AU623927B2 - Synergistically active compositions and process for preparing the same - Google Patents

Description

6239 COMMONWEALTH OF AUSTRALIA PATENS AC1T 1952 coMl~eBQFCmlQ 27 NAME ADDRESS OF APPLICANT: Egis Gyogyszergyar 30-38, Kereszturi ut Budapest Hungary NAME(S) OF INVENTOR(S): Karoly MAGYAR Ferenc SIMON Attila NAGY Laszlo PUSKAS Frigyes GORGENY1 Marton FEKETE Pal FEKETE Istvan SIMONY1 Janos EGRI Katalin ZUKOVICS Laszlo MOLNAR Gabor SEMJEN U 4 it It

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ADDRESS FOR SERIIICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

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t t 41 1 I I COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: Synergistically active compositions and process for preparing the same Vae following statement is a full description of this invention, incltOing the best method of pertuy-rn.ing it known to me/us:- I I I- I 0 4 I U

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la The invention relates to synergistically active compositions and process for preparing the same. More particularly, the invention relates to new synergistically active pharmaceutical composition and/or feed additive useful primarily in the treatment of diarrhoea 10 and process for preparing the same. The new composition Scan be used both in human and veterinary field.

So. According to the data of World Health Organization (WHO), many hundred million people fall ill in gastro- -enteritises of different cause, and the number of death cases caused by these kind of illniesses presumably exceeds ten million. Most illnesses and death cases of t this kind occur in the developing countries, but the numbe: of enteritises caused by the bacteria belonging e.g. to I t the genera Salmonella and Campylobacter in the developed countries is also growing.

Most of the economic losses in animal husbandry is caused by illr:esses of the digestive tract and respiratory organs. Just in Hungary, these losses are Sin the range of hundred million forints.

Most of the human and animal enteritises are cuased by pathogen microorganisms, but diarrhoea illnesses of non-infective (food or feed) origin also occur. Most i 2 of the enteritises of infective origin are caused by bacteria, viruses and protozoa, the most frequent pathogens are the following in humans and animals: Escherichia coli, Salmonella specieses of different serotypes, Campylobacter specieses, Yersinia enterolitica; and besides these, in human the Shigella specieses. In the tropical countries the enteritises caused by protozoas are very wide-spread.

Since there is no specific protection method against most of the human and animal enteritises, the medicinal treatment is playing central role in the protection, besides the improvement of the hygienic conditions. The necessity of the medical treatment must be therefore strongly emphasized since in most cases there is no diagnosis. But from this follows, that as far as possible, such a medicine must be used, which is effective against a wide range of potential patogens, Sand can cure the clinical symptoms.

Since the members of the normal intestinal flora supposedly exert a significant antagonistic effect against Si the different enteropatogen microorganisms, it is important not to disturb the intestinal flora. Namely, disbacteriosis leads to the protraction of the pathological process.

Significant portion of the normal intestinal flora consists of Gram-positive bacteria (Enterococcuses and Lactobacilli).

SFor the treatment of the enteritises antibiotics of wide spectra are used, supplemented with toxin J adsorbents and astringent agents. The most widely used B1

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O999 tC 9 Se antibiotics are the following: D-(-)-threo-2,2-dichloro- -N-/-2-hydroxy-l-hydroxy-methyl-2-(4-nitrophenyl)ethvl7acetamide (chloramphenicol); tetracyclines; potentiated sulphonamides, where 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) is used for potentiation; 3-/-5-nitro-furfurilydene-amino7-2-oxazolidinone (furazolidone); and the aminoglycosides, "Pharmacological Basis of Large Animal Medicine", Editors: J.A. Bogan, P. Lees and A. T. Yoxall, Blackwell Scientific Publications, 10 Oxford, London, Edinburgh, Boston, Melbourne, 19837.

The application of the chemotherapeutics presently used in the therapy has more or less disadvantages. There is a wide range tetracycline and aminoglycoside resistance among the intestinal bacteria which in most cases are 15 bound to plasmides /-"Veterinary Pharmacology and Therapeutics", Editors: L. Meyer Jones, N. H. Booth and L. E. McDonald Ames, The Iowa State University Press, 4th edition, p. 929-938 pages, 19777. If such individuals or stocks are treated with the antibiotics mentioned, this 20 results in wide spreading of the plasmids harboring the resistance. The application of chloramphenicol is more and more repressed because of its harmful effect to health /-Goodman and Gilman: "The Pharmacological Basis of Therapeutics", Macmillan Publishing Co., New York, 7. edition, p. 1179, 19807. Besides, the antibiotics of wide spectra are effective against both the Gram-positive and Gram-negative bacteria and can therefore easily cause non-desired disbacteriosis. Hardly forms any resistance 4 Ii

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-4- 4r '4 4 4.44 44 against furazolidone but its application is less desirable because of its carcinogenic effect. The degree of resistance is constantly growing against eulphonamides potentiated by trimethoprim, especially in cases of bacteria causing enteral infection L-Goddman end Gilman: "The Pharmacological Basis of Therapeutics", MacMillan Publishing Co., New York; 7. edition, p. 1107, 19807.

The aim of the present invention is to provide an effective composition for the treatment of diarrhoea, from which a low dose is enough to kill the pathogens, and this way the formation of resistance against the composition is less likely.

It has been found that 6,9,18-tris(2-amino-ethyl)- 15-benzyl-21-/-2,8-bis(2-amino-ethyl)-5-(l-hydroxy- 15 ethyl)-15-methyl-4,7,10-trioxo-3,6,9-triaza-heptadecaneamido7-3-(1-hydroxy-ethyl)-12-isobutyl-l,4,7,10,13,16,19hepta-aza-cyclotricosane-2,5,8,11,14,17,20-heptaon (polymyxin B) or a pharmaceutically acceptable acidaddition salt thereof and either 2,4-diamino-5-(3',4'-dimethoxybenzyl)pyrimidine (diaveridine); or 2,4-diamino-5-(3',4'-dimethoxybenzyl)pyrimidine (diaveridine) and 2-L-2,6-dimethyl-3-hydroxy- 4-(tertiary-butyl)-benzyl7-2-imidazolidine (oxymethazoline) or a pharmaceutically acceptable acidaddition salt thereof as a combination have very strong antibacterial effect against those bacterial strains which are the most frequent pathogens of diarrhoeal disease, and this way the combination of these compounds can be used in the treatment of diarrhoea.

911018,dbat087,41482res,4 ii 5 Polymyxin B is effective mainly against Gram- -negative bacteria, its minimal inhibitory concentration is generally around 1-5 /ug/ml. Diaveridine has an inhibitory effect against bacteria only in high concentration, while oxymethazoline has no therapeutically applicable antibacterial effect. That is why it is surprising for the experts of this field that polymyxin B and diaveridine or polymixi' B, diaveridine and oxymethazoline together exert i'ihibitory effect in very small concentrations against different Escherichia coli, 0 00 o Yersinia enterolitica, Campylobacter, Shigella and 0 0 0 60 S* Salmonella strains. This is supported by the following Soo experimental data.

0:0" The determination of inhihitory concentration 0 00 values was carried out in a broth containing phenolred indicator and glucose. The broths containing the compound(s) to be investigated are inoculated with a °drop of the 18-20 hours old nutrient broth culture of 0.6. the bacteria and the cultivation is carried out for 72 hours with constant controll of growth. After 72 hours the cultures are plated to solid media to determine the Sbactericide concentration. The minimal inhibitory concentrations (MIC) providing bactericidal effect are shown on Table 1. The bacterial strains used during the investigations, and appearing in Table 1, are the following: i -6-

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Escherichia coli 11 Escherichia coli 27 Escherichia coli 113 Escherichia ccli 258 Escherichia coli 43 Escherichia coli 53 Escherichia coli 128 Escherichia coli 284 (enteropa togen strains isolated from sucking pigs and calves) tt I I 6 4 4 4 4 *4 4 C 444 4 4 4 4 44 4 4~ 4644 4666 4 64 46 4 44441* 4 6 I Yersinia enterocolitica HESZ (strain isolated food sample) .J Yersinia enterocolitica OKI (strain isolated human) K Campylobacter jejuni Pen. 19 (strain isolated chicken meat) L Campylobacter coli 234 (strain isolated human, sickened M Shigella sonnei (strain isolated from human wi dysentery) f rom f rom f ii th rem rom n enteritis) Salmonella enteritidis Salmonella infantis Salmonella tiphy-murium Salmonella cholerae-sui s (strains isolated from human, sickened in enteritis, and strains isolated from swine paratyphy occurring epidemically) r

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r* 9 9 9' 9 p 9' 9 p 9, p 9 0 C a f L 0 4*0 S 9 p 9I- 9 9 0 Table 1 Compound investigated MIC values, /ug/ml A B C 0 E F G H I bacterial strains Polymyxin B 5 5 5 5 5 5 5 1 Diaveridine 200 200 200 200 200 200 200 200 200 Oxymethazoline >200 >200 >200 >200 >200 >200 >200 >200 200 Combination of /ug/ml diaveridine and polymyxin B: 0.5 0.5 0.5 1 0.5 1 0.5 1 1 Combination of /ug/ml diaveridine, 1 /ug/ml oxymethazoline and polymyxin B: <0.5 <0.5 <0.5 1 <0.5 1 (0.5 1 1 OIL p I a. a a a a a a 4 a a S a *Qa a aec S a a a a..

continuation of Table 1 Compound investigated MIC values, /ug/ml 3K L M N 0 P R ba ct er ial1 s tr a ins Polymyxin B 5 5 5 0.5 0.25 0.25 1 0.25 Diaveridine 100 25 25 25 50 50 100 Oxymethazoline '.200 >200 >200 1000 1000 1000 >'10O0 1000 Combination of /ug/oil diaveridine and polymyxin B: 0.5 0.5 0.5 0.25 0.12 0.25 0.25 0O.A12 Combination of /ug/ml diaveridine, 1 /ug/m1 oxymethazoline and polymyxin 8: 4 0.5 40.5 4.0.5 0.015 0.06 0.12 0.25 0.06 d

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-9- It is obvious from Table 1 that oxymethazoline in itself has no antibacterial effect, and the diaveridine I also has some effect in relatively small doses only against to Campylobacter strains. But at the same time the minimal inhibitory concentration of polymyxin B in the presence of only 20 pg/mg diaveridine, or in the presence of 1 pg/mg oxymethazoline plus 20 pg/ml diaveridine drops to one tenth of the original value against most of the bacterial strains investigated.

Thus, the present invention relates to new synergistic pharmaceutical compositions and/or feed additives active primarily against diarrhoea, and for the preparation of the same, which comprises mixing as active ingredients 1 part by weight of 6,9,18-tris(2-aminoethyl-15-benzyl-21-L--2,8-bis(2-amino-ethyl)-5-(l- I hydroxy-ethyl)-15-methyl-4,7,10-trioxo-3,6,9-triaza- Sheptadecane-amido7-3-(l-hydroxy-ethyl)-12-isobutyl- S..1,4,7,10,13,16,19-hepta-aza-cyclotricosane- 2,5,8,11,14,17,10-heptaon or a pharmaceutically 20 acceptable acid addition salt thereof and either 20 to 166 parts by weight of 2,4-diamino-5- (3',4'-dimethoxybenzyl)-pyrimidine; or 20 to 1340 parts by weight of 2,4-diamino-5- (3',4'-dimethoxybenzyl)-pyrimidine and 1 to 66 parts by weight of 2-L-2,6-dimethyl-3-hydroxy-4-(tertiary-butylbenzy17-2-imidazoline or a pharmaceutically acceptable acid addition salt thereof, optionally to pharmaceutically acceptable carrier(s) and/or additive(s) in order to prepare a pharmaceutical composition, or the compounds mentioned are mixed with carrier(s) and/or additive(s) conventionally used in the preparation of feed additives.

Preferably the acid addition salt of polymyxin B is its sulphate, and that of c ymethazoline is its hydrochloride.

The active agents of the invention are known, respectively commercially available.

i '7 911018,dbda87,4148res,9 -gpolymyxin B sulphate and 4_l-tsy weight of The new synergistic pharmaceutical composition of the invention can be used both in human and veterinary treatment.

The mixture of the active ingredients can be administered per se, for example filled to capsules, or Sthe active ingredients are mixed to usual pharmacologically acceptable carriers, and a pharmaceutical composition is formulated from the mixture. Solid compositions, for example tablets, dragees, boluses etc. and liquid compositions, for example suspensions, can be prepared.

As a carrier glucose, starch, silicon dioxide, silicates, lactose, talc, poly(vinyl-pyrrolidone), polyvinyl-polypyrrolidone, calcium phosphate, magnesium- -stearate, microcrystalline cellulose, etc. are used.

The carrier used in the preparation of liquid pharmaceutical compostions is generally water and/or an organic solvent. The mixture of different organic solvents can also be used.

The pharmaceutical compositions can contain one or more usual additives, for example emulgeating agents, disperging agents, suspending agents, wetting agents, antioxidants, stabilizing agents, sweeteners, etc.

The active ingredients used according to the present invention can be formulated to any known pharmaceutical composition, see for example Remington's

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-11- Pharmaceutical Sciences, 16th edition, Mack Publishing Company, Easton, USA, 1980. For this purpose the generally used, known methods and carriers, adjuvants and additives in the production of pharmaceuticals can be used as it is mentioned in the literature mentioned above.

By using the pharmaceutical composition of the present invention both in the human and veterinary medicine the treatment is preferably carried out daily 1-4 times. The preferred daily dose relative to the i

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total amount of the three active ingredients is 0.1 100 mg/kg body weight, preferably 1-5 mg/kg body weight.

If the mixtures of the active ingredients of the present invention are to be used in the veterinary treatment, then they can be admixed to the fodder.

In order to assure the uniform admixing, preferably feed-premix is prepared first from the active ingredients, and the premix is mixed to the fodder.

In preparing the feed premix the active ingredients 20 are mixed with the carrier(s) and/or additive(s) conventionally used in the preparation of premixes. The carriers can be for example: wheat, low-grade flour, wheat bran, oil-free rice bran, corn flour, soy flour, caoline, zeolit, calcium carbonate, starch, silicon dioxide, polyvinyl-polypyrrolidone, etc. The additives can be for example trace elements, vitamins, inorganic salts, etc. The fodder premix preferably contains 1-50% by weight, more preferably 1-10% by weight, of active ingredient.

911018,dbdat87,4148res,1 11 12 The fodder premix prepared according to the present invention is mixed to the fodder in such a ratio that the total concentration of the active ingredientsbe 5-100 ppm,, preferably 1-'50 ppm.

The pharmaceutical compositions according to the present invention can be successfully used in the treatment of diarrhoea at human beings and at each domestic mammalian farm animal (for example cattle, pig, sheep, goat, etc.), poultry (for example domestic poultry, and t 10 wild fowl and water poultry, like goose, duck, turkey, C t c, chicken) and pets (for example dog, cat, bird, etc.).

S For the treatment of animals the premix of the present glu invention mixed in the fodder can also be used.

The invention is illustrated in detail by the aid of the following non-limiting examples.

rE-r Example 1 rx, 400 g of diaveridine, 40 g of polymyxine B, 3 g taL of oxymethazoline and 245 g of polyvinyl-polypyrrolidine 20 are added into a L6dige 5M type laboratory fast-mixer.

a 6* The compounds are homogenized for five minutes, then the i solution of 16 g of polyvinyl-pyrrolidone in 20 ml ethanol is added to the mixture with continuous stirring, and mixing is continued for five more minutes. The granulate prepared this way is dried in a Retsch laboratory fluid bed drier with 60 oC air inlet temperature. (The time of drying is about 10 minutes.) The dry granulate is regranulated with an Erweka laboratory oscillating grainer 13 .1

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iI i using a sieve of 1.0 mm thread-distance. To the screened granulate 10 g of talc, 4 g of magnesium stearate and 2 g of colloidal silicon dioxide are added, and the mixture is further homogenized in an Erweka cube-homo- S genizer for 20 minutes.

The obtained mixed granulate is transformed to flat flanged tablets of 160 mg weight with a press of 8 mm diameter, or 320 mg weight with a press of 10 mm diameter.

I10 The composition of the tablets is the following: ra *11« iaveridine Polymyxin B "Oxymethazoline Polyvinyl-polypyrrolidone Poly(vinyl-pyrrolidone) Talc Magnesium-stearate Colloidal silicon dioxide Colloidal silicon dioxide t 4 Diameter of tablets 8 mm 10 mm 100 mg 200 mg 10 mg 20 mg 0.75 mg 1.5 mg 61.25 mg 122.5 mg 4 mg 8 mg 2.5 mg 5 mg 1 mg 2 mg 0.5 mg mg 180 mg 360 mg Example 2 600 g of diaveridine, 80 g of polymyxin B, 20 g of oxymethazoline, 80 g of microcrystalline cellulose and g of potato starch are added into the material container of a Glatt WSG 1 type fluid bed grainer, and the mixture 14

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is mixed for five minutes with a fluidizing air of °C temperature. Granulation is carried out with a solution of 48 g poly(vinyl-pyrrolidone) in 500 ml of distilled water, using 25 ml/min. feeding speed and 0.5 bar vaporizing pressure. After finishing granulation the granulate is dried for 10 minutes, then 20 g of talc, 12 g of magnesium stearate and 80 g of polyvinyl-poly- 4 pyrrolidone are added, and the system is further fluidized for 3 minutes. The dry granulate i; screened into an 4 o I Erweka laboratory oscillating grainer and further homogenized for another 10 minutes in an Erweka cubic-mixer.

0 The homogenized granulate is tabletted, using flat, flanged press of 8 or 10 mm diameter.

The composition of the tablets is the following: Diameter of tablets 8 mm 10 mm Diaveridine 100.00 mg 200.0 mg Polymyxin B 10.0 mg 20.0 mg Oxymethazoline 2.5 mg 5.0 mg Microcrystalline cellulose 10.0 mg 20.0 mg Potato starch 7.5 mg 15.0 mg Poly(vinyl-pyrrolidone) 6.0 mg 12.0 mg Polyvinyl-polypyrrolidone 10.0 mg 20.0 mg S Magnesium stearate 1.5 mg 3.0 mg Talc 2.5 mg 5.0 mg 150.0 mg 300.0 mg r <%o~i

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15 Example 3 28.0 g of diaveridine, 2.8 g of polymyxin B, 0.30 g of oxymethazoline, 100 g of polyvinyl-pyrrolidone, 4.9 g of colloidal silicon dioxide and 864 g of potato starch are added into a Lodige WS 5 type laboratory mixer, and the mixture is homogenized for 6 minutes.

1 part by weight of the premix obtained this way is mixed with 1000 parts by weight of fodder, and the fodder prepared this way is used for feeding animals suffering from diarrhoea, for example pigs.

144* Example 4 28.0 g of diaveridine, 2.8 g of polymyxin 8, 0.7 g of oxymethazrli e, 300 g of polyvinyl-polypyrrolidone 15 and 668.5 g of wheat flour are added into a Lodige WSG 5 type laboratory mixer, and the mixture is homogenized for 5 minutes.

1 part by weight of the premix obtained this way is mixed with 1000 parts by weight of fodder, and the fodder prepared this way is used for feeding animals suffering from diarrhoea, for example pigs.

Example 28.0 g of diaveridine, 2.8 g of polymyxin B, 300 g of polyvinyl-polypyrrolidine and 669 g of wheat flour are' homogenized.

1 part by weight of the premix obtained this way

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-16is mixed with 1000 parts by weight of fodder, and the fodder prepared this way is used for feeding animals suffering from diarrhoea, for example pigs.

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Claims (2)

1. 3. A composition as claimed in claim 1 or 2, 25 wherein the pharmaceutically acceptable salt of 6,9,18- tris(2-amino-ethyl-15-benzyl-21-.f-2, 8-bis(2-amino-ethyl)- 1-hydroxy-ethyl )-15-methyl-4, 7, 10-trioxo-3, 6, 9-triaza- heptadecane-amido7-3-( 1-hy.droxy-ethyl )-12-isobutyl- 1, 4,7, 10, 13, 16, 19-hepta-aza--cyclotricosane- 2,5,8,11,14,17,1O-heptaon is 6,9,18-tris(2-amino-ethyl)-
2. 15-benzyl-21-L-2, 8-bis( 2-amino-ethyl -hydroxy- ethyl )-15-methyl-4, 7, 10-trioxo-3, 6, 9-triaza-heptadecane- amido27-3-( l-hydroxy-ethyl)-12-isobutyl-l, 4,7,10,13,16,19- hepta-aza-cyclotricosane-2, 5,8, 11, 14, 17, sulphate and wherein the pharmaceutically acceptable salt of 2-E-2, 6-dimethyl-3-hydroxy-4-( tertiary-butyl-benzyi7- (2 911018,dbdaLO87,41482.res, 17 t ft 1 0 -18- 2-imidazoline is 2-L-2, 6-dimethyl-3-hydroxy-4(etay butyl) -benzyl7-2-imidazoline-hydrochloride. 4. Feed additive, useful primarily for the treatment of diarrhoea, which comprises 1 part by weight of 6 9 ,l8-tris(2-amino-ethyl-l5-benzyl21j-2,8-bis(2- l-hydroxy-ethyl)-15-methyl-4, 7, 3,6, 9-triaza-heptadecane-amido7-3-( 1-hydroxy--ethyl )-12- isobutyl-l, 4,7, 10,13,16, 19-heptaaza-cyclotricosane- 2 ,5,8,1l,14,17,10-heptaon or a pharmaceutically acceptable acid addition salt thereof and either 20 to 166 parts by weight of 2,4-diamino-5- L 4 4( 3 ',4'-dimethoxybenzyl)-pyrimidine; or j 15 20 to 1340 parts by weight of 2,4-diamino-5- 31 4 1 -dimethoxybenzyl)-pyrimidine and 1 to 66 parts by weight of 2 -E-2,6-dimethyl-3-hydroxy-4-(tertiary-buty1- benzyl7-2-imidazoline or a pharmaceutically acceptable acid addition salt thereof, together with carrier(s) and/or additive(s) commonly used in premix preparations. A feed additive as claimed in claim 4, wherein the pharmaceutically acceptable salt of 6,9,18-tris(2- amn-ty-5bny-1/-28bs2aioehl--l L~ 25 hydroxy-ethy1)-15-methyl-4,7,1o-trioxo-3,6,9-triaza- heptadecane-amido7-3-( 1-hydroxy-ethyl )-12-isobutyl- l, 4 7 ,lO,l3,16,19-hepta-aza-cyclotricosane- 2,5,8,11,14,17,l0-heptaon is 6,9,18-tris(2-amino-ethyl- 15-benzyl-21-E-2, 8-bis( 2-amino-ethyl 1-hydroxy- ethyl)-15-methyl-4, 7,10-trioxo-3, 6, 9-triaza-heptadecane- amid27-3-(1-hydroxy-ethyl)-12-isobutyl-1,4,7,1o,13,16,19. hepta-aza-cyclotricosane-2, 5,8,11,14,17, lO-heptaorz sulphate and wherein the pharmaceutically acceptable salt of 2-ZL-2, 6-dimethyl-3-hydroxy-4-(tertiary-butyl-beiizyi7- 2-imidazoline is 2-L-2, 6-dimethyl-3-hydroxy-4-(tertiary- butyl )-bk enzyl7-2-imidazoline-hydrochloride. 911018,dbdat087,41482.res, 18 rBie '^im ^c~ I .2 -19- tc t S* I 0 C I C: C C C C Lii C Ci i I 6. A process for the preparation of pharmaceutical composition or feed additives, useful particularly for the treatment of diarrhoea, which comprises mixing as active ingredients 1 part by weight of 6,9,18-tris(2- amino-ethyl-15-benzyl-21-L--2,8-bis(2-amino-ethyl)-5-(1- hydroxy-ethyl)-15-methyl-4, 7,10-trioxo-3, 6,9-triaza- heptadecane-amido7-3- (1-hydroxy-ethyl) -12-isobutyl- 1,4,7,10,13,16,19-hepta-aza-cyclotricosane- 2,5,8,11,14,17,10-heptaon or a pharmaceutically acceptable acid addition salt thereof and either 20 to 166 parts by weight of 2,4-diamino-5- 4'-dimethoxybenzyl)-pyrimidine; or 20 to 1340 parts by weight of 2,4-diamino-5- (3',4'-dimethoxybenzyl)-pyrimidine and 1 to 66 parts by weight of 2-/--2,6-dimethyl-3-hydroxy-4-(tertiary-butyl- benzyl7-2-imidazoline or a pharmaceutically acceptable acid addition salt thereof to carrier(s) and/or additive(s) commonly used in the pharmaceutical industry, or the active ingredients mentioned above are mixed with carrier(s) and/or additive(s) commonly used in premix preparations. 7. A method for the treatment of diarrhoea, which comprises administering an effective amount of the composition according to any one of claims 1 to 3 or the feed additive according to claim 4 or 5 to a subject in need of such treatment. 8. Pharmaceutical compositions or feed additives, substantially as hereinbefore descriked with reference to the Examples. ,t t 911018,dbdaLO87,4148Zres,19 20 9. Processes for the preparation of pharmaceutical compositions or feed additives, substantially as hereinbefore described with :eference to the Examples. 2.- 4* a 44 a. a a a a a a. 4ae* 4 a 4 A* 4 a .4,4 a .4 a a a a a cc a 4 at DATED this 18th day of October, 1991 Egis Gyogyszergyar 20 By Its Patent Attorneys DAVIES COLLISON 911018,dbdat087,41482.res,20