SE423858B - USE OF SALINOMYCIN TO IMPROVE NUTRITION AND GROWTH OF EDITORS AND BUNNIES - Google Patents

Description

7908636-9 agents for animals with the digestive physiology of ruminants, ie. animals capable of digesting raw fibers or cellulose, not only the ruminants as such, but also, for example, horses and rabbits being covered by the above definition.

Salinomycin, its salts and esters have been described, for example, in GB patent 1,378,413 and in DT Offenlegungsschrift 2,353,998. Its use as an anticoccidial agent is also mentioned there.

As according to the invention, instead of or together with salinomycin insertable, physiologically tolerable salts and esters, there are, for example, alkali metal salts, in particular sodium, potassium or ammonium salts, alkaline earth metal salts, in particular magnesium or calcium salts, and alkyl esters, in particular those having 1 to 8 , preferably 1 to 4 carbon atoms and the benzyl ester.

According to the invention, it has been found that salinomycin-containing agents, in particular feed materials, in ruminants result in an improved uptake of the feed and a faster growth as a result. Improved feed intake means that a specific weight gain is already achieved through smaller feed materials.

It was also found that the ratio of acetic acid azropropionic acid: butyric acid in ruminants' rumen by the administration of the agents proposed according to the invention, in particular in the form of feed, is affected by increasing the proportion of propionic acid more valuable for energy metabolism at the expense of acetic acid and butyric acid. , whereby a significantly better nutrient uptake is achieved. Of particular importance is that this effect is also clearly evident in the usual feeding of NPN compounds (non-protein nitrogen) in connection with the breeding of ruminants, e.g. urea, biuret, diammonium phosphate, etc. as a source of nitrogen for the protein supply.

Instead of salinomycin in pure form, the active substance can be given in the same way as dried mycelium or as a raw product.

A preferred form of application for the active substance in many cases is its addition to the feed in the form of a concentrate. Such a concentrate (premix) can be prepared, for example, by mixing the active substance or mycelium containing it, or the crude product with a physiologically tolerable, solid or liquid carrier. Suitable solid carriers are, for example, cereal by-products such as wheat flour, wheat bran or oiled rice bran, but also corn flour, soy flour, bolus alba or calcium carbonate. Physiological saline solutions, distilled water and physiologically tolerable 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. These concentrates can generally contain about 0.5 - 5% of the active substance, however, depending on the purpose of use, the concentrations can also be significantly exceeded or underestimated.

When administered together with feed, it is conveniently arranged that a premix is mixed with the feed by mixing, stirring, shaking, grinding, etc. It is particularly suitable to mix a powdered concentrate with the feed.

It is also possible to add the agents used according to the invention to the supplementary feed or the entire feed or also only to a part of the daily ration.

In the case of the feed, which is to be added with the active substance according to the invention, it is a question of the feed materials commonly used in the breeding of ruminants, for example cereals, e.g. barley, oats, maize and alfalfa, hay or mixed feedingstuffs derived therefrom. In the same way, it is possible to use ordinary concentrates or mineral mixtures, licking stones or feed cakes as well as liquid feed as feedstuffs. For example, supplementary feed for cattle as main constituents may contain dry slices, cornmeal, soybean cakes, molasses and oat seeds, as well as a mixture of minerals, wheat bran and urea or a licking stone for sheep, e.g. of bone meal and common salt.

Another possibility for feeding with the active substance is that it is added to the drinking water or another beverage, for example as such or in the form of a concentrate or a suspensible powder, e.g. milk. The mixing with the feed can also take place in such a way that the animals before, during or after the feeding are given an agent according to the invention directly by mouth, for example a tablet, capsule, a granulate, bolus, juice or syrup or in the form of a concentrate described above. In this way, the important mixing with the feed according to the invention takes place immediately after the introduction into the stomach and then gives in the same way the inventive effect of a significantly improved nutrient uptake and an increased growth rate.

For the administration in the form of tablets, capsules, boli, pills, granules, etc., the same excipients and additives may be used which are known from the pharmaceutical technology. The active substances can, for example, be mixed with powdered diluents, e.g. microcrystalline cellulose, sugar or starch to fill the capsule volume. The tablets can likewise be prepared in the usual way with the addition of such substances as e.g. cellulose, lactose, sodium chloride, starch, surfactants such as sodium lauryl sulphate, binders such as gelatin, starch, dextrin, cellulose derivatives, etc. The auxiliaries common in pharmacy can also be used for the preparation of liquid preparations, e.g. vegetable oils, collidone, cellulose derivatives and other suspending aids or emulsifiers, water, etc. An aqueous suspension of salinomycin may contain, for example, in addition to salinomycin, crude product or ground mycelium, carboxymethylcellulose, collidone 25, Aerosil (R) (highly dispersed silica-suitable aerosol) buffer substances and water.

The most practical mode of administration of the active substance according to the invention, and which is therefore generally also preferred, is to give it directly together with the feedingstuffs.

The content of the agents intended for use according to the invention varies depending on the method of feeding. Depending on the method of feeding, it can amount to 0.5 - 500 mg / kg feed, ie. a dose of 0.02 - 5.0 mg salinomycin per kg body weight and day. Preferably, a salinomycin content in the feed can be selected, which corresponds to a dosage of 0.1 - 1.0 mg / kg body weight and day. However, it is also readily possible, in appropriate cases, to significantly exceed the stated limits. If the active substance is given directly in the form of an oral preparation, the dosage must also be chosen in such a way that it corresponds to the above-mentioned amount per kg body weight and day. Thus, for example, formulations given directly to an adult cattle should contain about 10 to 500 mg of salinomycin. Preparations to be given to smaller livestock, such as sheep or goats, contain correspondingly reduced amounts of the active substance.

The following exemplary embodiments serve to illustrate the invention without limiting its scope, either in terms of animal species or application form.

Example 1 A feeding experiment with salinomycin sodium salt was performed with 12 fattening bulls, which were kept in separate feeding with automatic watering tied in a barn. 6 animals formed the salinomycin sodium salt experimental group and 6 animals the untreated control group. The average weight of the animals at the beginning of the experiment was 350 kg. The trial period was 8 weeks with weighing at 14-day intervals. The feed consisted of concentrate, which according to the nutritional needs was given to the animals in increasing amounts (from 2 - 4 kg per animal per day), and of corn silage (16 - 20 kg per animal per day). Composition of concentrates: Barley 26% Oats 20% Maize 45% Carbonated feed lime 2% Hostaphos (R) (Na-Mg-Ca-phosphate) 4% Urea 2% Sodium bicarbonate 1% 100% Starch units 657 St.E.

Digestible egg white 11.1% The salinomycin sodium salt dosage was chosen so that together with the concentrate (in flour form) 100 mg of the antibiotic per animal and day in the form of a 2-percent. concentrate with cornmeal uPPtOgS. 7908636-9 Results: Table 1 shows for comparison the weight increases in the experimental and control group and the additional increases achieved by salinomycin: Table 1 Experimental time Average Average Additional increase in weeks weight gain in weight gain in the experimental group control group experimental group kg kg% 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 the nutrient uptake in the experimental and control group and the improvement achieved by the salinomycin sodium salt: Table 2 Experimental time Average Average Improvement in weeks quality of life * in quality of life * in the saline control group experimental group mycin-Na-salt 2 3264 1865 +42.9 4 2843 2295 +19, 3 6 2777 2249 +19.1 8 3307 2777 +16.0 x Quality data = starch units per kg weight gain Tables 3 and 4 show how the rumen juice content of low molecular weight fatty acids during the 8-week trial period changed in the salinomycin-Na-salt group in comparison with the control group.

To determine the values, samples were taken with a probe and gas chromatographed. 7908636-9 Table 3 Type of fatty acid Average amount of the fatty acids present in 100 ml rumen juice after 8 weeks trial period in mg Control group Experimental group C2 190.73 135.65 C3 53.90 80.75 C4 41.92 19.72 Table 4 Nature of the fatty acid Ratio between the individual fatty acids in rumen juice as a percentage after 8 weeks test period Control group Experimental group C2 66.56 57.45 C3 18.80 34.20 C4 14.92 8.35 100% 100% Tables 3 and 4 show that the proportion of the propionic acid (C3) valuable for energy metabolism is significantly increased at the expense of acetic acid (C2) and butyric acid (C4), whereby a significantly improved nutrient uptake is achieved.

Example gel 2 A feeding experiment with salinomycin sodium salt was performed with 22 fattening bulls, with 11 animals forming the control group and 11 animals the experimental group. The animals were tied up in a barn with separate feeding and automatic watering. Their average weight at the beginning of the trial was 400 kg, the trial period 6 weeks with weighings in 14-day intervals. The feed consisted of concentrates given to the animals according to their nutritional needs in increasing amounts (from 2 - 4 kg per animal and day), and of maize silage (16 - 20 kg per animal and day).

Composition of concentrates: Oats 40% Maize 24% Urea 2% Sodium bicarbonate 1% Green alfalfa flour 15% ~ Dry cut 15% Mineral mixture 3% '(Phosca Bully) 100% Starch units 586 St.E.

Digestible egg white 12.4% The salinomycin sodium salt dosage in the experimental group was 100 mg each time per animal and day, the antibiotic being given to the animals in the form of a 2%. concentrate together with the concentrate.

Results: Table 5 shows the weight increases in the experimental and control group and the additional increases achieved by salinomycin sodium salt: 'Table 5 Experimental time Average Average Additional increase in weeks weight gain in weight gain in the experimental group control group experimental group kg kg% 17.3 23, 6 +36.4 32.1 35.2 + 9.7 49.8 53.6 + 7.6 Table 6 shows the nutrient uptake in the experimental and control group and the improvement achieved by salinomycin sodium salt: 7908636-9 9 Table 6 Trial period Average Average Improvement in weeks quality figures in quality figures in through salino checks. the experimental group mycin-Na-salt group% 3217 2363 +26.5 3477 3176 + 8.7 3387 3113 + 8.0 Tables 7 and 8 show how the rumen juice content of low molecular weight fatty acids during the 6-week long experimental period changed to salinomycin the sodium salt group in comparison with the control group. The determination was performed in the manner set forth in Example 1.

Table 7 Average amount of the fatty acids present in 100 ml rumen juice after 6 weeks of trial The fatty acid species in mg Control group Experimental group C2 278.80 205.92 C3 78.16 95.55 C4 55.90 26.07 Table 8 Relationship between the individual fats - the acids in rumen juice as a percentage after a 6-week trial period Fatty acid species Control group Experimental group C2 67.53 62.87 C3 18.93 29.17 C4 13.54 7.96 100% 100% 7908636-9 From the propionic acid increase the same conclusions can be drawn as already given in Example 1.

Example 3 A feeding experiment with salinomycin sodium salt was performed on 25 bulls (black variegated lowland breed), which were kept in separate feeding and automatic watering tied in a barn.

The average weight at the beginning of the experiment was about 260 kg and the trial period was 20 weeks with weighings every 4 weeks.

The feed consisted of concentrates, which were given in increasing amounts according to the animals' nutritional needs (from 2 - 4 kg per animal per day), and of maize silage (16 - 20 kg per animal per day).

Composition of concentrates: Barley 26% Oats 20% Maize 45% Carbonated feed lime 2% Hostaphos (R) (Na-Mg-Ca-phosphate) 4% Urea 2% Sodium bicarbonate 1% 100% Starch units: 657 St.E Digestible egg white 11.1 % The animals were divided into the following groups: Group I: 5 animals without treatment (control) Group II: 6 animals treated with 100 kg monensin per animal and day Group III: 7 animals treated with 50 mg salinomycin sodium salt per animal and day.

Group IV: 7 animals treated with 100 mg salinomycin sodium salt per animal per day The antibiotic doses in experimental groups II - IV were made daily with the concentrate (in flour form).

Results: Table 9 shows the average weight gain and nutrient uptake in the control group and the 3 experimental groups at 7908636-9 11 each Weighing after 4 ~ 20 weeks of experimental time. In addition to the absolute values, the experimental groups also state the relative values in comparison with the untreated control (in per cent).

In the weight development after a 20-week trial period, the salinomycin sodium salt administration of 50 mg and 100 mg / day and day, respectively, achieved dose-dependent additional increases of + 10% and + 17.8%, while 100 mg monensin / animal and day resulted in only one more- increase of + 0.2%.

Nutrient uptake was improved by the two salinomycin sodium salt donors (also dose dependent) by + 9.0% and + 15.5%, while the improvement for 100 mg monensin / animal and day was only at + 5.4%.

Table 9 Experimental control Monensin Salinomycin- Salinomycin- time n = 5 100 mg / day sodium salt sodium salt weeks Starting n = 6 50 mg / day 100 mg / day sevikt Beginning- n = 7 n = 7 258.8 kg weight Beginning- Beginning ~ abs. 261.2 kg weight weight (kg) abs. rel. 260.7 kg 260.7 kg (kg) (%) abs. rel. abs. rel. (kg) (8) (kg) (%) Genom- 4 29.0 34.0 117.2 33.9 116.9 35.9 123.8 ïïàtt '8 64.2 63.8 99.4 72, 6 113.1 74.3 115.7 weight- 12 96.4 96.5 100.1 106.2 110.2 112.6 116.8 increase per 16 130.2 126.0 96.8 144.9 111 .3 150.6 115.7 animals 20 164.6 165.0 100.2 181.0 110.0 193.9 117.8 +++ +++ Genom- 4 3305 2807 84.9 2855 86.4 2647 80.1 ïïàtt '8 3259 3145 96.5 2900 89.0 2793 85.7 nutrition- 12 3462 3246 93.8 3145 90.8 2929 84.6 äïäšag' 16 3509 3412 97.2 3152 89.8 3005 85, 6 sc.E / kg 20 3558 3366 94.6 3237 91.0 3005 84.5 +++ +++ +++ Significance: 99.9% probability 7908636-9 12 Example 4 A feeding experiment with salinomycin sodium salt was performed with 26 fattening bulls (red-spotted lowland breed), which were kept in separate feeding with automatic watering tied in a barn. The average weight at the beginning of the trial was about 225 kg and the trial period was 20 weeks with weighings every 4 weeks.

The feed consisted of concentrate, which according to the nutritional needs was given to the animals in increasing amounts (from 2 - 4 kg per animal per day), and of maize silage (16 - 20 kg per animal per day).

Concentration of concentrates: Barley 26% Oats 20% Maize 45% Carbonated feed lime 2% Hostaphos (R) (Na-Mg-Ca-phosphate) 4% Urea 2% Sodium bicarbonate 1% 100% Starch units: 657 St.E.

Digestible egg white 11.1% The animals were divided into the following groups: Group I: 6 animals without treatment (control) Group II: 6 animals treated with 100 mg monensin per animal and day Group III: 7 animals treated with 50 mg salinomycin sodium salt per animal and day Group IV: 7 animals treated with 100 mg salinomycin sodium salt per animal and day The antibiotic doses in experimental groups II - IV were made daily with the concentrate (in flour form).

Results: Table 10 shows the average weight gain and nutrient uptake in the control group and the 3 experimental groups at each Weighing after 4 - 20 weeks of experimental time. 13 7908636-9 In addition to the absolute values, the experimental groups state the relative values in comparison with the untreated control (in percent).

In the weight development, after a 20-week trial period, dose-dependent additional increases of +17.5% and 21.7% were obtained by the salinomycin sodium salt doses of 50 mg and 100 mg / day, respectively, while 100 mg monensin / animal and day only led to a more increase of +2.4% ._ Nutritional uptake was improved by the two salinomycin sodium salt dosages (also dose dependent) by +12.5% and + 1S, 4%, while 100 mg monensin / animal and day did not lead to any improvement .

Table 10 Pre- Control Monensin Salinomycin- Salinomycin- search- n = 5 100 mg / day sodium salt sodium salt time Beginning n = 6 50 mg / day 100 mg / day weeks sevikt Beginning- n = 7 n = 7 225.0 kg weight Beginning- Beginning- abs. 223.8 kg weight weight (kg) abs. rel. 223.6 kg 224.3 kg (kg) (%) abs. rel. abs. rel. (kg) (%) (kq) (%) Genom- 4 27.5 26.4 96.0 30.4 110.6 33.5 121.8 Dense '54 54.7 53.2 97.3 62, 0 113.4 62.7 114.6 weight- 12 83.5 86.4 103.5 98.0 117.4 101.0 121.0 gigmg 16 117.3 122.5104.4142.1 121.1 147 .6 125.8 animals 20 157.5 161.2 102.4 185.0 117.5 191.7 121.7 +++ +++ Genom- 4 2987 3014 100.9 2640 88.4 2318 77.6 ïgàtt '8 3089 3114 100.8 2693 87.2 2638 85.4 närings-12 3238 3134 96.8 2780 85.9 2691 83.1 upptag' 16 3228 3166 98 1 2739 84 6 2634 81 6 ning '' 'St .E / kg 20 3179 3175 99.9 2781 87.5 2691 84.6 +++ Significance: 99.9% probability 7908636-9 14 Example gel 5 Additive feed for cattle Dry cut Corn flour Soybean cookies Molasses Oat seeds Wheat bran Urea bran Mineral mixture Salinomycin-Na-salt -mycel- 3 1 1 1 1 premix (with 2,5 mg / g) 0 2,5 1,5, 0: 10 nW n \ ° 60 o \ ° 1,0 0% 1 kg of additive feed contains 25 mg of salt . o \ ° dP 0 \ o salinomycin-sodium-Grazing cattle receive 2 - 4 kg of supplementary feed per animal and day, ie. 50 - 100 mg salinomycin sodium salt.

Example gel 6 Licking salt for sheep Bone meal Saline Salinomycin-Na-salt-mycelium as 1-percent. premix 6 3 1 kg kg kg kg g licking salt contains 10 mg salinomycin-Na salt, ie. a day's death for a sheep.

Example Gel 7 Bolus for cattle Microcrystalline cellulose Maize starch Methylhydroxyethylcellulose Magnesium stearate Colloidal silicic acid (Aerosil (R)) Na-amylopectin glycolate 50% proc. salinomycin-Na salt crude product 8000 1200 900 300 mg 7908636-9 1 bolus of 12 g contains 100 mg of salinomycin-Na salt, ie. the daily dose for an animal.

Example gel 8 Tablet for sheep Microcrystalline cellulose 900 mg Maize starch 200 mg Carboxymethylcellulose 150 mg Magnesium stearate 50 mg Talc 50 mg Aerosil (R) 350 mg Na-amylopectin glycolate 180 mg NaCl 100 mg 50-percent. salinomycin Na salt crude product 20 mg 2000 mg 1 bolus of 2.0 g contains 10 mg salinomycin Na salt, i.e. the daily dose for a sheep.

Claims (8)

7908636-9 16 PATENT REQUIREMENTS Use of salinomycin as active substance to improve the uptake and growth of ruminants and rabbits in an amount of 0.02 - 5.0 mg / kg body weight per day, preferably 0.1 - 1.0 mg active substance per kg body weight and day. Use according to claim 1, characterized in that salinomycin is used in the form of its physiologically tolerable salts. Use according to claim 1, characterized in that alkali or alkaline earth salts are used as salts. Use according to claim 3, characterized in that the sodium, potassium or ammonium salt is used as alkali salts and that the magnesium or calcium salt is used as alkaline earth salts. Use according to claim 1, characterized in that salinomycin is used as mycelium or crude product. Use according to claims 1-5, characterized in that the active substance is introduced in the form of an additive feed concentrate or concentrate (premix). Use according to claims 1-4, characterized in that the active substance is used in the form of solid or liquid preparations intended for oral application, preferably tablets, capsules, boli, granules, juice or syrup. Use according to claims 1-7, characterized in that the active substance is introduced before or after, preferably during feed intake. ANNOUNCED PUBLICATIONS: