CS195733B2 - Method for ammeliorating the exploitation of nutrients and for ammeliorating the growth of ruminants and animal types with similar physiology of digestion - Google Patents

Abstract

The feed additive to promote nutrient conversion and growth in ruminants and animal species with a similar physiology of the digestive system contains salinomycin, its physiologically acceptable salts and/or esters and carrier material. The feed additive can be given together with the feed or before or after feeding.

Description

The present invention provides a means for improving nutrient utilization and for improving the growth of ruminants and animal species with similar digestive physiology.

It is already known to use antibiotics as feed additives in animal nutrition.

Conventional antibiotics such as bacitracin, oleandomycin and virginium-mycin are mainly used in animals with a single stomach; said antibiotics have no specific effect on rumen digestion in ruminants. It has now been found that salinomycin-containing compositions of the invention have a particular effect in cellulose-eating animals by specifically affecting the microflora required for this digestion.

The invention therefore relates to the use of salinomycin and its physiologically acceptable salts and esters as active substances for improving nutrient utilization and growth of ruminants and animal species with similar digestive physiology. The invention furthermore relates to compositions, in particular feedstuffs, characterized by the content of these active substances, and to a process for the preparation of such compositions.

The invention therefore relates in particular to improved animal feedstuffs with a physiology of ruminant digestion, i.e. animals which can digest raw fibers or cellulose, and the above definition includes not only ruminants as such, but also horses and rabbits.

Salinomycin, its salts and esters are described, for example, in British Patent 1,378,413 as well as in German Patent Publication 2,353,998. There is also mention of its use as an anticancer agent.

Suitable physiologically acceptable salts and esters useful in accordance with the invention in place of or together with salinomycin are, for example, alkali salts, in particular potassium, sodium or ammonium salts, alkali metal salts, in particular magnesium or calcium, and alkyl esters, in particular 1 to 8, preferably 1 up to 4 carbon atoms in the alkyl radical as well as the benzyl ester.

According to the invention, it has been found that salinomycin-containing compositions, in particular feedstuffs, result in improved feed utilization and accelerated growth in ruminants. Improved feed utilization means that given weight gains are achieved by lower feed rations. Furthermore, it has been found that in the rumen of ruminants, the ratio of acetic acid: propionic acid: butyric acid by the administration of the compositions according to the invention, in particular in the form of feed, is influenced by the proportions of propionic acid This results in a significantly better utilization of nutrients. It is particularly important that this effect also clearly occurs in the feeding of NPN compounds (i.e., compounds containing non-protein nitrogen), common in ruminants such as urea, biuret, ammonium phosphate, etc., as a nitrogen source for protein supply.

Instead of salinomycel as a pure substance, the active ingredient can be administered in the same manner as dried mycelium or a crude product.

The dosage form of the active ingredient, which is preferred in many cases, is its feed additive in the form of a concentrate. Such a concentrate (masterbatch) can be prepared, for example, by mixing the active ingredient or mycelium containing the active ingredient or the crude product with a physiologically acceptable solid or liquid carrier. Suitable solid carriers are, for example, cereal by-products such as wheat hind flour, wheat bran or oil-free rice bran, but also corn flour, soy flour, kaolin or calcium carbonate. Physiological saline solutions, distilled water and physiologically compatible organic solvents can be used as liquid carriers. It is also possible to add suitable additives such as emulsifiers, dispersants, suspending agents, wetting agents or gelling agents. As a rule, these concentrates may contain from about 0.5 to about 5% of the active ingredient, and depending on the intended use, the concentration of the active ingredient may be considerably lower or higher than this range.

For administration with the feed, it is expedient to mix the premix with the feed in mixing, mixing, shaking, milling, etc. The use of a powdered concentrate has proven particularly suitable for mixing.

It is also possible to add the composition used according to the invention to the supplementary feed or to the total feed or even to part of the daily dose,

The feed to which the active ingredient according to the invention is added is feed usually used in the feeding of ruminants, for example, cereals such as barley, oats, corn, alfalfa, hay or mixed feed produced therefrom. It is also possible to use conventional feedstuffs. nuclear feed or mixtures of 'minerals, licks or feed granulates' and 'liquid feed'. Thus, the bovine feedstuffs as main components may contain, for example, dried pulp, corn flour, soybean meal, molasses and oat bran, as well as a mixture of minerals, wheat bran and urea, or salt. For licking for sheep, it may consist, for example, of bone meal and rock salt.

A further possibility of feeding the active ingredient consists in adding the active ingredient as such or in the form of a concentrate or suspendable powder to the drinking water or other beverage, e.g. milk.

Mixing with the feed can also be done by directly orally administering to the animals prior to, during or after feeding the composition of the invention, for example in the form of a solid or liquid preparation such as a tablet, capsule, granulate, bolus, juice or a syrup, or in the form of a concentrate as described above. In this way, according to the invention, an important mixing with the feed immediately after application in the stomach is achieved in the same way by the purpose of the invention of significantly improved nutrient utilization and enhanced growth.

For administration in the form of tablets, capsules, boluses, pills, granules, etc., the usual excipients as known in the pharmaceutical art may be added. The active ingredients can be mixed, for example, with powdered diluents, such as, for example, cellulose crystalline, sugar or starch, to fill the capsule volume. Tablets can also be prepared in a conventional manner by adding substances such as cellulose, lactose, sodium chloride, starch, and the like. surfactants such as sodium lauryl sulfate, binders such as gelatin, starch, dextrin, cellulose derivatives, etc. Adjuvants customary in liquid formulations may also be used in the preparation of liquid preparations. pharmaceuticals such as vegetable oils, collidone, cellulose derivatives and other suspension aids or emulsifiers, water, etc. An aqueous salinomycin suspension may contain, for example, in addition to the crude salinomycin or ground mycelium product, carboxymethylcellulose, collidone 25, Aerosil, suitable buffers and water .

The most practical and, as a rule, advantageous application of the active ingredient according to the invention consists in its direct feeding with the feed.

The amount of the composition used according to the invention varies depending on the type of feed. By species. the feed may be in the range of 0.5-500 mg / kg feed, i.e. corresponding to a dosage of 0.02-5.0 mg salinomycin per kg body weight per day. _S: preferably may be selected salinomycin content. in feed corresponding to a dosage of 0.1 to 1.0 mg / kg body weight per day. However, it is also possible, if appropriate, to significantly exceed these limits. When the active substance is administered in the form of an oral preparation to an animal immediately, the dosage should also be chosen so that it corresponds to the above amount per kg body weight per day. For example, formulations which are directly administered to adolescent bovine animals contain, as an amount of active ingredient, about 10-500 mg of salinomycin. Preparations,. which are intended for smaller ruminants, for example sheep or goats, contain correspondingly reduced amounts of the active substance.

The following examples illustrate the invention in more detail, but do not limit it to the animal species or the forms of administration described.

Example 1

A feed test with salinomycin was performed with 12 grazed bulls kept in the Binding Shed, separately fed and spontaneously fed. Six animals consisted of the salinomycin-treated group and another 6 animals treated without salinomycin. Average weight. the animals at the start of the experiment are approximately 350 kg. The duration of the experiment is 8 weeks, with animals weighing every 2 weeks. The feed is a kernel fodder that is administered to the animals in increasing amounts according to the nutrients needed (2 kg to 4 kg each day) and from feed silage (16 to 20 kg per animal per day). Composition of nuclear feed:

barley 26% oats 20%.

corn 45% feed calcium carbonate 2%

Hostaphos (phosphate

Na-Mg-Ca) 4% ovina urea 2% sodium bicarbonate 1% \ 100% starch unit:

657 starch units digestible protein:

11.1%.

The dosage of salinomycin is selected by administering 100 mg of antibiotic as a 2% corn flour concentrate with the core feed (in powder form) per animal per day.

Results:

Table 1 shows a comparison of the weight gains in the group of test and control animals as well as the extra gains achieved with salinomycin administration.

TABLE 1

Duration of the experiment in weeks Average weight increment in control group in kg Average weight increment for the test group in kg Hm. additional increase for the experimental group in% 2 14.8 21.3 + 43.9% 4 35.3 39.0 + 10.5% 6 54.8 62.2 + 13,5% 8 61.5 68.7 + 11.1%

Table 2 shows a comparison of nutrient utilization in the experimental and control groups as well as the improvement achieved by salinomycin.

TABLE 2 Duration of the experiment Average usage number * Average usage number Improvement achieved in weeks in the control group in the experimental group administration of salinomycin, in% 2 3264 1865 + 42.9% 4 2843 2295 + 19.3% 6 2777 2249 + 19.1% 8 3307 2777 + 16,0%

* Usage number = number of starch units per 1 kg weight gain.

Tables 3 and 4 show how the low molecular weight fatty acid content of the rumen juices changes over the 8 weeks duration of the experiment for the salinomycin-treated group compared to the salinomycin-free control group. To determine these values, samples are sampled and subjected to gas chromatography.

Type of fatty acid TABLE 3 Mean amount of fatty acids in mg, present after 8 weeks of test duration in 100 ml rumen juice control group test group C2 Сз CD 190.73 135.65 53.90 80.75 41.92 19.72

TABLE 4 Type of fatty acid The ratio of the amounts of individual fatty acids in% in rumen juices after 8 weeks of experiment control group experimental group

С2 66.5657.45

Сз 18,8034,20

С4 14,928.35

100%

Tables 3 and 4 show that the proportion of propionic acid (Сз), important for the conversion of substances into energy, will increase substantially at the expense of acetic acid (C 2) and butyric acid (C4), thus achieving a significantly better use of nutrients.

Example 2

A salinomycin feed with 22 bulls per feed was performed, with 11 animals constituting the control group and the other 11 animals the experimental group. The animals are housed in a ligament, separately fed and watered independently. Their average weight at the start of the experiment is 400 kg, the duration of the experiment is 6 weeks, with animals weighing at 2 week intervals. The feed is the kernel feed, which is fed to the animals in increasing amounts of 2 to 4 kg per animal per day, as well as corn silage (16 to 20 kg per animal per day).

Composition of nuclear feed:

oat 40% maize 24% urea 2% sodium bicarbonate 1% green alfalfa meal 15% dried cuttings 15% a mixture of minerals 3% Starch units: 586 starch units, digestible proteins: 12.4%. 100%

The dose of salinomycline in the test group is always 100 mg per animal per day, with the antibiotic being administered with the feed in the form of a 2% corn flour concentrate.

Results:

Table 5 shows a comparison of the weight gains in the experimental and control groups, as well as the extra gains achieved with salinomycin administration.

TABLE 5

Duration of the experiment in weeks Average weight increment in control group in kg Average weight increment in test group in kg Additions for the experimental group, in% 2 17.3 23.6 + 36.4 4 32.1 35.2 + 9.7 6 49.8 53.6 + 7.6

Table 6 shows a comparison of nutrient utilization in the experimental and control groups as well as the improvement achieved with salinomycin administration.

TABLE 6

Duration of the experiment Average usage number Average usage number Improvements achieved in weeks nutrient control nutrients in experimental giving salinomycin, groups groups in% 2 3217 2363 + 26.5 4 3477 3176 + 8.7 6 3387 .3113 + 8.0

The data in Tables 7 and 8 show how the low molecular weight fatty acid content of the rumen juices changes over the 6 weeks duration of the experiment for the salinomycin treatment group compared to the control group. The values are determined as in Example 1.

TABLE 7

Type of fatty acid

The average amount of fatty acids in mg present in 100 ml of ruminal juice after 6 weeks of experiment

control group experimental group c ₂ 278,80 205.92 Сз 78.16 95.55 CD 55.99 26.07 TABLE 8 Type of fatty acid The ratio of the amount of individual fatty acids in rumen juice in% after 6 weeks of the experiment control group experimental group C ₂ 67.53 62.87 Сз 18.93 29.17 . CD 13.54 7.96 100% 100%

The same consequences as in Example 1 are derived from increasing the amount of proponic acid.

Example 3

With 25 bulls per feed (black-eyed bottom cattle), a feed experiment was performed consisting of salinomycin. The bulls are kept in a tie barn, separately fed and watered spontaneously. The average weight at the start of the experiment is approximately 260 kg. The duration of the experiment is -20 weeks, with animals weighing every 4 weeks.

Feed is nuclear feed which is fed to animals in increasing amounts of 2 to 4 kg per animal per day as well as maize silage (16 to 20 kg per animal per day) as needed.

Composition of nuclear feed:

barley 26% oats 20% corn 45% feed calcium carbonate 2%

Hostaphos (phosphate

Na-Mg-Ca) 4% urea · 2% sodium bicarbonate 1%

100% Starch Units:

657 starch units, digestible proteins: 11.1%.

Animals are divided into the following groups:

Group I:

animals without salinomycin administration (control animals).

Group II:

the animals are each given 100 mg of monensin per day.

Group III:

the animals are each given 50 mg salinomycin daily.

Group IV:

the animals are each given 100 mg salinomycin per day.

Antibiotic doses are administered to animals in experimental groups II-IV daily with kernel fodder (in meal form).

Results:

The table below shows the average weight gains and nutrient utilization of the control group and the three experimental groups at each weighing after 4 to 20 weeks of experiment duration. In addition to the absolute values, the experimental groups are given relative values compared to the control group (in percent).

In weight development, after 20 weeks of experiment duration, salinomycin at a dose of 50 mg or 100 mg / animal per day, plus + 10% and + 17.8% increments, respectively, while 100 mg monensin per animal / day only leads to an increase of + 0.2%.

Nutrient utilization is improved by both + 9.0% and 15.5% (also dose-dependent) with both salinomycin dosing, while an improvement of + 5.4% is achieved with 100 mg monensin per animal per day.

195733 11 12 Duration Control Monensin Salinomycin Salinomycin attempt group I 100 mg / animal per day 50 mg / animal per day 100 'mg / animal' per day in weeks 5 animals' Group II 6 animals Group III 7 animals Group IV 7 animals

initial weight initial weight

hm. 258.8 kg abs. (kg) 261.2 kg 260.7 kg 260.7 kg abs. (kg) rel. (%) abs. (kg) rel. (O / o) abs. (kg) rel. , (%) Average 4 29.0 34.0 117.2 33.9 116.9 35.9 123.8 hm. 8 64.2 63.8 99.4 72.6 113.1 74.3 115.7 growth 12 96.4 96.5 100.1 106.2 110.2 112.6 116.8 1 animal 16 130.2 126.0 96.8 144.9 111.3 150.6 115.7 Average 20 May 164.6 165.0 100.2 181.0 ’** 110.0 193.9 ** 117.8 use 4 3305 2807 84.9 2855 86.4 2647 80.1 of nutrients 8 3259 3145 96.5 2900 89.0 2793 85.7 starch. 12 3462 3246 93.8 3145 90.8 2929 84.6 unit / kg 16 ‘3509 3412 97.2 3152 89.8 3005 85.6 increment 20 May 3558 3366 94.6 1117 ’* · 91.0 3115 ’” 84.5

*** Statistical significance: 99.9% probability.

Example 1 a d 4

With 26 bulls per feed (red-necked long-range cattle) kept in a lagging stable, separately fed and spontaneously fed, salinomycin was fed. The average weight of the animal at the start of the experiment is approximately 225 kg. Duration of the experiment for 20 weeks with the animals weighing every 4 weeks.

Feed is a core feed which is administered to the animals in increasing amounts (from 2 to 4 kg / animal / day) as well as 1 maize silage (16 to 20 kg / animal / day) as needed. '

Composition of nuclear feed:

barley 22% oats 20% corn 45% feed calcium carbonate 2%

Hostaphos (phosphate

Na-Mg-Ca) 4% urea 2% sodium bicarbonate 1%

100 'o / o

Starch units:

657 starch units, digestible proteins:

11.1 'o / o.

The animals are divided into the following groups: Group I:

animals without salinomycin administration (control).

Group II:

the animals are given 'each 100 mg monensin' daily.

Group III:

the animals are each given 50 mg salinomycin daily.

Group IV:

the animals are each given 100 mg salinomycin per day.

Antibiotic doses are administered to animals in experimental groups II-IV daily with kernel fodder (in meal form).

Results:

The table below shows the average wt. increments and nutrient utilization in the control group and the three experimental groups at each weighing after 4 to 20 weeks of experiment duration. In addition to the absolute values, the experimental groups are given relative values compared to the control group (in percent).

In weight development, after 20 weeks of experimentation, salinomycin at doses of 50 mg and 100 mg / animal per day, respectively, results in an additional increase of + 17.5% and

21.7,% in a dose-dependent manner, while administration of 100 mg of monensin per animal per day results in an additional increase of only + 2.4%.

Nutrient utilization is improved by both + 12.5% and + 15.4% (both dose-dependent) with both salinomycin dosing, while no improvement is achieved with 100 mg monensin per animal per day.

Duration Control Monensin Salinomycin Salinomycin trial group I 100 mg / animal and day 50 mg / animal and day 100 mg / animal and day in weeks 5 animals group II 6 animals group III 7 animals group IV 7 animals

initial weight 225,0 kg abs. (kg) initial weight 223,8 kg initial weight 223,6 kg initial weight 224.3 kg abs. (kg) rel. (%) abs. (kg) rel. (%) abs. (kg) rel. (%) Average 4 27.5 26.4 96.0 30.4 110.6 33.5 121.8 hm. 8 54.7 53.2 97.3 62.0 113.4 62.7 114.6 growth 12 83.5 86.4 103.5 98.0 117,4 ' 101.0 121.0 1 animal 16 117.3 122.5 104.4 142.1 121.1 147.6 125.8 Average 20 May 157.5 161.2 102.4 185.0 ** ' 117.5 191,7 *** 121.7 use 4 2987 3014 100.9 2640 88.4. 2318 77.6 of nutrients 8 3089 3114 100.8 2693 87.2 2638 85.4 starch. 12 3 & 38 3134 96.8 2780 85.9 2691 83.1 unit / kg 16 3228 3166 98.1 2739 84.6 2634 81.6 increment 20 May 3179 3175 99.9 2781 * ’ 87.5 2691 *** 84.6

*** Statistical significance: 99.9% probability.

Example 5

Additional feed for cattle: dried cuttings 30 % cornflour 15 Dec % soya scrap 15 Dec '% molasses 15 Dec % Oat bran 15 Dec % wheat bran 2.5% urea 1,5%: a mixture of minerals 5 % salinomycin-mycelia masterbatch (2.5 mg / g) 1 % 100 ALIGN! %

Thus, 1 kg of additional feed contains 25 mg of salinomycin. Grazing animals receive 2 to 4 kg of additional feed, i.e. 50 to 100 mg of salinomycin per day.

Example 6

Lick salt for sheep: bone meal 6 kg rock salt 3 kg salinomycin mycelium as a 1% premix 1 kg

kg g of lick salt contains 10 mg salinomycin, i.e. a daily dose for 1 sheep.

Example Ί

Bolus for cattle:

microcrystalline cellulose 8 000 mg maize starch 1 200 mg methylhydroxyethylcellulose 900mg magnesium stearate 300mg colloidal silicic acid (Aerosil) 400mg sodium amylopectin glycolate 1 000 mg 50% salinomycin crude product 200 mg

OOOmg bolus o ^; weighing 12 g contains 100 mg salinomycin, i.e. a daily dose for 1 bovine.

Example

Tablet for sheep:

Microcrystalline cellulose 900mg Corn starch 200mg Carboxymethylcellulose 150mg Magnesium stearate 50mg Talc 50mg

Aerosil 350mg sodium amylopectin glycolate 180mg sodium chloride 100mg

50% salinomycin crude product 20mg

A 2.0 mg tablet weighing 2.0 g contains 10 mg salinomycin, i.e. a daily dose for sheep.

Claims (19)

OBJECT OF THE INVENTION A composition for improving the utilization of nutrients and for improving the growth of ruminants and animal species with a similar physiology of digestion, comprising salinomycin. 2. A composition according to claim 1 which is a feed. 3. A composition according to claim 1 which is an additional feed. 4. A composition according to claim 1 which is a solid or liquid concentrate (masterbatch). 5. A composition according to claim 1, wherein the composition is water for drinking or other beverage. 6. A composition according to claim 1, wherein the composition is a solid or liquid, orally administrable composition, preferably a tablet, capsule, bolus, granulate, juice or syrup. 7. A composition according to any one of claims 1 to 6, which comprises salinomycin in the form of its physiologically acceptable salts and / or esters. Composition according to Claim 7, characterized in that it contains alkali metal salts and / or alkaline earth metal salts as salts. 9. A composition according to claim 8, wherein the alkali salts include sodium, potassium, and ammonium salts, such as alkaline earth metal salts, magnesium and calcium salts. 10. A composition according to claim 7, wherein the ester is an alkyl ester or a benzyl ester. Composition according to Claim 10, characterized in that the alkyl ester is an alkyl ester of 1 to 8, preferably 1 to 4, carbon atoms. 12. A composition according to claim 1 comprising salinomycin as a mycelium or a crude product. Composition according to any one of Claims 1 to 12, characterized in that the concentration of salinomycin in the composition is selected such that it corresponds to a dosage in the range of 0.02 to 5.0 mg / kg body weight per day, preferably in the range of 0.1 to 1.0 mg / kg body weight per day. 14. A composition according to claim 2, wherein said feed is a feed which is common in feeding ruminants and animal species with similar digestive physiology. 15. The composition of Claim 14 wherein said feed is a liquid feed. 16. The composition of claims 2, 14 and 15, wherein the feed also comprises non-protein nitrogen compounds. 17. A process for the preparation of the compositions according to claims 1 to 16, characterized in that salionomycin, its physiologically acceptable salts and / or esters in a suitable form are mixed with liquid or solid feed or gallegic auxiliaries and additives. a dosage form suitable for oral administration. 18. The method of claim 17, wherein the active ingredient is added to the feed in the form of a concentrate (masterbatch). 19. The process of claim 17 wherein the added salinomycin is in the form of mycella or as a crude product.