GB1581826A

GB1581826A - Veterinary compositions for treating diarrhoea

Info

Publication number: GB1581826A
Application number: GB1241776A
Authority: GB
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1976-03-27
Filing date: 1976-03-27
Publication date: 1980-12-31
Also published as: BE852562A

Description

PATENTS ACT 1949 SPECIFICATION NO 1531326 The following a amendments were allowed under Section 29 on 10 arch 1986 Pa,, e 1 Line 21 Pag, 5 Line 50 Delete or insert and/or Page 1 Line 22 After citric acid insert alone Page 5 Line 51 Befcre, then insert alone THE PATENT OFFICE 23 April 1936 yX l ur amoxycx n but mere are occasions when an alternative therapy is required. Recently U. S. Patent No: 3898328 disclosed that compositions containing glycine, glucose and electrolytes are effec tive in the treatment of scours by bringing about a rehydration of the scouring animal.

A distinct class of compositions has now been discovered which combine effectiveness in diarrhoea (e. g. scours) treatment with ease of formulation, palatability and useful stability.

Accordingly the present invention provides a veterinary composition comprising 40 to 80% of an actively absorbed mono-saccharide, 7.5 to 30% of an actively absorbed naturally occurring amino acid, and 0.5 to 10% of an agent which is citric acid or a salt thereof; except that when the agent is a salt of citric acid, then the amino acid represents no more than 13 % of the composition.

All percentages used herein are calculated on a weight/total weight basis.

Active absorption (or active transport) is well known to the skilled man, as are the monosaccharides and amino acids which are actively absorbed. In this regard the reader is referred to standard text books such as'Medicinal Physiology'by Guyton (published by W. B.

Saunders and Company) 4th Edition pages 769 to 771. Of course whether or not a particular monosaccharide or amino acid is actively absorbed may also readily be determined by experiment as for example described in Wilson T. H. 1962 Intestinal Absorption (Saunders, Philadelphia).

To be actively absorbed, monsaccharides must have (a) at least six carbon atoms in their chain (b) a D-pyranose ring structure and (c) an intact hydroxyl group at carbon 2. Thus suitable examples of monosaccharides for use in this invention include the naturally occurring D-pyranoses such as glucose and galactose. Other examples of suitable monosaccharides include naturally occurring D-pyranoses that have been chemically modified whilst retaining the necessary structural features (a), (b) and (c). Examples of such modified monosaccharides include C2-7 acylated and C,-4 alkylated derivatives, such as acetyl, methyl, ethyl and n-and iso-propyl derivatives. Specific examples include oc-methyl glucoside, 3-0-methyl glucose and 6-deoxygalactose.

Preferably the monosaccharide will be glucose or galactose. The monosaccharide of choice for use in this invention is glucose (e. g. dextrose). The stability of the resultant composition is enhanced if the monosaccharide used is anhydrous, for example anhydrous glucose.

Suitable examples of actively absorbed naturally occurring amino acids include neutral amino acids such as glycine and alanine and basic amino acids such as arginine. Preferably the (54) VETERINARY COMPOSITIONS FOR TREATING DIARRHOEA (71) We, BEECHAM GROUP LIMITED, a British Company of Beecham House, Great West Road, Brentford, Middlesex, 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 present invention relates to veterinary compositions useful for treating diarrhoea (e. g. scours) in domestic animals and to the use of such compositions in the treatment of diarrhoea by rehydration.

A common and highly debilitating disease affecting young domestic animals such as calves and piglets is diarrhoea. Diarrhoea causes severe dehydration which in turn causes a signific ant weight loss in the animal and can in severe cases lead to death. It is believed that often the diarrhoea symptoms are caused by a toxin or toxins of bacterial origin so that one method for the treatment of diarrhoea is the administration of anti-bacterial agents. Considerable success can be achieved by using such anti-bacterial agents as ampicillin or amoxycillin but there are occasions when an alternative therapy is required. Recently U. S. Patent No: 3898328 disclosed that compositions containing glycine, glucose and electrolytes are effec tive in the treatment of scours by bringing about a rehydration of the scouring animal.

Accordingly the present invention provides a veterinary composition comprising 40 to 80% of actively absorbed mono-saccharide, 7.5 to 30% of an actively absorbed naturally occurring amino acid, and 0.5 to 10% of an agent which is citric acid or a salt thereof; except that when the agent is a salt of citric acid, then the amino acid represents no more than 13 % of the composition.

All percentages used herein are calculated on a weight/total weight basis.

To be actively absorbed, monsaccharides must have (a) at least six carbon atoms in their chain (b) a D-pyranose ring structure and (c) an intact hydroxyl group at carbon 2. Thus suitable examples of monosaccharides for use in this invention include the naturally occurring D-pyranoses such as glucose and galactose. Other examples of suitable monosaccharides include naturally occurring D-pyranoses that have been chemically modified whilst retaining the necessary structural features (a), (b) and (c). Examples of such modified monosac charides include C2, acylated and C-4 alkylated derivatives, such as acetyl, methyl, ethyl and n-and iso-propyl derivatives. Specific examples include x-methyl glucoside, 3-0-methyl glucose and 6-deoxygalactose.

Suitable examples of actively absorbed naturally occurring amino acids include neutral amino acids such as glycine and alanine and basic amino acids such as arginine. Preferably the amino acid is glycine.

The veterinary compositions of the invention will normally contain 10 to 25 % electrolytes.

Suitable electrolytes for such inclusion include salts containing ions such as sodium, potassium, calcium, magnesium, chloride, phosphate, gluconate, sulphate, bicarbonate, carbonate and the like. Other favoured electrolytes for inclusion in the compositions include potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium chloride and the like, with potassium dihydrogen phosphate being particularly suitable.

One particularly preferred electrolyte for inclusion in the composition of the invention is sodium chloride which will normally account for 7 to 20% of the composition, for example 10 -16% of the composition.

The monosaccharide is defined as representing 40 to 80% of the composition. More suitably it will represent 50 to 75%, for example 60 to 75% of the composition. Often the monosaccharide will represent at least 65% of the composition. Similarly while the amino acid in the composition can represent 7.5 to 30% of the composition, more suitably it will represent 7.5 to 20% of the composition, for example 8 to 15 % of the composition. 8 to 12% has been found to be a particularly suitable inclusion range for the amino acid.

One suitable veterinary composition comprises 40 to 80% of an actively absorbed monosaccharide, 7.5 to 30% of an actively absorbed naturally occurring amino acid, and 0.5 to 10% of citric acid.

The citric acid represents 0.5 to 10% of this composition. More suitably the citric acid will represent 0.5 to 5%, preferably 0.5 to 2%, for example 0.6 to 1.2% of the composition. Often the composition will contain both citric acid and a salt thereof, but combined the citric acid and the salt thereof will not represent more than 10% of the composition. Suitable examples of such salts include sodium or potassium salts such as mono-, di-or tri-sodium, or mono-, dior tri-potassium citrate. Often the composition will include 0.1 to 5 % of a salt of citric acid, more suitably 0.1 to 0.5 % of such a salt.

From the aforesaid it will be seen that one particularly suitable veterinary composition of the invention will comprise 50 to 75 % glucose or galactose, 7.5 to 20% of glycine, alanine or arginine, 0.5 to 10% citric acid and 7 to 20% of sodium chloride.

More suitably, such compositions will contain 0.5 to 5 % citric acid, and 0.1 to 5 % of a salt of citric acid.

Preferably such compositions contain glucose as the monosaccharide and glycine as the amino acid.

Thus a particularly preferred composition of the invention comprises 60 to 75% glucose, 8 to 15 % glycine, 0.5 to 2 % citric acid, 0.1 to 0.5 % of a salt of citric acid, and 10 to 16 % sodium chloride. Such compositions often include 5 to 10% of potassium dihydrogen phosphate.

A second suitable veterinary composition comprises 40 to 80% of an actively absorbed monosaccharide, 7.5 to 13 % of an actively absorbed naturally occurring amino acid, and 0.5 to 10% of a citrate salt.

The citrate salt represents 0.5 to 10% of this composition. More suitably the salt will represent 0.5 to 5%, preferably 0.5 to 2%, for example 0.6 to 1.2% of the composition.

Suitable examples of citrate salts include sodium or potassium salts such as mono-, di-or tri-sodium, or mono-, di-or tri-potassium citrate.

From the aforesaid it will be seen that one particularly suitable veterinary composition of the invention will comprise 50 to 75 % glucose or galactose, 7.5 to 13 % of glycine, alanine or arginine, 0.5 to 10% of a citrate salt and 7 to 20% of sodium chloride.

More suitably, such compositions will contain 0.5 to 5% of a salt of citric acid.

Preferably such compositions contain glucose as the mono-saccharide and glycine as the amino acid.

Thus a particularly preferred composition of the invention comprises 60 to 75% glucose, 8 to 12% glycine, 0.5 to 2% of a salt of citric acid, and 10 to 16% sodium chloride. Such compositions often include 5 to 10% of potassium dihydrogen phosphate.

These compositions suitably contain at least 65% monosaccharide.

If desired the compositions of this invention can contain other substances such as vitamins, minerals, buffers, excipients or the like in conventional manner.

In general the compositions of this invention will be in the form of a dry powder for example one which is readily soluble in water. However in an alternative aspect the compositions of this invention will comprise an aqueous solution containing dissolved therein the previously defined solutes in the previously defined relative proportions.

The powders of this invention may be prepared by mixing together the individual components in conventional manner. Once mixed the composition may be put into sachets or other conventional containers. It is frequently advantageous to separate the monosaccharide component from the other components of the composition. This can be effected by using double sachets or other double containers. In such cases components other than the monosaccharide can be mixed and filled into one half of the double sachet and the monosaccharide can be filled into the other half of the double sachet. In such form the compositions of the invention have been found to be particularly stable.

The composition of the invention will normally be administered to the diarrhoeic animal in the form of an aqueous solution, by the oral route. Such solutions may for example contain 20 to 45 g./litre of the composition, suitably 25 to 35 g./litre, for example 30g./litre. In general calves will be administered from 2 to at least 4 litres per day of such solutions while piglets will normally be administered from a quarter to a one litre per day. The solutions may be administered ad libitum or in two to four or more equal doses per day or by any other similar conventional regime.

From a further aspect this invention provides a method of treating diarrhoea in domestic animals which method comprises administering to the animal suffering from diarrhoea a liquid composition of this invention.

It will be realised that in the treatment of severely scouring animals anti-bacterial agents may be administered in conjunction with the compositions of the invention. Examples of suitable anti-bacterial agents for such use include ampicillin, amoxycillin and tetracyclines.

The skilled man will realise that the effective absorption properties found with the liquid compositions of the invention will enable them to be used with advantage whenever liquid absorption by animals is a problem. For example the compositions may be used in treating the general dehydration found in post-operative conditions in animals such as dogs and cats.

They may also be administered with advantage to stressed animals, such as recently purchased calves and the like. It is however believed that the compositions of the invention will be of the greatest use in the treatment of diarrhoea in calves.

The following Examples illustrate the invention: EXAMPLE 1 1 kg. of the following composition was prepared by mixing together the ingredients in dry powder form :---.- Glycine 10.3% Dextrose (anhydrous) 67.6 Sodium Chloride 14.3 Potassium Dihydrogen Phosphate 6.8 Citric Acid 0.8 Tri-potassium Citrate. 0.2 60g. of the composition was then dissolved in 2 litres of water.

EXAMPLE 2 The following composition was prepared by a method analogous to that of Example 1: Glycine 10% Dextrose (anhydrous) 72 Sodium Chloride 10 Citric Acid 5 Tri-potassium Citrate. 3 60g. of the composition was then dissolved in 2 litres of water.

EXAMPLE 3 For storage, the composition according to Example 1 was prepared in the same manner, but the dextrose (676g.) was filled into one container and the remaining ingredients (324g.) were filled into a second container.

EXAMPLE 4 By way of comparison, acute absorption studies were carried out on the composition of Example 1, hereinafter referred to as composition J, and a composition X: w/w% Sodium Chloride 11.6 Calcium Gluconate 2.2 Magnesium Sulfate 0.6 Monopotassium Phosphate 8.7 Glycine 21.2 Dextrose, anhydrous 55.7 Composition X corresponds to Formulation 1 of Example 2 of US Patent No: 3898328.

Composition J and Composition X were made up into isotonic aqueous solutions of approximately 300 milliosmoles/kg.. Isotonic Saline was used as a control.

The method used was to anaesthetise scouring calves, and identify points along the small intestine at about 10%, 30%, 50%, 70% and 90% of the distance from the pyloric sphincter to the ileocaecal valve. At each of these points, a series of short lengths of intestine were isolated by ligatures. Solutions under investigation were injected into these loops and the water movement followed by measuring changes in phenol red concentration.

The results obtained were as shown in the Table below: % Distance Water Pyloric Absorbed Stan.

Sphincter Composition ml/cm/30 min Dan. to the Ileo- (mean ev. caecal valve seven tests) 10 Saline-0. 083 0. 023 X-0. 016 0. 019 J +0. 078 0. 012 30 Saline-0. 007 0. 020 X + 0. 036 0. 024 J + 0. 070 0. 022 50 Saline 0.031 0. 020 X 0.079 0. 032 J 0.146 0. 040 70 Saline 0.108 0. 027 X 0.085 0. 036 J 0.128 0. 007 90 Saline 0.099 0. 038 X 0.129 0.032 J 0. 145 0. 034 These results show that absorption of water by the scouring calves from composition J is significantly more rapid than from saline (p < 0. 01) or from composition X (p < 0. 05, analysis of variance).

EXAMPLE 5 1 kg. of the following composition was prepared by mixing together the ingredients in dry powder form: Glycine 10. 3% Dextrose (anhydrous) 67.6 Sodium Chloride 14. 3 Potassium Dihydrogen Phosphate 6.8 Tri-potassium Citrate. 1. 0 60g. of the composition was then dissolved in 2 litres of water.

EXAMPLE 6 The following composition was prepared by a method analogous to that of Example 5: Glycine 10% Dextrose (anhydrous) 72 Sodium Chloride 10 Tri-potassium Citrate. 8 60g. of this composition was then dissolved in 2 litres of water.

EXAMPLE 7 For storage, the composition according to Example 5 was prepared in the same manner, but the dextrose (676g.) was filled into one container and the remaining ingredients (324 g.) were filled into a second container.

EXAMPLE 8 To 60g. of a composition prepared according to Example 1 was added 400mg. of amoxycil- lin.

Claims

EXAMPLE 9

1 kg. of each of the following compositions D, I and G were prepared by mixing together the ingredients in dry powder D I G D I G % % % NaCI 31. 33 14. 8 15 Glucose 50.5 66.87 61 Glycine 10.11 9.39 12 Citric acid 3.00 1. 33 3 K3 citrate 5.06 1. 23 3 KH, Posa-6. 38 6 WHAT WE CLAIM IS: 1. A veterinary composition comprising 40 to 80% of an actively absorbed monosaccharide, 7.5 to 30% of an actively absorbed naturally occurring amino acid, and 0.5 to 10% of an agent which is citric acid or a salt thereof; except that when the agent is a salt of citric acid, then the amino acid represents no more than 13% of the composition.

2. A veterinary composition as claimed in claim 1, comprising 40 to 80% of an actively absorbed monosaccharide, 7.5 to 30% of an actively absorbed naturally occurring amino acid, and 0.5 to 10% of citric acid.

3. A composition as claimed in claim 2, wherein the monosaccharide is glucose.

4. A composition as claimed in claim 2 or 3, wherein the monosaccharide represents at least 65% of the composition.

5. A composition as claimed in claim 2,3 or 4, wherein the amino acid is glycine.

6. A composition as claimed in any one of the claims 2 to 5, wherein the amino acid represents 8 to 12% of the composition.

7. A composition as claimed in any one of the claims 2 to 6, additionally comprising 7 to 20% sodium chloride.

8. A composition as claimed in any one of the claims 2 to 7, wherein the citric acid represents 0.5 to 5% of the composition.

9. a composition as claimed in claim 8 additionally comprising @@ to 5% of citric acid.

10. A composition as claimed in claim 2, comprising 60 to 75 % glucose, 8 to 15% glycine, 0.5 to 2% citric acid, 0. 1 to 0.5% of a salt of citric acid, and 10 to 16% sodium chloride.

11. A composition as claimed in any one of the claims 2 to 10, additionally comprising an antibacterial agent.

12. A composition as claimed in any one of the claims 2 to 11, in aqueous solution.

13. A veterinary composition as claimed in claim 1, comprising 40 to 80% of an actively absorbed monosaccharide, 7.5 to 13% of an actively absorbed naturally occurring amino acid, and 0.5 to 10% of a citrate salt.

14. A composition as claimed in claim 13, wherein the monosaccharide is glucose.

15. A composition as claimed in claim 13 or 14, wherein the monosaccharide represents at least 65% of the composition.

16. A composition as claimed in claim 13,13 or 15, wherein the amino acid is glycine.

17. A composition as claimed in any one of the claims 13 to 16, wherein the amino acid represents 8 to 12% of the composition.

18. A composition as claimed in any one of the claims 13 to 17, additionally comprising 7 to 20% sodium chloride.

19. A composition as claimed in any one of the claims 13 to 18, wherein the citrate salt represents 0.5 to 5% of the composition.

20. A composition as claimed in claim 13, comprising 60 to 75% glucose, 8 to 12% glycine, 0.5 to 2% of a salt of citric acid, and 10 to 16% sodium chloride.

21. A composition as claimed in any one of the claims 13 to 20, additionally comprising an antibacterial agent.

22. A composition as claimed in any one of the claims 13 to 21, in aqueous solution.

23. A process for the preparation of a veterinary composition according to claim 1, which process comprises mixing together the ingredients in the necessary proportions.

24. A method of treatment of diarrhoea in animals, which method comprises administer ing to the animal a composition as claimed in claim 1 in the form of an aqueous solution.

25. A method of treatment of diarrhoea in animals, which method comprises administer ing to the animal a composition as claimed in any one of the claims 2 to 12.

26. A method of treatment of diarrhoea in animals, which method comprises administer ing to the animal a composition as claimed in any one of the claims 13 to 22.

27. A veterinary composition substantially as hereinbefore described with reference to Example 1, 2,3,5,6,7,8 or 9.

28. A veterinary composition substantially as hereinbefore described with reference to EXample 1.

HR DAWSON