CA1099571A - Salinomycin as ruminant feed additive - Google Patents

Abstract

AGENT FOR THE IMPROVEMENT OF THE NUTRIENT EFFICIENCY AND THE
GROWTH OF RUMINANTS AND ANIMAL SPECIES HAVING A SIMILAR
DIGESTIVE PATTERN
Abstract of the disclosure:
Agent for the improvement of the nutrient efficiency and the growth of ruminants and animal species having a similar digestive pattern which contains Salinomycin and a process for preparing said agent.

Description

The present invention relates to agents for the improve-ment of the nutrient efficiency and the growth of ruminants and animal species having a similar digestive pattern.
It has already been known to use antibiotics as feed additives in the animal nutrition.
The common antibiotics, such as Bacitracin, Ol~andomycin and Virginiamycin are mainly used for animals having a single gastric cavity; thcy do not have any specific effect on the rumen digestion in ruminants. It has now been found that the agents of the in~ention which contain Salinomycin have a special effect on the animal species digesting cellulose, due to the fact that they show a speci~ic positive influence on the microflora necessary for this ~ind of digestion.
The present invention therefore provides the use of Salinomycin and the physiologically acceptable salts and esters thereof as acti~e substances improving the nutrient efficiency and the growth of ruminants and animal species having a similar digestive pattern. The invention also pro-~ides agents, in particular feeding stuffs, which contain these substances as well as a process for preparing them.
~hus, the invention relates in particular to improved fesding stuffs for animals having the digestive pattern of ruminants, i.e. animals which can digest crude fibers or cellulose, the above~entioned definition comprising not only ruminants as such, but also, for example, horses and rabbits.
Salinomycin, its salts and esters have been described, for example, in British Patent Specifica-tion No~ 1 378 413 and in German Offenlegungsschrift No, 2 353 gg8. In -these 29 places, its use as anticoccidiosis agent has also been mentioned,

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As physiologically acceptable salts and esters to be used according to the invention instead of, or together with, Salinomycin, there are use~, for example, alkali metal salts, especially sodium, pota5sium or ammonium salts, alkaline earth metal salts, particularly magnesium or calcium salts, and alkyl esters, especially those having from 1 to 8, pre-ferably from 1 to 4 carbon atoms, as well as benzylester.
According to the invention it has been found that agents, in particular feeding stuffs, which contain Salinomycin, effect an improved nutrient efficiency as well as an accele-rated growth in ruminants. An impro~ed nutrient efficiency means that a determined weight increase is reached already by a reduced fodder supply~ It has also been found that in the rumen of ruminants the rati~ of acetic acidspropionic acid : butyric acid is influenced by the administration of the agents of the invention, particularly in the form of feeding stuffs, in such a manner that.the proportion of pro-pionic acid - which is more valuable for the energy meta-bolism - is increased to the debit of acetic acid and butyric acid, due to which process a nutrient efficiency is obtained which i5 considerably improved. It is of particular importance that this e~ect becomes also obvious in the feeding of NPN
compounds (non protein nitrogen) common for the nutrition of ruminants, for example, urea, biuret, diammonium phosphate, etc. as nitrogen sourcs for the supply of protein~
Instead of being administered in the form of Salinomycin as the pure substance, the active substance may be given in the same way as a dried mycelium or raw product~

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~ 9 5~ ~ HOE 75~ 240 A preferred method of administering the active substancs is in many cases its addition to the fodder in the form of a concentrate.
A concentrate (premix) of this kind may be prepared, ~or e~ample, by mixing the active substance or the mycelium con-taining the same or the raw product with a physiologically acceptable solid or liquid carrier, As solid carriers there may be mentioned, for example, by-products of careals, such as wheat flour of inferior quality, wheat bran or de-oilcd rice bran, but also corn meal, soy meal~ bolus alba or calcium carbonate. As liquid carriers, there may be used physiological salt solutions, distilled water and physiologie-ally acceptable organic solvents. It is also possible to add suitable additives, such as emulsifying agents, dispersing agents, wetting agents or gelatinizing agents. These con-centrates may contain as a rule from about 0.5 to about 5 of the active substance, however the concentration of this substance may also be considerably higher or lower, depending on the purpose of application.
For administering the active substances together with feeding stuffs) a premix is suitably mlxed with tha fodder by stirring, shaking, grinding, etc. The use of a powdery con-centrate has proved to be particularly useful for being mixed with fodder.
It is possible to add the substances used according to the invention to the supplementary fodder or to the entire fodder, or only to part of the daily feed ration.
The feed to which the active substance is added in 29 accordance with the invention comprises the feeding stuffs _ 4 .
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commonly used in the nutrition of ruminants, for example cereals, such as barley, oats, corn, as well ae alfalfa (lucerne), hay, or mixed fodder containing the above ingre-dient~. It is also possible to use R protein con~en-trato, which is common as feed, or mixtures or mineral substances, salt in block form or feed blocks, as well as liquid ~eed.
Thus, the supplementary feed for cattle may con-tain, for example, as the main ingredients dry chips, corn meal, coarse soybean meal, molasses and bran of peeled oats, and further-more a mixture of mineral substances, wheat bran and urea, or a salt in block form for ~heep may consist, for example t of bone meal and sodium chloride.
Another possibility to feed the active substance consists in adding the same, for example as such, or in the form of a ccnoentrate or a suspendable powder, to the drinking water or to another drink, such as milk.
The mixing with the feed may also be 0ffected in a way that a substance of the invention is admini~tered directly orally to the animals before, during or after feeding, for example in the form of a solid or liquid preparation, such as a tablet, a capsule, granules~ a bolus, a juice or syrup, or in tho form of a concentrate mentioned abova. In this way the mixing with the fodder - which is important according to the invention - is effected immediately after the application in 2~ the stomach, thus producing the ef~ect of a c~n~iderably im-proved nutrient ef~iciency and an increased growth according to the invention in the same manner.
For the administration in the form of tablets, capsules, 29 boli, pills, granules, etc., the same auxiliary agents and additives may be added, as they are ccmmonly kncwn frQm pharmaceutical technology. The active substan oe s may be mixed, for example, with p~dery diluents, such as microcrystalline cellulose, sugar or starch for filling u~ the volume of the capsule. rrhe preparation of the tablets may also be perfQrmed in cQ~non mannerl while adding substances, for example, cellulose, lactose, sodium chloride, starch, surface-active agents, such as sodium laurylsulfate, binding agents, such as gelatinl starch, dextrin, cellulose derivatives, etc. For the preparation of liquid formulations, use may also be made of the auxiliary agents which are ccmmon in phc~rmacy, sw h as vegetable oils, collidone, cellulose derivatives, nter alia auxiliary dispersing agents or emulsifying agents, water, etc. An aqueous suspensicn of SalinQ~Lycin may for example contain, besides Salinomycin, raw product or ground mLyceliun, carboxymethyl cellolose, Collidone 25 (polyvinylpyrolidone), Aerosol (trade mark for colloidal silicic acid), appropriate buffer substances, and water.
The most conve~ient method of applying the active substance aocording to the invention, which is therefore to be preferred as a rule, consists in feeding said substan oe directly together with the feeding stu~fs.
m e content of the substances to be used according to the inventiQn may vary, depending on the type of feeding. According to the latter it may be in the range of frQm 0.5 to 500 mg/kg of feed, i.e. it corresponds to a dosage of from 0.02 to 5.0 mg of Salincmycin per kg of body weight and day. It is advantageous tochoose a content of SalinQmycin in the fodder which correspQnds to a dosage of from 0.1 to 1.0 mg/kg of body weight and day. However, it is easily possible to 10 ~ 9 ~ ~ H ~

excead the above-mentioned limits considerably in appropriate cases. If the activ0 substance i9 administered to the animal directly in the form of an oral preparation, ths dosage i~ to be chosen also in a manner that it corresponds to the above-mentionad amount per kg of body weight and day. Thus, for e~ample~ those preparations which are administered to ~ull-grown cattle directly will contain an amount o~ active sub-stance which is in the ra~ge of from about 10 to 500 mg of Salinomycin, Preparations whioh a~e to be administered to smaller ruminants, for example, sheep or goat~, will contain an amount Or active ingre~ient which has been r~duced accordingly.
The following examples ser~e to illustrate the invention~
however, without restricting the same with regard to ani~al species or form of administration.
E X A M
A feeding test u~ing Salinomycin was oarried out on 12 fattening bulls that were kept with indi~idual feedin~ and self-watering and were bound to a barn. Six animals formed the Salinomycin test group, and the other 9iX animals ~ormed the untraated control group~ The average weight of the ani~
mals was about 350 kg at the beginning of the test. The test period was 8 weeks with individual weighing at intervals Or 2 weeks. - The feed consisted of a protein concentrate which was given to the animals according to their nutrient demand in an increasing am~unt (from 2 to 4 kg per animal and day~, : and of corn silage (from 16 to 20 kg per animal and day).
The composition of the protein concentrate was as follows~

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Barley ~6 Oats 20 ~
Corn 4s %
Carbonate of feed lime 2 %
5 ~ Hostaphos (Na-Mg-Ca-phosphate) 4 %
Urea 2 Sodium bicarbonate 1 100 q?O
Starch equivalents: 657 st.e.
Digestible protein 11.1 The S~linom~cin dosa~e was chosen in a way that 100 mg o~
the antibiotic agent per animal and day were ingested~together with the protein concentrate (in the form of a meal), in the form of a 2 ~ concentrate with corn meal.
Results:
Table 1 shows as a comparison the weight gain in the test and control groups, as well as the additional weight gain obtained by means of Salinomycin:
Table 1 Average weight Average weight Additional weight Test . gain in the gain in the gain in the period in control group test group test group weeks in kg in kg in %

2 14,8 21-3 + 43.9 ~
4 35 3 39.0 ~ 10~5 ~o :;r 6 54.8 62.2 + 13.5 ~
:~ 8 61.5 68.7 ~ 11.1 ~p ~ ___ _ , eR~te~ 7~r~de m~"~

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Table 2 shows as a comparison the nutrient efficiency in the test and control groups, as well as the improvemen-t obtained by means of Salinomycin:
Table 2 .. .... ........
___ _ _ . .
est period Average ef- Avarage ef- Improvement by in weeks ficiency ficiency Salinomycin number in number in in the control the test group group ~_ _ 2 3264 186~ , 42.9 ~
4 2~43 2295 ~ 19.3 %
6 2777 2249 ~ 19.1 %
8 337 2777 + 16.0 _ ,,,, _~ _ Efficiency number = starch equivalents per kg of weight g~i~i . , Tables 3 and 4 show how the content of low-molecular-weight fatty acids in the rumen juice has changed in the course of a test period of 8 weeks within the Salinomycin group, as compared against the control group. In order to determine the values, samples were taken by meansof astomach tube and were ~: subjected to gas chromatography.

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A~erage amount of the fatty acids present in 100 ml of rumen juice after a test period Or 8 wceks in mg Type of fatt ~ Control group Test group acid . _. _ 2 . 190.73 135.65 C3 53.90 ~0~75 - 4 . . __ l9.7Z

Table 4 ~ .
Proportion of the individual fatty acids in the rumen juice in ~ after a test period of 8 weeks Type of fattyControl group Test group acid .-C2 66.56 57.45 C3 ~8.80 34.20 C4 14.92 .8.35 ,, ..._ . ~
100 %

Tab~es 3 and 4 show that the proportion of propionic acid(C3) which is valuable for the energy metabolism ~as con~
siderably increased to the debit of acetic acid (C2) and butyric acid (C~), which results in a far better nutrient efficiency.
E X A M P L E ?~

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A feeding test using Salinomycin was carried out on 2?
fattening bulls, with 11 animals forming the control group, and the other 11 animals forming the test group. The animals . ~

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were kept being bound to a barn with individual feeding and self-watering. Their average weight at the beginning of the test was 400 kg, the test period was 6 weeks including indi-vidual weighing at intervals of 2 weeks. The feed consisted of protein concentrate which was gi~en to the animals accor-ding to their nutriQnt demand in an increasing amount (from 2 to 4 kg per animal and day), and of corn silage (from 16 to 20 kg per animàl and day).
The composition of the protein concentrate was as follows:
Oats 40 Corn 24 Urea 2 Sodium bicarbonate 1 ~
Lucerne green meal (alfalfa 15 %
meal) Dry chips 15 Mixture of mineral substances 3 ~Phosca Bully~
~ 100 ~
Starch equivalents 586 st.e.
Digestible protein 12.4 ~
, The Salinomycin dosage in the test group was 100 mg each per animal and day, the antibiotic agent being administered in the form of a 2 ~ concentrate with corn meal, together with the protein concentrate.
Results:
Table 5 shows as a comparlson the weight increase in the test and control groups, as well as the additional weight - 29 gain ob-tained by means of Salinomycin.
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Average weight Average weight Additional weight ~est per- gain in the gain in the gain in the iod incontrol group test group test group weeks in kg in kg in ~
~ _ 2 17~3 23.6 ~ 36.

4 32.1 35.2 + 9.7 6 49.8 53-6 + 7.6 ~ . . . .. _ . . .

Table 6 shows as a comparison the nutrient efficiency in the test and control groups, as well as the improvement obtained by means of Salinomycin:
Table 6 rest period Average ef- Average ef- Improvement by ~.
in weeks ficiency ficiency Salinomycin number in number in in %
the control the test ~ ~r~up ~ ~ _ : 2 32l7 2363 + 26 ! 5 4 3477 3176 ~ 8.7 6 33~7 3113 i ~.0 _ Tables 7 and 8 show how the content of low-molecular-weight fatty acids in the rumen juice has changed in the course of a test period of 6 weeks within the Salinomycin group, as compared against the control group. The values were deter-mined according to the method indicated in Example 1.

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Average amount of the fatty acids present in 100 ml of rumen juice after a test period of ~ weeks in mg Type of fatty Control group Test group acid C2 278.80 , ~05.9Z
C3 78.16 95.55 ~, 26.07 Table 8 Proportion of the individual fatty acids in the rumen juice in ~ after a test period of 6 weeks Type o~ fatty Control group Test group ,..~
C2 67.53 62~87 -~ C3 ~8.93 29.17 C 13.54 7.96 100 ~ ~0O %
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The increase of propionic acid led to the same consequences as those mentioned already in Example 1.
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A feeding test using Salinomycin was carried out on 25 fattening bulls (Holstein ~riesians) that were kept being bound to a barn with individual feeding and self-watering;
the average weight at the beginning of the test was about 260 kg; the test period was 20 weeks, including an individual weighing every four weeks.

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The feed consisted of a protein concentr~te which was given to the animals according to their nutrient demand in an increasing amount (from 2 to 4 kg per animal and day~, as well as of corn silage (~rom 16 to 20 kg per animal and day).
The composition of the protein concentrate was as follows:
Barley 26 Oats 20 ~
Corn 45 %
Carbonate of feed lime 2 %
10 ~ Hostaphos (Na-Mg-Ca-phosphate) 4 %
Urea 2 ~o Sodium bicarbonate 100 %
Starch equivalents 657 st.e.
Digestible protein 11~1 The animals were distributed into the following groups:

Group I : 5 Animals without treatment (control) ' Group II : 6 Animals treated with 100 mg each of Monensin per animal and day Group III : 7 Animals treated with 50 mg each of Salino-mycin per animal and day Group IV : 7 Animals treated with 100 mg each of Salino~
mycin per animal and day The antibiotics were administered to the test groups II to IV
daily in doses, together with the protein concentrate (in the form of a meal).

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Results:
The following Table shows the average weight gain and nutrient ef~iciency in the control group and the 3 test groups at each weighing a~ter a test period of ~rom 4 to 20 weeks.
In addition to the abs~lute values, the relative values have been indicated for the test groups, as compared against the untreated control group (in per cent)~
In the weight development, an additional weight gain of ~ 10 ~ and + 17.8 ~0 was obtained after a test period of 20 weeks by the administration of Salinomycin of 50 mg and/or 100 mg/animal and day, depending on the dose, whereas 100 mg of Monensin per animal and day resulted only in an additional weight gain of ~ 0.2 ~.
The nutrient efficiency was improved by the two Salino-mycin dosages (also depending on the dose)by + 9.0 ~0 and + 15.5 ~, whereas the improvement for 100 mg of Monensin per animal and day was + 5.4 ~.

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~ 09957~ HOE ~ F 240 E X A M P L E 4:
A feeding test using Salinomycin was carried out on 26 fattening bulls (red and white Holstein ~riesians) that were kept being bound to a barn with individual feeding and self-watering; the average weight at the beginning of the test was about 225 kg; the test period was 20 weeks, including an individual weighing every 4 weeks.
The feed consisted of a protein concentrate which was given to thc animals according to their nutrient demand in an increasing amount (from 2 to 4 kg per animal and day), as well as of corn silage (from 16 to 20 kg per animal and day).
The composition of the protein concentrate was as follows:
Barley 26 Oats 20 ~
Corn 45 %
Carbonate of feed lime 2 %
Hostaphos (Na-Mg-Ca-phosphate)4 %
Urea 2 Sodium bicarbonate 1 100 %
Starch equi~alents 657 st.e.
Digestible protein: 11 r 1 %
The animals were distributed into the following groups:
Group I : 6 Animals without treatment (control~

Group II : 6 Animals treated with 100 mg each of Monensin per animal and day Group III : 7 Animals treated with 50 mg each of Salino-mycin per animal and day eq Ote~ ~le ~rl~

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Group IV : 7 Animals treated with 100 mg each of 5alino- ..
mycin per animal and day .
The antibiotics were administered to the test groups II to IV
daily in doses, together with the protein concentrate (in the form of a meal).
Results:
The following Table shows the a~erage weight gain and nutrient efficiency in the control group and the 3 test groups at eac.h weighing after a test period of from 4 to 20 weeksO
In addition to the absolute values, the relative ~alues have been in~icated for the test groups, as compared against the untreated control group (in per cent).
In the weight de~elopment, an additional weight gain of + 17.5 % and 21.7 % was obtained after a test period of 20 weeks by the administration of Salinomycin of 50 mg and/or 100 mg per animal and day, depending on the dose, whereas 100 mg of Monensin per animal and day resulted only in an additional weight gain to +.2.4 %~ `
The nutrient e~ficiency was impro~ed by the two Salino-mycin dos.ages (also depending on the dose) by + 12.5 ~ and + 15.4 ~, whereas 100 mg of Monensin per animal and day did not result in any impro~ement.

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Corn meal 15 %
~oarse soybean meal 15 Molasses 15 ~
Bran of peeled oats 15 ~o Wheat bran 2.5 %
Urea 1-5 10 Mixture of mineral substances 5.0 Salinomycin-mycelium premix ~with 2.5 mg/g) 1.0 100 ~
Thus, 1 kg of supplementary feed contained 25 mg of Salinomycin. Grazing cattle were gi~en from 2 to 4 kg of supplementary feed per day, i.e. from 50 to 100 mg of Salinomycin.
E X A M P L E 6:

Bone meal 6 kg Sodium chloride 3 kg Salinomycin-mycelium as 1 ~o premix 1 kg 10 kg 25 10 Grams of salt in block form contained 10 mg of Salinomycin~

i.e. a daily dose for a sheep.
E X A M P L E 7:
Bolus for _cattle -- ZO _ . . ~

~ 7~ HOE 7~/F 240 Microcrystalline cellulose 8000 mg Corn starch 1200 mg Methylhydroxyethylcellulose 900 mg Magnesium stearate 300 mg Colloidal silicic acid (Aerosil) 400 mg Na-amylopectine-glycolate 1000 mg 50 ~ Salinomycin raw product ~
12000 ~g ======== .

1 Bolus of 12 g contained 100 mg of Salinomycin, i.e. the daily dose for cattle.
E X A M P L E 8s Tablet for_sheeP
Microcrystalline cellulose 900 mg Corn starch 200 mg Carboxymethylcellulose 150 mg Magnesium stearate 50 mg Talcum . 50 mg Aerosil 350 mg Na-amylopectine-glycolate 180 mg NaCl 100 mg 50 ~ Salinomycin raw product __~ e_ 2000 mg =======

1 Bolus of 2~0 g contained 10 mg of Salinomycin, i.e. the daily dose for a sheep.

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Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A feed composition for ruminants and animal species having a similar digestive pattern, the composition containing sufficient Salinomycin to increase the proportion of propionic acid to the debit of acetic and butyric acids in the rumen of the ruminant or animal thereby increasing the feed efficiency.

2. A feed composition as claimed in claim 1, in which the Salinomycin is present in the form of a physiologically acceptable salt, ester or mixture thereof.

3. A feed composition as claimed in claim 2, in which the salt is selected from the group of alkali metal salts and alkaline earth metal salts.

4. A feed composition as claimed in claim 3, in which the salt is selected from the group of sodium, potassium, ammonium, magnesium and calcium salts.

5. A feed composition as claimed in claim 2, in which the ester is an alkylester or benzylester.

6. A feed composition as claimed in claim 5, in which the alkylester contains from 1 to 8 carbon atoms.