NZ197520A

NZ197520A - Analgesic/anti-inflammatory compositions based on combination of certain analgesics and 3-phenylbenzoic acid derivatives

Info

Publication number: NZ197520A
Application number: NZ197520A
Authority: NZ
Inventors: T-Y Shen
Original assignee: Merck & Co Inc
Priority date: 1980-03-24
Filing date: 1980-03-24
Publication date: 1984-07-31

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 97520 ! NEW ZEALAND PATENTS ACT, 1953 No.: 197520 Date: 24 March 1980 COMPLETE SPECIFICATION & [*■*4 JUL 1981 ^/VE« IMPROVED ANTI-INFLAMMATORY COMBINATION HAVING REDUCED ULCEROGENICITY X/We, MERCK & CO., INC., a corporation duly organized and existing under the laws of the State of New Jersey, United States of America, of 126 East Lincoln Avenue, Rahway, State of New Jersey, United States of America, hereby declare the invention for which X / we pray that a patent may be granted to tax/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - 197520 The present invention relates to a novel drug combination for more effective treatment of pain, fever, and inflammation with reduced ulcerogenicity. Particularly, the present invention is concerned with the combination of (a) one or more members selected from the group consisting of (1) a-methyl-4-(2-methylpropyl)-benzene acetic acid (ibuprofen) (2) metabenzoylhydratropic acid (ketoprofen) (3) (+)-6-methoxy-a-methyl-2-naphthalene-acetic acid (naproxen) (4) 2-/(2,6-dichlorophenyl)amino7~ benzeneacetic acid monosodium salt (diclofenac sodium) (5) 1-methyl-5-(4-methylbenzoyl)-lH-pyrrole-2-acetic acid I (tolmetin) (6) 2-fluoro-a-methyl-(1,1 -biphenyl)-4-acetic acid (flurbiprofen) (7) 4-(1,3-dihydro-l-oxo-2H-isoindol- 2-yl)-a-methylbenzeneacetic acid (indoprofen) (8) (+) a-methyl-2-(4-chlorophenyl)-5-benzoxazole acetic acid (benoxa-profen) and (9) 4-hydroxy-2-methyl-N-2-pyridinyl-2H-l,2- - 3 - 1 975 2 benzothiazine-3-carboxamide lfl-dioxide (piroxicam), and (b) a member selected from phenyl benzoic acid compounds, especially 2-hydroxy-5-(2',4'-difluoro-phenyl) benzoic acid (diflunisal). 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (indomethacin) has long been an effective therapeutic agent in the treatment of pain, fever, and inflammation, and has been especially useful in treating / ' rheumatoid arthritis. However, it has long been recognized that use of indomethacin also results in undesirable irritation of the gastrointestinal mucosa, eventually leading, in many cases, to ulceration. '(All non-steroidal anti-inflammatory agents, including those named above, are also, to a greater or lesser extent, ulcerogenic; and it is hypothesized that a contributing factor to the basic mechanism of gastrointestinal irritation by these agents is the inhibition of prostaglandin production in the gastrointestinal mucosa. The phenyl benzoic acid compounds employed in the novel drug combination of the present invention are described in United States Patents Nos. 3,674,870 and 3,714,226 and in New Zealand Patent Specification No. 147913. The use of various compounds, particularly salicylic acid derivatives, to combat the gastrointestinal ulceration associated with use of various anti-inflammatory drugs, is known. See, for example, (1) Hanchar et al., "Antiulcer - 4 - 197520 Effect of Aspirin", Gastroenterology, Vol. 72, No. 5, Part 2 (1977) which reports the protective effect of aspirin, sodium salicylate, and aminopyrine when used with indomethacin; (2) British Patent Specification No. 1,483,165 which describes anti-inflammatory compositions having decreased gastrointestinal side-effects comprising indomethacin or other anti-inflammatory agents together with salicyclic acid or an alkali metal salicylate; (3) U.S. Patent No. 4,016,268 which describes the use of bismuth subsalicylate co-administered with anti-inflammatory drugs to combat gastric ulceration associated with such drugs; (4) Robert and Asano, t Prostaglandins, Vol. 14,"No. 2, pp. 333-338 (1977) which describes the use of 16, 16-dimethyl PGE2 to prevent intestinal lesions from indcmethacin in experimental animals; (5) Japanese Patent Publication No. 5 3062 839 (available on request) which discloses the u?e of mepirizole with non-steroidal anti-inflammatory agents to reduce ulcer formation caused by the latter; (6) Rainsford, Agents and Actions, Vol. 7, 516, pp. 573-577 (1977) which discloses that while the mixture of indomethacin and probenecid is effective in reducing the gastric damage by indomethacin, the effect of aspirin and indomethacin is almost additive; (7) Goburdhum et al. J. Pharma. Methods, Vol. 1, pp. 109-114 (1978) which discloses that copper salicylate is more effective than sodium salicylate in achieving inhibition of the ulcerogenic effects of indomethacin; (8) U.S. - 5 - 197520 Patent No. 4,066,756 and New Zealand Patent Specification No. 186033 which disclose the use of sodium cromoglycate to inhibit the gastrointestinal irritation caused by ixidanethacin; and (9) Scrip, Oct. 14, 1973, p. 24 (available on request), which discloses the use of parsalamide or rimazolium methyl-sulfate to reduce the ulcerogenic potential of indomethacin. However, unlike the majority of co-administered agents described in the prior art, particularly sodium salicylate and aspirin, the phenyl benzoic acid compounds employed in the present invention are, surprisingly, many times more effective on a molar basis. Gastric ulceration in the rat has also been shown to be inhibited by salicylic acid or aspirin alone. See Pauls et al., Science, Jan. 2, 1948 . In accordance with our New Zealand Patent Specification No. 193239 there is provided a novel drug combination for more effective treatment of pain, fever, and inflammation with reduced ulcerogenicity comprising (a) 1-(p-chloro-benzoyl)-5-methoxy-2-methylindole-3-acetic acid (indomethacin), and (b) a member selected from phenyl benzoic acid compounds, especially 2-hydroxy-5-(2',4'-difluorophenyl)benzoic acid (diflunisal), wherein the molar ratio of (b) to (a) is from 0.5 to 1.0 to 15.0 to 1.0,. and, preferably, from 1.5 to 1.0 to 10.1 to 1.0. It has been found that this novel drug combination, in addition to having reduced ulcerogenicity, also results ' ^ in a significantly increased plasma drug level of indo methacin over a period of time. 197520 - 6 - The phenyl benzoic acid compounds employed in Patent Specification No. 193239 are also effective in reducing the ulcerogenic effects of other non-steroidal antiinflammatory agents. In accordance with the present invention there is provided additional novel drug combinations for more effective treatment of pain/ fever and inflammation with reduced ulcerogenicity comprising (a) a member selected from phenyl benzoic acid compounds as described herein, especially 2-hydroxy-5-(2' , 4'-difluorophenyl) benzoic acid (diflunisal) and (b) one or more members selected from the group consisting of (1) a-methyl-4-(2-methyl-propyl) benzene acetic acid (ibuprofen) (2) meta-benzoyl-hydratropic acid (ketoprofen) (3) (+)-6-methoxy-a-methyl-2-naphthaleneacetic acid (naproxen) (4) 2-^/(2,6-dichloro-phenyl) amino/benzeneacetic acid monosodium salt (diclofenac sodium) (5) l-methyl-5-(4-methylbenzoyl)-lH-pyrrole-2-acetic acid (tolmetin) (6) 2-fluoro-a-methyl-(1,1'-biphenyl)-4-acetic acid (flurbiprofen) (7) 4-(1,3-dihydro- 1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetic acid (indo-profen) (8) (+) a-methyl-2-(4-chlorophenyl)-5-benzoxazole acetic acid (benoxaprofen) and (9) 4-hydroxy-2-methyl-N- 2-pyridinyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide (piroxicam). The phenyl benzoic acid compounds employed in the novel drug combination of the present invention to reduce the ulcerogenicity of the non-steroidal anti-inflammatory - 7 - component of the combination are selected from compounds of the general formula: O (I) wherein X (1-5) is halo, such as fluoro or chloro, but especially fluoro; X being on one or more of the phenyl carbon atoms; R-^ is selected from the group consisting of hydroxy,, phenoxy, diloweralkylamino (such as dimethylamino) , and diloweralkylamino loweralkoxy (such as diethyl-aminoethoxy); R2 is selected from the group consisting of hydrogen; lower alkanoyl (such as acetyl, propionyl and butyryl); and lower alkoxycarbonyl (such as n-butoxycarbonyl); and R^ is selected from the group consisting of hydrogen and methyl. Also included are the pharmaceutically non-toxic salts of the acids of the compounds of Formula I such as the ammonium, alkali metal (such as sodium or potassium); alkaline earth metals (such as calcium, barium or magnesium) ; amine; aluminum; iron; choline; glucosamine; S-methyl methonine salts, piperazine, a diloweralkylamino - 8 - 1975 20 lower alkanol, chloroquine and hydroxy chloroquine; the anhydride of said acids, the mixed anhydrides of the said acids and 2-acetoxy benzoic acid. In the present patent specification and the appended claims, the terms "lower alkyl", "lower alkoxy" and "lower alkanoyl" denote alkyl, alkoxy and alkanoyl groups each containing up to a maximum of 6 carbon atoms. The term"lower alkanol" denotes an alkanol containing from / J 1 to 6 carbon atoms. Especially preferred phenyl benzoic acid compounds are those wherein: is hydroxy, R2 is hydrogen, R^ is hydrogen, and X is fluoro, X being on any position of the phenyl moiety when X is one fluoro group, but particularly on the 4'-position; and where X represents two fluoro groups, particularly on the 2' and 4'-positions. Representative phenyl benzoic acid compounds are as follows: 2-hydroxy-5-(2'-4'-difluorophenyl)benzoic acid; 2-acetoxy-5-(21,4'-difluorophenyl)benzoic acid; 2-hydroxy-5 —(2'-fluorophenyl)benzoic acid; 2-hydroxy-5-(4'-fluorophenyl)benzoic acid; 2-hydroxy-5-(3'-fluorophenyl)benzoic acid; 2-hydroxy-5-pentafluorophenyl benzoic acid; 2-hydroxy-3-methyl-5-(2',4'-difluorophenyl)benzoic acid; 2-hydroxy-5-(2 *-chloro-4'-fluorophenyl)benzoic acid; N,N-dimethyl-5-(2'-4 1-difluorophenyl)salicylamide; f?-diethylaminoethyl-5- (2 *,4'-difluorophenyl) salicylate phenyl-5-(2 * , 4 '-difluorophenyl)salicylate; aluminum-2-acetoxy-5-(2',4'-difluorophenyl)-benzoate salt; aluminum-2-hydroxy-5-(2',4'-difluorophenyl)-benzoate i salt; choline-2-acetoxy-5- (2' , 4 '-difluorophenyl)-benzoate f. salt; choline-2-hydroxy-5-(2• , 4'-difluorophenyl)-benzoate salt; sodium-2-acetoxy-5-(2',4'-difluorophenyl)-benzoate salt; sodium-2-hydroxy-5- (2',4 ' -difluorophenyl)-benzoate salt; 2-acetoxy-5-(pentafluorophenyl)-benzoic acid; B-diethylaminoethyl-2-hydroxy-5-(21,4'-difluorophenyl) -benzoate; g-diethylaminoethyl-2-acetoxy-5-(2', 4 '-difluorophenyl) -benzoate ; and 2-(n-butoxycarbonyloxy)-5-(2',4 *-difluorophenyl)-benzoic acid. The present invention is also concerned broadly with a method of reducing the ulcerogenicity of a selected 197520 - 10 - non-steroidal anti-inflammatory agent when given perorally to a host to treat pain, fever, and inflammation, comprising co-administering to said host an amount sufficient to reduce the ulcerogenicity of the anti-inflammatory agent, of a phenyl benzoic acid compound as utilized in the present invention. Such co-administration may simply take the form of simultaneous administration of the anti-inflammatory agent and phenyl benzoic acid compound, without any requirement that the two compounds be physically combined. More, advantageously however, co-administration will take the form of treatment utilizing a physical mixture of the antiinflammatory agent and phenyl benzoic acid compound''together with a pharmaceutically acceptable carrier. The treatment of pain, fever, and inflammation with reduced ulcerogenicity in accordance with the preferred method of the present invention is thus accomplished by orally administering to patients in need of such treatment a composition having as its active ingredient a mixture of the non-steroidal anti-inflammatory agent and a compound of Formula I, in proportional weight amounts such that the molar ratio of the compound of Formula I to the antiinflammatory agent is from 0.5 to 1.0 to 15.0 to 1.0, in a non-toxic pharmaceutically acceptable carrier, preferably in tablet or capsule form. The non-toxic pharmaceutical carrier may be for example, either a solid or a liquid. Exemplary of solid carriers are lactose, corn starch, belatin, talc, stearic acid, magnesium 197520 - n - stearate, terra alba, sucrose, agar, pectin, cab-o-sil, acacia. Examplary of liquid carriers are peanut oil, olive oil, sesame oil and water. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl disterate alone or with a wax. Several pharmaceutical forms of the therapeutically useful compositions can be used. For example, if a solid carrier is used, the compositions may take the form of tablets, capsules, powders, troches or lozenges, prepared by standard pharmaceutical techniques. If a liquid carrier is used, the preparation may be in the form of a so'ft gelatin capsule, a syrup or a liquid suspension. Particularly desirable are pharmaceutical forms which provide sustained release, such as sustained release capsules, and constant rate delivery, such as tablets coated with a semipermeable membrane where the drug and excipients develop an osmotic pressure which delivers a saturated solution of the drug through an orifice of controlled size at a constant rate. See U.S. Patents Nos. 3,845,770 and 3',916,899. The anti-inflammatory agent and active compounds of Formula I, and of the compositions of this invention are present in an amount sufficient to treat pain, fever, and inflammation, that is, to reduce pain, fever, and inflammation. Advantageously, the composition will contain the active ingredient, namely, the anti-inflammatory agent IC11510 4 - 12 - and compound of Formula I in an amount of from about 1 mg. to 7 0 mg. per kg. body weight per day (50 mg. to 5 g. per patient per day), preferably from about 2 mg. to 35 mg. per kg. body weight per day (100 mg. to 2.5 g. per patient per day). The preferred method of treatment of this invention comprises internally administering to a patient (non-human animal or human), the anti-inflammatory agent and a compound of Formula I, admixed with a non-toxic pharmaceutical carrier such as examplified above. The mixture of the antiinflammatory agent and compound of Formula I will be present in an amount of from 1 mg. to 70 mg./kg. body weight per day, preferably from about 2 mg. to about 35 mg. per kilogram body weight per day and especially from 4 mg. to 2 0 mg./kg. body weight per day. The most rapid and effective analgesic, anti-pyretic, and anti-inflammatory effect is obtained from oral administration of a daily dosage of from about 4 to 2 0 mg./kg. day. It should be understood, however, that although preferred dosage ranges are given, the dose level for any particular patient depends upon the activity of the specific compound employed. Also many other factors that modify the actions of drugs will be taken into account'by those skilled in the art in the therapeutic use of medicinal agents, for example, age, body weight, sex, time of administration, route of administration, rate of excretion, drug combination, reaction sensitivities and severity of the particular disease. 1 7 2 13 The more effective treatment of pain, fever, and inflammation with reduced ulcerogenicity achieved with the novel drug combination of Specification No. 193239 was evaluated in a bioassay designed to measure the reduced ulcerogenicity of the novel drug combination as compared to indomethacin alone. In accordance with the procedures of this bioassay, a total of 10 young adult male Sprague-Dawley rats weighing 125 g. to 175 g. are used for each different treatment group. The animals are marked, weighed, and distributed randomly into groups.' All drugs are given in a single dose, suspended in 0.5% methylcellulose using a Virtis -23 homogenizer. Tlie animals are allowed food and water during the test period. After 72 hours the animals are weighed and then sacrificed using carbon dioxide. The abdominal cavity is opened and the entire length of the small intestine is removed. A 20 ml. syringe containing water with a rat dosing needle attached is inserted into the pyloric end of the intestine. The intestine is flushed and the opposite end clamped with a hemostat. The intestine is distended by injecting additional water until the intestinal wall becomes firm. A performation is indicated by a leak or bursting of the intestinal wall. One perforation or adhesion of two loops of intestine constitutes a positive result. The study is performed blind and the score for a group is recorded as incidence or percent. If a dose-response curve is determined, then the amount of drug required to 1975 20 - 14 - produce perforations in 50% of the animals.can be estimated. The results of the bioassay for the combination of diflu-nisal and indomethacin on a 4:1 weight ratio basis are illustrated in the table of values below. TABLE I Dose of Percent of Rats with Perforations indomethacin Indomethacin Indomethacin + (mg./kg.) alone Diflunisal (1:4) 6.7 50 10 8.0 90 0 9.6 100 0 11.5 100 80 The above data clearly shows that diflunisal, on a 4:1 weight basis, has the ability to dramatically reduce the ulcerogenicity of indomethacin. The bioassay described above was employed to compare the effectiveness of the phenyl benzoic acid compounds employed in the novel drug combination of Specification No. 193239 in reducing the ulcerogenicity of indomethacin with sodium salicylate and aspirin (acetyl-salicylic acid). The results of the bioassay are illustrated in TABLE II below. 1975 2 - 15 -TABLE II Dose Approximate Percent of Indomethacin Protective (mg./ Molar Rats with Dose(mg./kg.) Agent leg.) Ratio Perforations 8.0 None (Vehicle) — — 100 9.6 «l — — 100 8.0 Diflunisal 5.6 1 80 9.6 91 6.7 1 80 8.0 M 11.2 2 60 9.6 fl 13.4 2 60 8. 0 91 22.4 4 0 9.6 M % 26. 8 4 0 . 8.0 None 100 (Vehicle) fi'00 9.6 VI ' — -- 8. 0 Aspirin ; 32.0 8 80 9.6 tt 38.4 8 80 8. 0 It 64.0 16 20 9.6 n 76. 8 16 60 8. 0 «i 128.0 32 20 9.6 n 153.6 32 20 o • 00 # None (Vehicle) — • 100 9.6 «1 — — 100 8.0 Sodium Salicylate 16.0 4.5 80 9.6 ft 19.2 4.5 100 8.0 fl 32.0 9 80 9.6 fl 38.4 9 80 8.0 tl 64.0 18 20 9.6 ft 76. 8 18 40 10 15 20 25 30 35 The data in the above table clearly demonstrates the surprisingly greater effectiveness of the phenyl benzoic acid compounds employed in the novel drug combination of Specification No. 193239 in reducing the ulcerogeni" city of indomethacin, as compared to asoirin and sodium salicylate. 1 975 20 - 16 - Another bioassay was designed to measure the reduced ulcerogenicity of the novel drug combination of Specification No. 193239. This bioassay was intended to observe the acute effects of various treatments 5 on the gastric mucosa. In accordance with the procedures of this bioassay, a total of 22 young adult male Sprague-Dawley rats of a particular offspring available from Camm Research of New Jersey, weighing between 120 g. and 200 g. are used for each different 10 treatment group, including controls. The animals are marked, weighed, and distributed randomly into groups and the bioassay is done blind. The rats are fasted for at least 24_ hours and then given 20 mg./kg. of indomethacin, suspended in 0.5% rr/etftyl-15 cellulose, a dose known to produce gastric lesions within 4 hours. The control animals receive no additional treatment, while the test animals receive various dosages of the protective compounds together with the indomethacin. All drugs, including the 20 combinations, ere .given in a single dose, suspended in 0.5% methylcellulose using a Virtis -23 homogenizer. The animals are not allowed food and water during the test period. After 4 hours the animals are weighed and then sacrificed using carbon dioxide. The 25 stomach is exposed, excised, and opened along its lesser curvature, and then washed gently with saline. The surface of the gastric mucosa is then examined for bloody lesions equal to or greater than 2 millimeters in diameter, and these, if present, are counted. If 30 the number of such lesions exceeds 10, it is recorded as 10. In addition to counting the number of lesions, a record is kept of the number of animals free of lesions. The results of the bioassay are illustrated in TABLE III below. TABLE III Dose Indomethacin Protective (mg./ Approximate Dose (mg./kg.) Agent kg.) Molar Ratio Gastric Lesions Number and % Change % of Rats Total from Having Number Control Lesions 20 20 20 20 20 20 20 None (Vehicle) Diflunisal Sodium Salicylate 28 56 112 36 72 144 2 4 8 4 16 131 119 57 v25 99 90 45 -9.2 -56.5 -80.9 -24.4 -31.3 -65.6 21 22 22 22 18 22 6 21 22 12 18 22 11 72 95 100 82 27 100 86 50 197 - 18 - The same bioassay was repeated with indomethacin but using a decreased number of animals. The results of the bioassay are illustrated in Table IV below and show that the decreased number of animals in the tests does not affect the accuracy of the method. The same bioassay was repeated but with naproxen, diclofenac sodium and flurbiprofen respectively instead of indomethacin. The results of these bioassays are illustrated in Tables V, VI and VII below and show the effectiveness of diflunisal in reducing the ulcerogenicity of naproxen, diclofenac sodium and flurbiprofen. 1975 20 - 19 -TABLE IV EFFECT OF DIFLUNISAL ON GASTRIC LESIONS INDUCED BY INDOMETHACIN INDOMETHACIN DIFLUNISAL vM0LAR RATIO N GASTRIC LESTIONS > 2 mm Dose (mg/k g) Dose (mg/kg) Total tt X Change #of with animals le s i on i 0 0 - 6 0 0 0 20 0 - 6 20 - 6 out of 6 20 28 2 6 8 -60 3 out of 6 r 112 8 6 3 -85 2 but of 6 N - Total number of animals # = Number TABLE V EFFECT OF DIFLUNISAL ON GASTRIC LESIONS INDUCED BY NAPROXEN (L-620/-012) NAPROXEN Dose (mg/k g) 0 20 20 20 20 DIFLUNISAL Dose (mg/k g) 0 0 36.8 73.6 147.2 MOLAR RATIO 2 4 8 N 6 6 6 6 6 GASTRIC LES.TIONS : > 2 mm Total # 0 28 25 7 0 X Change -11 - 75 -100 # of animal-with lesion- 6 out of 6 5 out of 6 3 out of 6 0 out of 6 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 20 - 197520 TABLE VI EFFECT OF DIFLUNISAL ON GASTRIC LESIONS INDUCED BY DICLOFENAC SODIUM (L-628,0: DICLOFENAC MOLAR SODIUM DIFLUNISAL RATIO N GASTRIC L E STI ON S > 2 mm Dose Dose # of animals Cmg/kg) (mg/kg) Total # X Change with lesions 0 0 - 6 0 - - ) 10 0 - 6 33 - 6 out of 6 10 17.5 2 6 16 - 52 5 out of 6 10 35.0 4 6 18 - 46 5 out of 6 10 h 70.0 8 6 9 - 73 1 out of 6 TABLE VII EFFECT OF DIFLUNISAL ON GASTRIC LESIONS INDUCED BY FLURBIPROFEN (L-631,231) FLURBIPROFEN DIFLUNISAL MOLAR RATIO N GASTRIC LESIONS > 2 mm Dose (mg/kg) Dose (mg/kg) Total # % Change # of animals with lest ions 0 0 - 6 0 - - 20 0 - 6 29 - 6 out of 6 20 40 2 6 23 _ 21 6 out of 6 20 80 4 6 2 - 93 2 out of 6 > 20 160 8 6 .2 - 93 2 out of 6 xv- te /tS 9^ -&\v 197520 21 WHAT WE CLAIM IS: 1. In combination: (a) One or more members selected from the group consisting of (1) a-methyl-4-(2-methylpropyl) benzene acetic acid (ibuprofen) (2) metabenzoylhydratropic acid (ketoprofen) (3) (+)-6-methoxy-a-methyl-2-naphthalene-acetic acid (naproxen) (4) 2-/72,6-dichlorophenyl) amino/ benzeneacetic acid monosodium salt (diclofenac sodium) (5) l-methyl-5-(4-methylbenzoyl)-lH-pyrrole-2-acetic acid (tolmetin) (6) 2-fluoro-a-methyl-(1,1'-biphenyl)-4-acetic acid (flurbiprofen) (7) 4-(1,3-dihydro-l-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetic acid (indoprofen) (8) ( + ) a-methyl-2-(4-chlorophenyl)-5-benzoxazole acetic acid (benoxaprofen) and (9) 4-hydroxy-2-methyl-N-2-pyridinyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide (piroxicam); and (b) a member selected from phenyl benzoic acid compounds of the formula:

1 C—R (I) R 3 wherein X(l-5) "*"S ka^0' x being on one or more of the phenyl carbon atoms; \ 41510 1S7520 - 22 - R-^ is selected from the group consisting of hydroxy, phenoxy, diloweralkylamino, and diloweralkylamino loweralkoxy; R2 is selected from the group consisting of hydrogen; lower alkanoyl; and lower alkoxycarbonyl; and R^ is selected from the group consisting of hydrogen and methyl; and pharmaceutically acceptable, non-toxic salts of the acids of the conpounds of Ebrmula (I); wherein the molar ratio of (b) to (a) is from 0.5 to 1.0 to 15.0 to 1.0. 2. The combination of Claim 1 wherein the phenyl benzoic acid compound is 2-hydroxy-5-(2',4'-difluorophenyl)-benzoic acid. 3. A method of treating pain, fever, and inflammation which comprises orally administering to a non-human animal patient in need of such treatment, daily doses of from 1 mg. to 70 mg./kg. of body weight of the combination of (a) one or more members /selected from the group consisting of (1) a-methyl-4-(2-methylpropyl) benzene acetic acid (ibuprofen) (2) metabenzoylhydratropic acid (keto-profen) (3) (+)-6-methoxy-a-methyl-2-naphthaleneacetic acid (naproxen) (4) 2-/X2,6-dichlorophenyl)amino/ benzene-acetic acid monosodium salt (diclofenac sodium) (5) 1-methyl-5-(4-methylbenzoyl)-lH-pyrrole-2-acetic acid (tolmetin) (6) 2-fluoro-a-methyl-(1,11-biphenyl)-4-acetic ?a£:id (flurbiprofen) (7) 4-(1,3-dihydro-l-oxo-2H-isoindol- - 23 - 197

2-yl)-a-methylbenzeneacetic acid (indoprofen) (8) (+) a-methyl-2-(4-chlorophenyl)-5-benzoxazole acetic acid (benoxaprofen) and (9) 4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-

3-carboxamide 1,1-dioxide (piroxicam) and (b) a member selected from phenyl benzoic acid compounds of the formula: wherein X(l-5) "*"S k3--!-0' x being on one or more of the phenyl carbon atoms; is selected from the group consisting of hydroxy, phenoxy, diloweralkylamino, and diloweralkylamino loweralkoxy; R2 is selected from the group consisting of hydrogen; lower alkanoyl; and lower alkoxycarbonyl; and R3 is selected from the group consisting of hydrogen and methyl; and pharmaceutically acceptable, non-toxic salts of the acids of the compounds of Formula (I); wherein the molar ratio of (b) to (a) is from 0.5 to 1.0 to 15.0 to 1.0. 4. The method of Claim 3 wherein the phenyl benzoic 1 975 24 acid compound is 2-hydroxy-5-(2',41-difluorophenyl)-benzoic acid. 5. A pharmaceutical composition for treating pain, fever, and inflammation consisting of an effective amount of the combination of (a) one or more members selected from the group consisting of (1) a-methyl-

4-(2-methylpropyl) benzene acetic acid (ibuprofen) (2) metabenzoylhydratropic acid (keto-profen) (3) (+)-6-methoxy-a-methyl-2-naphthaleneacetic acid (naproxen) (4) 2-/(2,6-dichlorophenyl) amino/ benzene acetic acid monosodium salt (diclofenac sodium) (5) 1-methyl-

5-(4-methylbenzoyl)-lH-pyrrole-2-acetic acid (tolmetin) (6) 2-fluoro-a-methyl-(1,11-biphenyl)-4-acetic V acid (flurbiprofen) (7) 4-(1,3-dihydro-l-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetic acid (indoprofen) (8) (+) a-methyl-2-(4-chlorophenyl)-5-benzoxazole acetic acid (benojcaprof en) and (9) 4-hydroxy-2-methyl-N-2-pyridinyl-2H-l,t -benzothiazine-3-carboxamide 1,1-dioxide (piroxicam) and (b) a member selected from phenyl benzoic acid compounds of the formula: 0 II C R 1 •y (1-5) OR 2 (I) R 3 - 25 - 197520 wherein is halo; X being on one or more of the phenyl carbon atoms; is selected from the group consisting of hydroxy, phenoxy, diloweralkylamino, and diloweralkylamino loweralkoxy; R2 is selected from the group consisting of hydrogen; lower alkanoyl; and lower alkoxycarbonyl; and R^ is selected from the group consisting of hydrogen and methyl; and pharmaceutically acceptable, non-toxic salts of the acids of the compounds of Formula (I); wherein the molar ratio of (b) to (a) is from 0.5 to 1.0 to 15.0 to 1.0. 6. The composition of Claim 5 wherein the phenyl benzoic acid compound is 2-hydroxy-5-(2',4'-difluorophenyl)-benzoic acid. 7. A method of reducing the ulcerogenicity of a member selected from the group consisting of (1) a-methy1-4-(2-methylpropyl) benzene acetic acid (ibuprofen) (2) metabenzoylhydratropic acid (ketoprofen) (3) (+)-

6-methoxy-a-methyl-2-naphthaleneacetic acid (naproxen) (4) 2-/12,6-dichlorophenyl) amino/ benzeneacetic acid monosodium salt (diclofenac sodium) (5) l-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid (tolmetin) (6) 2-fluoro-a-methyl- (1,1'-biphenyl)-4-acetic acid (flurbiprofen) (7) 4-(l,3-dihydro-l-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetic acid (indoprofen) (8) (+) a-methyl-2-(4-chlorophenyl)-5- 1^7 no * C,o f) i.I . JiV u 26 benzoxazole acetic acid (benoxaprofen) and (9) 4-hydroxy-2—methyl-N—2-pyridinyl-2H—1,2—benzothiazine-3—carboxamide 1,1-dioxide (piroxicam) when given perorally to a non-human animal host to treat pain, fever, and inflammation, comprising coadministering to said host an amount sufficient to reduce the ulcerogenicity of said compound, of a member selected from phenyl benzoic acid compounds of the formula: carbon atoms; is selected from the group consisting of hydroxy, phenoxy, diloweralkylamino, and diloweralkylamino loweralkoxy; R2 is selected from the group consisting of hydrogen; lower alkanoyl; and lower alkoxycarbonyl; and R^ is selected from the group consisting of hydrogen and methyl; and pharmaceutically acceptable, non-toxic salts of the acids of the compounds of Formula (I). 8. The method of Claim 7 wherein the phenyl benzoic acid compound is 2-hydroxy-5-(2',41-difluorophenyl) benzoic I (I) X wherein X ^ is halo; X being on one or more of the phenyl acid. AGENTS FOR THE APPLICANTS </div>