25 (1965); Leonard et al.: Clin. Pharmacol. No. of Dosage No. of Ulcer- ani Ther. 14, No. 1, 62 (1973). test mg/kg ulcer/ free mals In prolonged treatments of various arthritic condi Compound animals p.O. stomach No. % tions two or more different antiphlogistic agents can Indomethacin 2O 5 1. 5 72 sometimes be administered simultaneously to the pa 28 10 6.5 5 18 120 20 15.0 6 5 tients. The antiphlogistic effects arising upon the simul rt 41 30 24 O O taneous administration of indomethacin and acetylsali Nifuminic acid 8 12.5 0.6 14 78 cylic acid were investigated first in animal tests (Miel Fa 6 25 10.2 2 12 ons et al.:J. Pharm. Pharmac. 20, 567 (1968); Swingle et t 15 50 9.0 O O 35 f 15 100 23.0 O O al.; J. Pharmacol. Exp. Ther. 172,423 (1970); Yesair et Phenylbutazone 18 25 0.5 13 73 al.: Biochem. Pharm. 19, 1591 (1970). Since the oedema 16 50 0.6 4. 25 tests had not indicated the additivity of antiphlogistic 7 00 6.5 4. 23 effects, clinical tests were performed in order to eluci 5 200 20.0 7 Aspirin 25 25 4. 2 8 date this question (Champion et al.: Clin. Pharm. and FF 25 SO S4 3 10 Ther. 13, 239 (1972); Lindquist et al.; Clin. Pharm. and 40 120 OO 6.5 18 14 Ther. 15, 247 (1974). These clinical tests have shown AF 58 400 110 7 12 that the blood indomethacine level is not affected by the Sodium salicylate 45 50 0. 37 82 r 28 100 0. 27 96 simultaneous administration of acetylsalicylic acid, that t 64 200 1.2 37 50 is, these two types of antiphlogistic agents do not a 45 400 1.1 32 7 worsen the effects of one another. 45 So far only the main effect, i.e. the antiphlogistic activity was investigated in the tests utilizing two differ The following tests aimed at investigating the effects ent antiphlogistic agents simultaneously, and the gastro which appear upon the administration of two different intestinal side-effects have not been analyzed. Our ex antiphlogistic agents in combination with each other. In periments aimed at investigating both the main anti 50 the first tests combinations of indomethacin and sodium phlogistic effect and the ulcerogenic side-effects ap salicylate were studied. It has been found, unexpect pearing upon the administration of various combina edly, that these compounds mutually suppress the ul tions of antiphlogistic agents, and preparing a pharma cerogenic side-effects of one another, while leaving the ceutical composition in which the original antiphlogis main antiphlogistic effects unchanged. This fact could tic effects of the individual components are retained but 55 not be foreseen at all, since it is well known that the the gastrointestinal side-effects are decreased to the above two compounds possess marked ulcerogenic minimum. The primary subjects of these experiments side-effects when added separately. were the most widely applied antiphlogistic agents, i.e. In the tests the animals received the same dosages of the salicylates (particularly acetylsalicylic acid) and indomethacin, and the amount of sodium salicylate ad indomethacin. 60 ministered was varied. It has been found that the num The antiphlogistic effects were studied on Wister rats ber of ulcer-free animals increases proportionally to the of both sexes, each weighing 100 to 150 g. The animals increase in the amount of sodium salicylate added, and were starved for 24 hours, and then 0.1 ml portions of a when sodium salicylate is administered in a 20-fold 1% carrageenin solution were injected under mild ether amount with respect to indomethacin, the ulcerogenic anaesthesia into the plantar region of one of the hind 65 effect disappears completely, i.e. sodium salicylate an paws in order to provoke inflammation (oedema). The tagonizes entirely the deleterious side-effect of indo antiphlogistic agent or a combination thereof was intro methacin. Table 2 shows the ulcerogenic effects and duced into the stomach of the animals via a stomach Table 3 shows the antiphlogistic effects of combinations 4,198,402 3 4. containing varying amounts of sodium salicylate besides acid, i.e. two different salicylic acid derivatives mutu indomethacine. ally suppress the harmful side-effects of each other. The Table 2 results of these tests are summarized in Tables 5 to 7. Inhibition of indomethacin-indiced ulcer by the simultaneous Table 5 administration of sodium salicylate Antagonizing the ulcerogenic side-effects of phenylbutazone Dosage, and niflumic acid by sodium salicylate administered simultaneously mg/kg. p.o. Ulcerogeneous side Ulcerogenic side No. of Sodiurn effect Ulcer-free No. of Dosage, mg/kg p.o. effect Ulcer-free animals Indo salicy No. of ul Inhibi- animals animals Phenyl- Sodium No. of ul. Inhibi- animals tested methacin late cera stomach tion No. 2. 10 tested butazone salicylate cer/stomach tion 7 No. % 2O 20 S.O. O.5. w 6 5 17 20 25 6.1 13 60 2 12 17 OO m 6.5 ow- 4. 23 8 2O SO 7.5 14xx 50s 2 O 30 100 50 4.4 32 8 27 22 20 100 4.0 - 0.8 73x 3 3 2O 100 100 3.3 50 8 40 58 2O 200 O.27 O.'s 98. 5. 88 18 OO 200 2.8 57 O 56 22 20 400 O 100X 22 100 5 Nifluminic p < 0.0 (significance level determined by Student's “t"-test) acid 'corrected with the near standard error 25 50 m 19 O O 2O 50 50 2 O O 20 50 100 13 40 O O Table 3 2O 50 200 5.5 73 6 30 Antiphlogistic effects of sodium salicylate, indomethacin and 20 combinations thereof determined by carrageenin-oedeme test Dosage of the compounds tested Oedema-inhi Table 6 mg/kg p.o. biting effect Antagonizing the ulcerogenic side-effects of acetylsalicylic Sodium salicylate Indomethacin tested % acid by sodium salicylate administered simultaneously 50 3. 15 25 Dosage, mg/kg. p.o. Ulcerogenic side OO 28 43 No. of Sodium effect Ulcer-free - 5 2 40 O 28 45x animals Acetylsali- salicy- No. of ul- Inhibi- animals 50 5 29 40 tested cylic acid late cer/stomach tion 26 No. % 200 5 O 41. 120 100 6.5 - 0.7 w 18 14 p < 0.05 (significance level determined by Student's 't-test) 30 22 100 25 2.5 x 0.5- 58 3 15 36 OO 50 2.4 - 0.6 60 6 45 In the following tests animals treated for 3 days with 31 100 100 0.2 0.1 99 29 97 various combinations of indomethacin and sodium sali 40 100 200 0.3 - 0.1- 98 36 90 cylate were examined. The non-starved test animals p < 0.01 (significance level determined by Student's "t'-test) were treated orally for 3 days with compositions con 35 taining 20 mg/kg of indomethacin and increasing Table 7 amounts of sodium salicylate. 73% of the animals re Antiphlogistic effects of sodium salicylate, acetylsalicylic ceiving only indomethacin died on the 3rd day in peri acid and combinations thereof determined by carrageenin-oedema tonitis resulting from intestinal perforation, and clearly test visible ulcers appeared in the intestines of the survivals. 40 Dosage mg/kg p.o. No. of Inhibition In contrast, when indomethacin was administered in Sodium Acetylsalicylic animals of oedema combination with sodium salicylate, this severe side-ef salicylate acid tested % fect could be antagonized completely. The results are 50 3. 15 summarized in Table 4. 100 w 28 43 45 --- 50 13 15 Table 4 100 23 20X Antagonizing the gastrointestinal side-effects of indometh 50 50 50 21X acin by sodium salicylate administered simultaneously 100 OO 100 39.x (tests performed for 3 days on non-starved animals) - p < 0.05 (significance level determined by Student's 't' test) No. of Dosage mg/kg p.o. Ulcerous animals Indo- Sodium Died animals animals 50 The results listed above prove unambiguously that tested methacin saicylate No. % No. % sodium salicylate antagonizes the gastrointestinal ha 45 3 x 20 3 3. 73 45 100 2O 3 x 20 3 x 50 5 25 55 emorrhagic or ulcerogenic side-effects of other non 3 x 20 3 x 100 3 5 3 15 steroidal antiphlogistic agents, without affecting the 45 3 x 20 3 x 2 O O O O 55 main antiphlogistic effect. Similar effects are shown by compositions which contain other salicylic acid salts, or It has also been studied whether sodium salicylate in certain cases even salicylic acid itself, instead of so also antagonizes the ulcerogenic side-effects of anti dium salicylate. phlogistic agents other than indomethacin. These tests Thus the invention relates to pharmaceutical compo have shown that the ulcerogenic side-effects of phenyl 60 sitions containing as active agent a non-steroidal anti butazone, nifulmic acid and acetylsalicylic acid (aspirin) phlogistic substance or a pharmaceutically acceptable or its salts can also be antagonized effectively by admin salt thereof and salicylic acid or an alkali salicylate in an istering them together with sodium salicylate, and the amount of 0.2 to 50 parts by weight calculated for one main antiphlogistic effects of these compounds remain part by weight of said non-steroidal antiphlogistic sub unchanged, or even the antiphlogistic effects of the two 65 stance, optionally together with another biologically active agents are superimposed. It is particularly sur substance or a carrier or diluents. prising that the salts of salicylic acid exert a protective As alkali salicylate preferably sodium or lithium sali effect even against ulcers provoked by acetylsalicylic cylate is applied. 5 4,198,402 6 The above compositions can be prepared by methods suppositories. The active agents are homogenized with commonly applied in the pharmaceutical industry. The the molten carrier, and the massis cast into suppository pharmaceutical compositions can be presented, e.g. in molds...... is a . the form of tablets, sugars, or film-coated; tablets, cap Compositions for parenteral administration are pres Sules, suppositories, injeetable solutions, etc. Rii is 5 ented in injectable forms. To prepare injectable solu The pharmaceutical compositions according to, t tions the active agents are dissolved e.g. in distilled invention can be administered orally, rectally and/or water and/or various organic"solvents, such as lower parenterally either in a single dosage or in subdivided aliphatic alcohols or glycol ethers (particularly ethyl forms. For oral administration the compositions are eneglycolmonaethyl ether), optionally containing dis presented preferably in the for of tablets, sugar- or 10 solution aids, such as polyoxyethylene sorbitan monor particularlyfilm-coated tablets,preferable or capsules,unit dosage Film-coated forms. These tablets orally are laurate, monooleate or monostearate (Tween 20R, administerable compositions contain generally no filler, Tween 60R or Tween 80R). The injectable solutions but in some cases conventional filling agents, e.g. lac may contain various other additives, such as preserving tose or starch can also be admixed to then. As binding 5 agents (e.g. benzyl alcohol, methyl or propyl p-hydrox or granulating agent e.g. gelatine, sodium carboxy ybenzoate, phenylmercuric borate or benzalkonium methylcellulose, methyl cellulose, polyvinylpyrroli chloride), antioxidants (e.g. sodium pyrosulfate, ascor done or gellified starch can be used.The most appropri bic acid, tocoferol, etc.), complexing agents for binding ate disintegrating agents are potato.starch and micro traces of heavy metals (e.g. ethylenediamine tetraace crystalline cellulose, but other disintegrating agents, 20 tate), substances for adjusting the pH, buffers, and op such as ultraamylopectine, formaldehyde-caseine con tionally local anaesthetic agents (e.g. lidocaine). densates, etc. can be used as well. As lubricating and The injectable solutions are filtered, filled into vials antiadhesive substances e.g. talc, colloidal silicic acid, the vials are closed and sterilized. m stearine, calcium or magnesium stearate, etc. can be The invention is elucidated in detail by the aid of the used, : ...... 25 following non-limiting Examples. The tablets caribe prepared e.g. by the conventional EXAMPLE1 wet granulations compression-method. In this instance a dry blend of the active agents, fillers and optionally a Film oated tablets containing indomethacin and part of the disintegrating agents is kneaded with an sodium salicylate as active agents. aqueous, alcoholic or aqueous-alcoholic solution of the 30 appropriate binding agent, the mass is granulated, and Composition of one tablet: the obtained grafiiles are: dried. Thereafter the other additives (e.g. the remaining part of the disiitegrating ...sindomethacine ::::::::ii ... sodium salicylate. ... agents, lubricants, atitiadhesive substances, etc.) are magnesium stearate blended with the granular substanice; and the blendis. 35: polyvinyl pyrrolidone compressed into tablets. If desired, the tablets can be Eudragit-L ...... ; provided with parting incisions in order to facilitate talc 'x their division at administration. If desired, the tablets ...... potato starch:...... ": L. : : can be film-coated with substances resistant towards gastric juice, such as shellac-cellulose-acetate phthalate 40 or Eudragit-LR. These film forming substances are usu The tablets are prepared by the conventional wet ally deposited onto the tablet from an alcohol, particu granulation-compression-technique, -and-film-coated larly isopropanol solution. '...' ...'..... x , -" . ...-xx. -r' '..s- K...... v'-';x with Eudragit-LR. retire From the appropriate combinations of the active In the above composition sodium salicylate can be agents and additives the tablets can also be prepared by direct pressing method, and, if desired, the resulting 45 repaced by another alkali salicylate, such as lithium tablets can be provided with an intestinosolvent coat salicylate to obtain tablets with the same effect. 1ng...... : 33 N. EXAMPLE 2 If desired, the tablets can be coated with conven Suppositories containing indomethacin and sodium tional protecting, flavouring and/or colouring agents, 50 salicylate as active agents such as sugar, cellulose derivatives (methyl or ethylcel lulose, sodium earboxymethylcellulese, etc.), polyvinyl !, Composition of one suppository:...... ; pyrrolidone, calcium phosphate, calcium carbonate, coloring agents and varnishes cominorily used in the indomethacine food and pharmaceutical industry; iron oxide pigments, 55 sodium salicylate aroma substances, etc. For the sake of convenienice the !...... Witepsol Hill 5R...... thus-obtained coated, tablets are referred to in the specis fication and claims as "sugar-coated tablets', with the understanding that this term also coversicoated tablets which contain no sugar in-the-coating layer...... ; i. 60 The above components are admixed with each other Capsules are prepared by filling the mixture of the and th mixture is cast into supposit as wa ds. " active agents into hardgelatine capsules... : :::::::::: In the above composition sodium salicylate can be Compositions for rectal administration are presented replaced by lithium salicylate. in the form of suppositories. The suppositories contain, EXAMPLE 3 besides the active agents, conventional carriers, such as 65 vegetable fats (e.g. hardened vegetable, oils) or triglyc Film-coated tablets containing acetylsalicylic acid and erides of C12-18 fatty acids. Witepsol proved to be a sodium salicylate as active agents particularly preferable, carrier; for, the preparation; of Composition of one tablet: 4,198,402 7 8 The intestinosolvent tablets are prepared as described acetylsalicylic acid 200 mg in Example 1...... sodium salicylate 200 mg In the above composition phenylbutazone may be magnesium stearate 4 mg replaced by its sodium or calcium salt, and sodium sali : ; ; ; ; , Eudragi-Li, 15 mg cylate may be replaced by salicylic acid or lithium sali ; : talc . . 18 mg cylate. ; : ...... ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; , . polyvinylpyrrolidone 20 mg potato starch 58 mg microcrystalline cellulose 100 mg EXAMPLE.7. : ; ; ; ...... total 615 mg Injectable compositions containing phenylbutazone and ...... '; ...... O - sodium salicylate as active agents The tablets are prepared by direct pressing and film Composition of one unit dosage; - coated with Eudragit-LR to obtain intestinosolvent : . , , s : ... " compositions. ... phenylbutazone '100 Tablets containing another alkali salicylate instead of 15: sodium salicylate:...... ; ...... 250 mg sodium pyrosulfite, - . . . . ; is 0.3 mg sodium salicylate, or containing a salt (e.g. calcium salt) ethylenediamine tetraacetate. 0.6 mg of acetylsalicylic acid instead of the free acid can be ilidocaine hydrochloride 6.0 mg prepared by similar methods. ...'... sodium hydroxide ...... 14.0 mg benzyl alcohol; . . . . : ;... 30.0 mg ...... EXAMPLE 4 ... ethyleneglycol monoethylether 000.0 mg Suppositories containing acetylsalicylic acid and 20 distilled water, pro inj...... 30 ml sodium salicylate as active agents Phenylbutazone is dissolved in sodium hydroxide Composition of one suppository: solution under heating, and ethyleneglycol monoethyl 25 ether is added to the solution. In paralle, sodium salicyl acetylsalicylic acid 0.2g ate, sodium pyrosulfite and ethylenediamine tetraace sodium salicylate 0.2g tate are dissolved in a part of the distilled water (oxy Witepsol H-15 1.6 g gen-free...and saturated with nitrogen). The two solu : - ; total 2.0 g tions are combined, then a solution of lidocaine hydro 30 chloride in the remainder of the distilled, water, and The suppositories are prepared as described in Exam finally, the benzyl alcohol are added. The solution is ple 2. Suppositories containing calcium acetylsalicylate filtered, filled into dark, vials, the vials are closed and instead of the free acid, or another alkali salicylate in sterilized by heating. : : ::::::::::t. i. 2 s, , , , stead of sodium salicylate can be prepared by com In the above composition sodium salicylate can be pletely analogous methods. 35 replaced by another alkali salicylate. Similarly, phenyl EXAMPLES butazone can be replaced by a salt thereof. . . Film-coated tablets containing acetylsalicylic acid and EXAMPLE 8 sodium salicylate as active agents Film-coated tablets containing.nifluminic acid and omposition of one tablet: ... sodium salicylate as active agents, or Composition of one tablet: acetylsalicylic acid 200 mg - sodium salicylate 300 mg nifluminic acids: 150 mg magnesium stearate 5 mg sodium salicylate, 250 mg ! E::, risi talc...... 20 mg 45 magnesium stearate 3 mg Eudragi-Li is . . 20 mg * polyvinylpyrrolidone." 12 mg polyvinyl pyrrolidone 25 mg - Eudragit-LG) it iii., iii. : (; 15 mg potato starch . . . 100 mg talc 18 mg microcrystalline cellulose 150 mg potato starch } 167 mg - total 820 mg 50 total 615 mg The intestinosolvent tablets are prepared as described The intestinosolventitablets are prepared as described in Example 3. in Example i. i.i... ', 'fier 3: ... iii is EXAMPLE 6 What we claim is: . . . . " ; ; ; 55 1. A pharmaceutical composition containing as the Film-coated tablets containing phenylbutazone and active ingredient a combination of one part by weight of sodium salicylate as active agents phenylbutazone or a pharmaceutically acceptable salt Composition of one tablet: thereof and 0.2 to 50 parts by weight of an alkali salicyl ate in effective: amounts to reduce ulcer-lesion forma tion and at the same time being antiflammatory. phenylbutazone 100 mg sodium salicylate 250 mg 2. The composition defined in claim 1 wherein said magnesium stearate 3 mg ingredient is a combination of phenylbutazone and so polyvinyl pyrrollidone 10 mg dium salicylate in: effective amounts to reduce ulcer talc 15 mg lesion formation and at the same time being antiflamma Eudragit-L 15 mg 65 tory...... potato starch 122 mg. 3. A method of treating an animal 'subject for an in total 515 mg flammatory condition without ulcerogenesis and for reducing the tendency to ulcer-lesion formation in anti 9 4,198,402 10 flammatory treatments with ulcerogenic compounds E.and 0.2 to 50 parts by weight of an alkali-metal which comprises administering to said subject an effec- 4. The method defined in claim 3 wherein the combi nation phenylbutazone and sodium salicylate is adminis tive amount of a combination of one part by weight of 5 tered to said subject. phenylbutaZone or a pharmaceutically acceptable salt ::

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