GB1585630A - Pharmaceutical compositions - Google Patents

Description

(54) PHARMACEUTICAL COMPOSITIONS (71) We. EGYT GYOGYSZERVEGYESZETI GYAR. a Hungarian body corporate of 30 Kereszturi ut. Budapest X. Hungary. do hereby declare the invention for which we pray that a patent may be granted to us. and the method by which it is to be performed. to be particularly described in and by the following statement: The invention relates to novel pharmaceutical compositions showing an enhanced antiphlogistic effect.

As is known. indomethacin [l-(p-chlorobenzoyl) -5-methoxy-2-methyl -indole-3-acetic acid] and phenylbutazone (4-butyl- 1. 2-diphenyl-3. 5-pyrazolidinedione) have recently been the most widely used antiphlogistic agents. The administration of these compounds is.

however. frequently followed by the manifestation of undesired side effects. A further characteristic of the above compounds is that their therapeutic effects cannot be increased.

beyond a certain limit. by increasing the dosage administered.

The invention is concerned with novel pharmaceutical compositions in which the effect of known antiphlogistic agents such as indomethacin and phenylbutazone is potentiated so that.

by use of a reduced dosage. the undesired side effects characteristic of these agents are largely avoided.

According to the present invention there is provided a pharmaceutical composition exhibiting an enhanced antiphlogistic effect. containing 1 part by weight of a known antiphlogistic substance together with 1 to 99 parts by weight of 2 (cyclopropylamino-acetamido) -4-(3'-pyridyl)-thiazole or a pharmaceutically acceptable salt thereof and optionally a pharmaceutical adjuvant. 2-(Cyclopropylamino-acetamido)-4 -(3'-pyridyl)-thiazole is known to exert ulcer inhibiting effects (Hungarian patent specifica tionNo. 168.776).

The invention permits the use of the known antiphlogistic agents. such as indomethacin.

phenylbutazone. acetvlsalicylic acid and amidazophen in dosages lower than the usual.

whereby the undesirable side effects of these compounds can be considerably reduced. The potentiating effect of 2-(cvcloprop)lamino-acetamido) -4-(3'-pyridyl)-thiazole has been shown with everv antiphlogistic agent we have tested. and to the best of our belief this effect will be shown independently of the nature of the antiphlogistic agent.

This is surprising to one skilled in the art since it is well known that when antiphlogistic agents are used in combination with one another. the activities of the individual constituents are not additive: on the contrary. the activities are mutually decreased. Thus e.g. the administration of non-steroidal antiphlogistics in combination with one another leads to a weaker therapeutic effect than their administration individually [Van Arman et al.: Phar macol. Exp. Ther. 187, 400 (1973); Van Arman et al.: Pharmacologist 12, 202 (1970); Swingle et al.: J. Pharmacol. Exp. Ther. 172.,423 (1970); Mielens et al.: J. Pharm. Phar macol.20, 567(1968)].

The results we observed from the combined and separate administration of phenylbutazone and indomethacin fully support the above statement (cf Table 1).

Tablet Combined effects ofindomethacin andphenylbutazone in carrageenin oedema test Indomethacin 0.9%NaCI solution Phenylbutazone mg/kgp.o 0.2ml/100g 25 mg/kg p.o.

Inhibi- Increase of Inhibi- Increase of tion, % sole volume tion, % sole volume 1 -18 51.0+4.0 -18 50.6+6.1 3 -29 44.1 + 1.8 -29 44.0t2.1 10 -42 35.4t1.7 -24 46.9+3.2 0 0 62.owl.2 -30 43.1+1.4 The tests were performed according to Winter et al. [Proc. Soc. Exp. Biol. Med. 111, 544 (1962)].

The data of Table 1 clearly show that when indomethacin is administered along with an effective dosage (25 mg/kg) of phenylbutazone, the activity of indomethacin does not increase but rather is reduced.

Thus it could not be foreseen that the administration of a known antiphlogistic agent along with 2-(cyclopropylamino-acetamido) -4-(3'-pyridyl)-thiazole can greatly increase the activity of the antiphlogistic agent.

A particularly preferred composition according to the invention contains indomethacin and 2-(cyclopropylamino-acetamido) -4-(3'-pyridyl)-thiazole in a weight ratio of about 1:2.

The compositions according to the invention contain preferably indomethacin, phenylbutazone or acetylsalicylic acid as antiphlogistic agent.

The pharmacological tests performed with the compositions according to the invention and the results thereof are summarized below.

I. Examination ofthemain effects A) Examination of antiphlogistic effect The antiphlogistic effects of the substances and compositions studied were determined by the carrageenin oedema test [Winter et al.: Proc. Soc. Exp. Biol. Med. 111, 544 (1962)].

The percentage inhibition values exerted by indomethacin on the development of rat sole oedema are summarized in Table 2.

Table 2 Antiphlogistic effect or indomethacin in carrageenin cedema test Dosage, mg/kg p.o. Inhibition. % Increase of sole volume 0.3 -13 53.62.5 1.0 -18 51.0+4.0 3.0 -29 44.1 + 1.8 10.0 -42 36.4+ 1.7 30.0 -50 31.0t2.1 ED, N20mg/kgp.o.

The results of the tests performed with a combination of indomethacine and GYKI 43,185 are given in Table 3.

Table 3 Joint effect ofindomethacin and GYKI 43, 185 + 25 mg/kg p.o. of GYKI 43,185 Indomethacin Inhibition, %. Increase of mg/kgp.o. sole volume 0.3 -43 35.8#2.9 1.0 -43 35.6l2.1 3.0 -45 34.5+ 3.0 10.0 -62 23.9#2.0 30.0 -66 21.3#2.0 ED50: 2.6 mg/kg p.o.

The comparison of the data of the above Tables shows that the ED50 value of indomethacin (about 20 mg/kg) decreases considerably (to 2.6 mg/kg) when this antiphlogistic agent is administered along with GYKI 43,185. This decrease in ED50 value corresponds to a nearly eightfold increase in activity.

The test data characteristic of the antiphlogistic effect of phenylbutazone are listed in Table 4.

Table 4 Antiphlogistic effect ofphenylbutazone in carrageenin oedema test Dosage mg/kg p.o. Inhibition, % Increase of sole volume 6.25 0 63.83.0 12.5 -11 55.3#1.9 25.0 -30 43.4 1.4 50.0 -46 33.7+2.3 100.0 -50 31.5#2.3 200.0 -50 31.0+2.5 ED50 > 100 mg/ kg p.o. - 200 mg/kg p.o.

The results of the tests performed with a combination of phenylbutazone and GYKI 43.185 are listed in Table 5.

TableS Joint effect of phenyl butazone and G YKI 43,185 + 25 mg/ kg p.o. of GYKI 43.185 Phenylbutazone Inhibition. % Increase of mg/kg p.o. sole volume 6.25 -17 51.6#3.0 -48 32.3+ 1.7 25.0 -53 29.5#2.3 50.0 -62 24.1#1.5 100.0 -67 20.0+ 1.3 ED50: 25 mg/kgp.o.

The comparison of the calculated ED50 values shows a 4 to 8 fold increase in activity when phenylbutazone is administered along with GYKI 43.185. The initial ED50 value of phenyl butazone (100.0 to 200.0 mg/kg) decreases to 25 mg/kg when phenylbutazone is administered in combination with 25 mg/kg of GYKI 43,185.

The results of the tests performed with a combination of acetylsalicylic acid and GYKI 43,185 are listed in Table 6.

Table 6 Joint effort ofacetylsalicylic acid and GYKI 43,185 0.9% NaCl solution GYKI 43,185 Acetylsali- 0.2 ml/ 100 g 25 mg/kg p.o.

cyclic acid mg/kg Inhibi- Increase of Inhibi- Increase of p.o. tion, % sole volume tion,% sole volume 30.0 -14 53.5#5.0 -60 24.8+4.0 100.0 -38 38.4+4.8 -73 16.7+3.4 300.0 -62 23.613.1 -76 14.912.9 The test results given in Tables 2 to 6 also indicate that when administering an otherwise ineffective dosage of indomethacin, phenylbutazone or acetylsalicylic acid along with GYKI 43,185, marked biological effects can be obtained.

Taking into account that the antiphlogistic agents used in clinical practice possess analgesic and antipyretic effects as well, the combined compositions according to the invention have also been tested for these activities.

B) Examination of analgesic effects The tests aimed at determining how GYKI 43,185 influences the analgesic effect of indomethacin, phenylbutazone and acetylsalicylic acid. The tests were performed according to the method of Randall and Selitto [Arch. Int. Pharmacodyn. 111,409(1957)]. The results are summarized in Tables 7 to 9.

Table 7 Joint effect ofindomethacin and GYKI 43,185 in Randall Selitto test +0.9%NaClsolutidn + GYKI43,185 Indomethacin 0.2ml/ lOOg 25 mg/kg p.o.

mg/kgp.o. Thresh., g. Incr. Thresh.,g. Incr.

0.1 123#1.6 13 226+29.8 116 0.3 156+2.1 46 255119.5 145 1.0 16513.1 55 290+21.6 180 3.0 158110.8 48 261118.2 151 11011.8 176#8.7 66 Table 8 Joint effect ofphenylbutazone and GYKI 43,185 in Randall-Selitto test +0.9% Na Cl Solution +GYKI43,185 Phenylbutazone 0.2 ml/ 100 g 25 mg/kg p.o.

mg/kgp.o. Thresh., g. Incr. Thresh., g. Incr.

3.0 147+6.8 22 211+13.2 86 10.0 256+ 14.4 \ 131 379+53.4 254 30.0 246#25.0 121 441136.7 316 100.0 331#25.9 206 598+32.2 473 12513.3 229111.7 104 Table 9 Joint effect ofacetylsalicylic acid and G YKI 43,185 in Randall-Selitto test Acetylsali- + 0.9% NaCl solution + GYKI 43.185 cynic acid 0.2 ml/ 100 g 25 mg/kg p.o mg/kgp.o Thresh.. g. Incr. Thresh.. g. Incr.

3.0 153+7.1 45 190+3.5 82 10.0 259+26.8 151 323+19.7 215 30.0 340+ 19.0 232 401+26.3 293 100.0 320126.4 212 499+42.9 391 300.0 355+21.3 227 400#17.8 292 108#1.5 221111.7 113 Abbreviations used in Tables 7 to 9: Thresh.. g.: pain threshold in grams (determined 3 hours after the administration of the inflammatory agent) Incr.: increase of the threshold value The data of Tables 7 to 9 demonstrate that GYKI 43,185, when administered in combination with indomethacin. phenylbutazone or acetylsalicylic acid. has a favourable influence on the analgesic effects of the agents tested.

C) Examination of antipyretic effects The tests were performed according to the method of Fleming [Arch. Int. Pharmacodyn.

178.423 (1969)] on rats. Pyrexia was provoked on the test animals by the administration of yeast. The results are listed in Table 10.

Table 10 Joint effects of indomethacin and GYKI 43,185 and phenyl butazone and GYKI 43,185 on rats madepyrexic with yeast +0.9%NaClsolution + GYKI43.185 Substance tested 0.2 ml/ 100 g 35 mg/kg p.o.

Antipyretic index Indomethacin 1 mg/kgp.o. -1.3 -4.7 Indomethacin 3 mg/kg p.o. -2.7 -7.2 Indomethacin lOmg/kgp.o. -4.0 -9.0 Phenylbutazone 50 mg/kg p.o. -3.5 -10.6 The data of Table 10 indicate that GYKI 43.185 also increases the antipyretic effects of known antiphlogistic agents.

II. Examination ofside effects A) Examination of the ulcerative effect of indomethacin when administered in combined tion Mith GYKI 43,185 The tests were performed on rats. The compositions tested were administered to the animals on five consecutive days in single daily dosages. The results of the tests are given in Table 11.

Table 11 Influence ofGYKI 185 on the toxicity and ulcerative effect ofindomethacin Frequen Compounds administered cy of Ulcer Mortality ulcer, % index % Indomethacin 75 mg/kg/day p.o. 50 16.0 45 Indomethacin 75 mg/kg/day p.o.

GYKI43,18525mg/kg/dayp.o. 20 1.8 40 Indomethacin 20 mg/kg i.p. 6h 100 89.5 0 Indomethacin 20 mg/kg i.p. 6h GYKI43,1852.5mg/kgi.p.6h 17 0.3 0 The data of Table 11 clearly show that GYKI 43,185 greatly decreases both the toxicity and the ulcerative side effect of indomethacine.

B) Examination ofhaematological effects During the analysis of side effects we also examined whether or how GYKI 43,185 influences the adverse effect of phenylbutazone and indomethacin on bone marrow, and whether GYKI 43,185 itself exerts such a side effect.

Rat tests have shown that GYKI 43,185 has no significant influence on the leukocyte count. and when administered in combination with indomethacin or phenylbutazone, it does not increase the leukopenic effect of the latter substances. No significant change in the thrombocyte and reticulocyte counts could be observed in any of the tests.

The data collected in the examination of side effects prove that, in our tests, GYKI 43,185 did not increase the toxic side effects of phenylbutazone and indomethacin.

Based on the above it can be stated unambiguously that in the combined compositions according to the invention the therapeutic effects of indomethacin, phenylbutazone and acetylsalicylic acid are enhanced whereas at least the major side effects are not.

Consequently, the combined compositions according to the invention enable the safe administration of lower amounts or more active forms of the known antiphlogistic agents.

These combined compositions can be used successfully in the treatment of rheumatic diseases and inflammations.

It is a further advantage of the combined compositions according to the invention that they enable one to decrease certain side effects of the known antiphlogistic agents to a considerable extent.

The weight ratio of the two components of the combined compositions may vary within wide limits. The combined compositions may contain 1 to 99 parts by weight of 2-(cyclopropylamino-acetamido) -4-(3'-pyridyl-thiazole or its salt and one part by weight of the antiphlogistic agent, preferably indomethacin or phenylbutazone.

The combined compositions according to the invention can be formulated in conventional ways. e.g. as tablets. suppositories. ointments or injections.

The invention is illustrated elucidated in more detail by the following non-limiting Examples.

Example I Preparation oftablets covered with an intestino-solvent coating Composition of one tablet: 2-(cyclopropylamino-acetamido)-4-(3'-pyridyl)- thiazole dihydrochloride 37.8 mg (1 -p-chlorobenzoyl-5-methoxy-2-methyl-indol 3-yl)-acetic acid 15.0 mg Microcrystalline cellulose (NF-XIII) 93.5 mg Magnesium stearate (PH. Hg. VI) 3.0 mg Colloidal silicon dioxide (Ph. Hg. VI) 0.5 mg Average weight: 150.0 mg The two biologically active components and the powdered microcrystalline cellulose are admixed. and the mixture is homogenized by passing it through a sieve with a pore diameter of 0.3 mm. The powdery substance is wetted uniformly with a solution of polyvinylpyrrolidone prepared with 90 v/v % aqueous ethanol (PH. Hg. VI), and the resulting wet mass is granulated through a sieve with a pore diameter of 1.0 mm. The resulting granulates are dried at 40"C in a chamber protected from light. The half-dried granulates are regranulated through a sieve with a pore diameter of 0.8 mm. then the air-dry substance is homogenized under gentle blending with a mixture of the magnesium stearate and the colloidal silicon dioxide. previously passed through a sieve with a pore diameter of 0.15 mm. The resulting mixture is compressed into tablets of 150 mg average weight. The breaking strength of the tablets is 3 to 4 kg (measured with an Erweke apparatus).

The tablets are coated with an isopropanol solution or aqueous dispersion of a methacrylic acid - methacrylic ester copolymer. or with a solution of hydroxypropylmethylcellulose phthalate in a 1:1 mixture of acetone and ethanol. The film coating formed ensures the absorption of the active agents from the intestinal tract only.

Example 2 Preparation ofcapsules Composition of one capsule: 2-(cyclopropylamino-acetamido)-4-(3'-pyridyl) thiazole dihydrochloride 37.8 mg (l-p-chlorobenzoyl-5-methoxy-2-methyl-indole- 3-yl)-acetic acid 15.0 mg microcrystalline cellulose (NF-XIII) 44.7 mg magnesium stearate (Ph. Hg. VI) 2.0 mg colloidal silicon dioxide (Ph. Hg. VI) 0.5 mg The biologically active components and the microcrystalline cellulose are homogenized as described in Example land the mixture is wetted with a 5%polyvinylpyrrolidone solution.

The wet mass is granulated through a sieve with a pore diameter of 0.7 mm. and the half-dried granulates are regranulated through a sieve with a pore diameter of 0.5 mm. The granulates are dried at 40"C in a chamber protected from light. and the dry substance is homogenized under gentle blending with a mixture of the magnesium stearate and the colloidal silicon dioxide. previously passed through a sieve with a pore diameter of 0.15 mm. 100 mg portions of the resulting powder are filled into hard gelatine capsules.

Claims (8)

WHAT WE CLAIM IS:-

1. A pharmaceutical composition exhibiting an enhanced antiphlogistic effect, containing 1 part by weight of a known antiphlogistic substance together with 1 to 99 parts by weight of 2-(cyclopropylamino-acetamido) -4-(3'-pyridyl)-thiazole or a pharmaceutically acceptable salt thereof and optionally a pharmaceutical adjuvent.

2. A composition as claimed in claim 1 wherein said known antiphlogistic substance is indomethacin.

3. A composition as claimed in claim 2 wherein the weight ratio of indomethacin to 2-(cyclopropylamino-acetamido) -4-(3'-pyridyl)-thiazole or pharmaceutically acceptable salt thereof is about 1:2.

4. A compositions as claimed in claim 1 wherein said known antiphlogistic substance is phenylbutazone.

5. A compositions as claimed in claim 1 wherein said known antiphlogistic substance is acetylsalicylic acid.

6. A composition as claimed in any of the preceding claims formulated for oral administration.

7. A composition as claimed in claim 1 substantially as described herein.

8. A composition as claimed in claim 1 substantially as illustrated in Examples 1 or 2.