ANTICOCCIDIAL COMPOSTIONS

Abstract: The present invention relates to new, safe and effec­ tive methods for controlling and preventing coccidiosis in poultry by orally administering thereto compositions contain maduramicin and nicarbazin in extremely low (previously considerd subtherapeutic) total doses of drugs. Unexpectedly, these compositions containing such low doses of drugs are observed to synergistically control and/or prevent coccidiosis in poultry without affecting growth.

Description: ANTICOCCIDIAL COMPOSITIONS BACKGROUND OF THE INVENTION The present invention relates to compositions containing subtherapeutic doses of maduramicin and nicarbazin which synergistically control and/or prevent coccidiosis in poultry. Both maduramicin and nicarbazin have been reported as effective anticoccidial agents. For instance, nicarbazin has been used as an anticoccidial but has been reported as inhibiting growth (German Patent 2,154,049). As such, attempts to alleviate the negative aspects of nicarbazin use such as growth inhibition or other safety concerns, have been and continue to be pursued. Therefore, combinations utilizing nicarbazin with other therapeutic compounds have been developed. For instance, combinations of nicarbazin with guanidines are disclosed in German Patent 2,154,049; as well as purines formulated with monensin and nicarbazin being disclosed in U.K. Patent 1,463,519; further, metichorpindol in combination with 4hydroxyquinolines is disclosed in U.S. Patent 3,761,594. Maduramicin, on the other hand, is a new antibiotic that has been shown to be an effective anticoccidial agent (U.S. Patent 4,278,663; U.S. Patent 4,368,265; and U.S. Patent 4,407,946). Although combinations of nicarbazin with polyether antibiotics are disclosed in U.S. Patent 4,218,438 and Reexamined U.S. Patent B4,218,438, compositions containing maduramicin and nicarbazin at extremely low subtherapeutic doses for effective control of coc cidiosis in poultry have not been disclosed. SUMMARY OF THE INVENTION The present invention unexpectedly has been found to synergistically control and/or prevent coccidiosis in poultry by combining the relatively new anticoccidial agent, maduramicin, with nicarbazin. Not only that, but the present invention also relates to a method for preventing and/or controlling said disease by orally administrating maduramicin and nicarbazin to poultry in compositions which synergistically control said coccidiosis. It is an object of this invention, therefore, to provide a method whereby coccidiosis is controlled and/or prevented in poultry by utilizing compositions containing maduramicin and nicarbazin. It is a further object of the present invention to provide such compositions wherein said drugs are present in previously considered subtherapeutic doses and wherein said drugs synergistically control and/or prevent coccidiosis. These and further objects will become more apparent by the following more detailed description of the invention. DESCRIPTION OF THE INVENTION The compositions useful in the present invention contain both components at subtherapeutic doses. By subtherapeutic is meant a dose which is less than that normally required in therapeutic effect when the component is used alone or as usually combined with a polyether antibiotic or nicarbazin. The dose according to the invention is, of course, therapeutic. For instance, maduramicin is usually orally administered to poultry at doses of about 5 ppm or more. However, in the present feedstuff compositions, doses as low as 1.00 ppm are useful in controlling coccidiosis in poultry. Thus, maduramicin is present at levels of 1.00 ppm to 8.00 ppm, preferably 1.25 ppm to 5.00 ppm, and most preferred 2.50 ppm to 5.00 ppm. Likewise, nicarbazin's usual dose level, when orally administered in feedstuff compositions to poultry, is 125 ppm. Animal feed stuff compositions of the present invention contain nicarbazin at levels of 1.5 to 125 ppm, preferably 1.5 to 50 ppm, and most preferred 1.5 ppm to 25 ppm. Therefore, combination dosages of therapeutic agents present in animal feedstuff compositions of the present invention contain as little as 2.50 ppm to 130 ppm, preferably 3.75 ppm to 55 ppm, most preferred 4.00 ppm to 30 ppm drugs, whereas other compositions containing nicarbazin with polyether antibiotics contain 40 ppm to 245 ppm of total drugs. Thus, the combination dose of the present invention is subtherapeutic to those of other compositions. These levels of maduramicin and nicarbazin demonstrate significant control of coccidiosis caused by strains of Eimeria, as evidenced by increased survival of chickens and decreased lesion scores. Further, no adverse effects on weight gain are observed in the treated birds. Animal feedstuff compositions containing the therapeutic and/or prophylactic levels of maduramicin and nicarbazin may be readily prepared by admixing these drugs with the feedstuff directly or by admixing a premix containing one or both of the drugs with the desired feedstuff. Poultry feedstuffs of all types and formulae normally used in the poultry industry are appropriate for use in the present invention. The following provide examples of such formulae. Broiler Starter Weight Ingredients Percent Corn, Yellow, Ground 50.0 Soybean Oil Meal, Solvent Extracted Dehulled (50%) 30.9 Animal Fat 6.5 Fish Meal with Solubles (60%) 5.0 Corn Distillers Dried Solubles 4.0 Dicalcium Phosphate, Feed Grade 1.8 Calcium Carbonate (Ground Limestone) 0.8 Vitamin Premix TK-01 (1.03) 0.5 Salt (NaCi) 0.3 Trace Mineral Premix TK-01 (1.02) 0.1 Methionine Hydroxy Analog 0.1 TOTAL 100.0 Broiler Grower Weight Ingredients Percent Corn, Yellow, Ground 57.7 Soybean Meal, Solvent, Extracted dehulled (50%) 31.7 Animal Fat (Beef tallow) 6.0 Dicalcium Phosphate, Feed Grade 2.7 Calcium Carbonate (Ground limestone) 0.9 Vitamin Premix TK-01 (1.03) 0.5 Salt (NaCl) 0.2 Methionine Hydroxy Analog 0.2 Trace Mineral Premix TK-01 (1.02) 0.1 TOTAL 100.0 Chick Starter, Light Breeds Weight Ingredients Percent Corn, Yellow, Ground 56.3 Soybean Meal, Solvent Extracted, Dehulled (50%) 17.9 Wheat Middlings 10.0 Corn Distillers Dried Solubles 5.0 Fish Meal with Solubles 5.0 Alfalfa Meal, Dehydrated (17%) 2.5 Dicalcium Phosphate, Feed Grade 1.3 Calcium Carbonate 0.9 Vitamin Premix 0.5 Salt (NaCl) 0.3 Methionine Hydroxy Analog 0.2 Trace Mineral Premix 0.1 TOTAL 100.0 Pullet Grower Weight Ingredients Percent Corn, Yellow, Ground 73.5 Soybean Meal, Solvent Extracted, Dehulled (50%) 21.9 Dicalcium Phosphate, Feed Grade 2.5 Calcium Carbonate 1.0 Vitamin Premix 0.5 Salt (NaCl) 0.3 Methionine Hydroxy Analog 0.2 Trace Mineral Premix 0.1 TOTAL 100.0 Pullet Developer Weight Ingredients Percent Corn, Yellow, Ground 67.5 Oats, Ground Whole 15.0 Soybean Meal, Solvent Extracted, Dehulled (50%) 13.4 Dicalcium Phosphate, Feed Grade 2.1 Calcium Carbonate 1.0 Vitamin Premix 0.5 Methionine Hydroxy Analog 0.3 Salt (NaCl) 0.2 Trace Mineral Premix 0.1 TOTAL 100.1 Turkey Starter Weight Ingredients Percent Soybean Meal, Solvent Extracted, Dehulled 40.7 Corn, Yellow, Ground 39.7 Fish Meal with Solubles 5.0 Beef Tallow 5.0 Corn Distillers Dried Solubles 2.5 Alfalfa Meal, Dehydrated (17%) 2.5 Dicalcium Phosphate, Feed Grade 2.5 Calcium Carbonate 1.2 Vitamin Premix 0.5 Salt (NaC1) 0.2 Trace Mineral Premix 0.1 Methionine Hydroxy Analog 0.1 TOTAL 100.0 Turkey Finisher Weight Ingredients Percent Corn, Yellow, Ground 71.2 Soybean Meal, Solvent Extracted Dehulled (50%) 9.9 Corn Distillers Dried Solubles 5.0 Alfalfa Meal, Dehydrated (17%) 5.0 Animal Fat 3.0 Fish Meal with Solubles 2.5 Dicalcium Phosphate, Feed Grade 1.7 Calcium Carbonate 0.5 Vitamin Premix 0.5 Salt (NaCl) 0.4 Methionine Hydroxy Analog 0.2 Trace Mineral Premix 0.1 TOTAL 100.0 The anticoccidial activity of compositions of the present invention are illustrated by the following nonlimiting examples. EXAMPLE 1 Preparation of a premix composition of maduramicin The ammonium salt of maduramicin (55 g, 1.1% on a weight basis) is dissolved in 385 g, 7.7% on a weight basis of benzyl alcohol, thereby forming a murky suspension. This suspension is fed in a fine stream into a ribbon blender (one cubic foot capacity) holding 4,460 g, 89.2% on a weight basis of granular corncob (Grit-O-Cob) and is followed by the addition of 100 g, 2.0% on a weight basis, oil as a rinse of the container. The mixture is allowed to blend until uniform, about ten minutes, and a free-flowing dry granular product results. EXAMPLE 2 Preparation of medicated poultry feed containing nicarbazin and maduramicin Sufficient quantities of a 1% by weight maduramicin premix and 25% commercially available nicarbazin premix containing wheat middlings and soybean oil are admixed until homogeneous with a poultry diet containing the ingredients listed in Table I below, to provide medicated feed compositions containing from 1.5 ppm to 125 ppm of nicarbazin and 1.25 ppm to 5 ppm of maduramicin. In these examples, when 5.0 ppm of maduramicin is preferred, 5% of a 1% maduramicin premix is mixed with nicarbazin in a feedstuff. Of course, this quantity changes according to the amount of drug used for testing. Likewise, when 125 ppm of nicarbazin are required, 0.05% of a 25% premix is utilized. Again, this percentage changes with the amount of nicarbazin used in testing. Table I Weight Ingredients Percent Vitamin-amino acid premix 0.5 Trace minerals 0.1 Sodium chloride 0.3 Dicalcium phosphate 1.2 Ground limestone 0.5 Stabilized fat 4.0 Dehydrated alfalfa, 17% protein 2.0 Corn gluten meal, 41% protein 5.0 Menhaden fish meal, 60% protein 5.0 Soybean oil meal, 44% protein 30.0 Ground yellow corn, fine to 100.0 The vitamin-amino acid premix in the above feed composition is prepared from the following formulation. The expressions of quantity relate to units per kilogram of the finished feed composition. Butylated hydroxytoluene 125.0 mg dl-Methionine 500.0 mg Vitamin A 3300.0 I.U. Vitamin D3 100.0 I.C.U. Riboflavin 4.4 mg Vitamin E 2.2 I.U. Niacin 27.5 mg Pantothenic acid 8.8 mg Choline chloride 500.0 mg Folic acid 1.43 mg Menadione sodium bisulfate 1.1 mg Vitamin B12 11.0 mcg Ground yellow corn to 5.0 g For the examples used in the test compositions of the present invention, the following provide the quantity amounts of maduramicin and/or nicarbazin in mg per kg of feed. (mg/kg) (mg/kg) 25% 1% Nicarbazin Maduramicin ppm Premix Premix 1.25 -- 125 1.50 6 2.50 -- 250 5.00 - 500 6.00 24 - 12.50 50 25.00 100 - 50.00 200 - 85.00 340 - 125.00 500 - EXAMPLE 3 Evaluation of test compositions as anticoccidial agents Anticoccidial activity of maduramicin and nicarbazin compositions administered to chickens is demonstrated in the test described herein. The poultry diets prepared as in Example 2 are the ones utilized in this experiment. A sufficient number of oocysts of Eimeria tenella to produce 60% to 75% mortality in untreated controls were given to one-day-old chicks, by direct inoculation into the crops of all chicks. The chicks were given free access to feed and water during the entire test period. Two days before inoculation, medicated feed, with several levels of drug, was presented to the various groups of chicks. The chicks were weighed 3 days after inoculation. Then seven days after inoculation, the experiments were terminated, and the chicks were weighed, sacrificed and their intestinal tracts were examined for lesions. The results appear in Table II. TABLE II A. % Survivability Eimeria strain EMI11.1 <tb> <SEP> Maduramic <SEP> in <SEP> <tb> Nicarbazin <SEP> ppm <tb> <SEP> ppm <SEP> 0.0 <SEP> 1.25 <SEP> 2.5 <SEP> 3.75 <SEP> 5.0 <tb> <SEP> 0.0 <SEP> 47.0 <SEP> 67.0 <SEP> 100.00 <SEP> 100.00 <SEP> 100.00 <tb> <SEP> 1.5 <SEP> -- <SEP> -- <SEP> -- <SEP> 100.00 <SEP> 100.00 <tb> <SEP> 3.0 <SEP> -- <SEP> -- <SEP> -- <SEP> 100.00 <SEP> 100.00 <tb> <SEP> 6.0 <SEP> -- <SEP> -- <SEP> -- <SEP> 100.00 <SEP> 100.00 <tb> <SEP> 12.5 <SEP> 53.0 <SEP> -- <SEP> -- <SEP> 100.00 <SEP> 100.00 <tb> <SEP> 25.0 <SEP> 67.0 <SEP> -- <SEP> -- <SEP> 100.00 <SEP> 100.00 <tb> <SEP> 50.0 <SEP> 80.0 <SEP> 100.00 <SEP> 100.00 <SEP> -- <SEP> 100.00 <tb> <SEP> 85.0 <SEP> 93.0 <SEP> 100.00 <SEP> -- <SEP> -- <SEP> -- <SEP> <tb> <SEP> 125.0 <SEP> 100.00 <SEP> -- <SEP> -- <SEP> -- <SEP> 100.00 <tb> B. % Weight gain - three to seven days Eimeria strain EMI11.2 <tb> <SEP> Maduramicin <tb> Nicarbazin <SEP> ppm <tb> <SEP> m <SEP> 0.0 <SEP> 1.25 <SEP> 2.5 <SEP> 3.75 <SEP> 5.0 <tb> <SEP> 0.0 <SEP> 38.0 <SEP> 67.0 <SEP> 78.00 <SEP> 104.00 <SEP> 98.00 <tb> <SEP> 1.5 <SEP> -- <SEP> -- <SEP> -- <SEP> 106.00 <SEP> 107.00 <tb> <SEP> 3.0 <SEP> -- <SEP> -- <SEP> -- <SEP> 110.00 <SEP> 110.00 <tb> <SEP> 6.0 <SEP> -- <SEP> -- <SEP> -- <SEP> 111.00 <SEP> 106.00 <tb> <SEP> 12.5 <SEP> 12.0 <SEP> -- <SEP> -- <SEP> 114.00 <SEP> 93.00 <tb> <SEP> 25.0 <SEP> 43.0 <SEP> -- <SEP> -- <SEP> 106.00 <SEP> 105.00 <tb> <SEP> 50.0 <SEP> 32.0 <SEP> 97.00 <SEP> 100.00 <SEP> -- <SEP> 109.00 <tb> <SEP> 85.0 <SEP> 93.0 <SEP> 72.00 <SEP> -- <SEP> -- <SEP> - <tb> <SEP> 125.0 <SEP> 1 <SEP> 104.00 <SEP> -- <SEP> -- <SEP> -- <SEP> 90.00 <tb> TABLE II (Continued) C. Lesion scores Eimeria strain EMI12.1 <tb> <SEP> Maduramic <SEP> in <SEP> <tb> Nicarbazin <SEP> ppm <tb> <SEP> ppm <SEP> 0.0 <SEP> 1.25 <SEP> 2.5 <SEP> 3.75 <SEP> 5.0 <tb> <SEP> 0.0 <SEP> 3.6 <SEP> 3.4 <SEP> 3.2 <SEP> 2.2 <SEP> 0.7 <tb> <SEP> 1.5 <SEP> -- <SEP> -- <SEP> -- <SEP> 0.3 <SEP> - <tb> <SEP> 3.0 <SEP> ¯¯ <SEP> <SEP> ¯¯ <SEP> <SEP> -- <SEP> 0.1 <SEP> 0.4 <tb> <SEP> 6.0 <SEP> -- <SEP> -- <SEP> -- <SEP> 0.2 <SEP> 0.0 <tb> <SEP> 12.5 <SEP> 3.5 <SEP> -- <SEP> -- <SEP> 0.8 <SEP> 0.0 <tb> <SEP> 25.0 <SEP> 3.3 <SEP> -- <SEP> -- <SEP> 0.0 <SEP> 0.0 <tb> <SEP> 50.0 <SEP> 3.2 <SEP> 0.7 <SEP> 0.0 <SEP> -- <SEP> 0.0 <tb> <SEP> 85.0 <SEP> 1.1 <SEP> 0.0 <SEP> -- <SEP> -- <SEP> 0.0 <tb> <SEP> 125.0 <SEP> 0.5 <SEP> -- <SEP> -- <SEP> -- <SEP> 0.0 <tb> These results indicate not only improved survivability of infected chicks when treated with the present compositions and no detrimental effect on percent weight gain but also show significant suppression of lesions due to E. tenella infection with administration of the present compositions even at extremely subtherapeutic doses of drugs.

Claims: WHAT IS CLAIMED IS: 1. A poultry feedstuff composition characterized by: maduramicin and nicarbazin; wherein said maduramicin and nicarbazin are present at doses synergistically effective for controlling coccidiosis in poultry. 2. A feedstuff composition according to Claim 1, wherein said maduramicin and nicarbazin synergistic combined doses are subtherapeutic doses of maduramicin in amounts of 1.00 ppm to 8.00 ppm and subtherapeutic doses of nicarbazin in amounts of 1.5 ppm to 125 ppm. 3. A composition according to Claim 2, wherein said subtherapeutic doses of maduramicin and nicarbazin are maduramicin in amounts of 1.25 ppm to 5.00 ppm and nicarbazin in amounts of 1.5 ppm to 50 ppm. 4. A composition acording to Claim 3, wherein said subtherapeutic doses of maduramicin and nicarbazin are maduramicin in amounts of 2.50 ppm to 5.00 ppm and nicarbazin in amounts of 1.50 ppm to 25 ppm. 5. An improved poultry feedstuff composition for controlling coccidiosis in poultry containing nicarbazin, said improvement characterized by: maduramicin and nicarbazin present in said compositions at combined subtherapeutic doses; wherein said subtherapeutic doses of maduramicin are in amounts of 1.00 ppm to 8.00 ppm and of nicarbazin are in amounts of 1.5 ppm to 125 ppm. 6. An improved poultry feedstuff composition according to Claim 5, wherein said subtherapeutic doses of maduramicin and nicarbazin are maduramicin in amounts of 1.25 ppm to 5.00 ppm and nicarbazin in amounts of 1.50 ppm to 50 ppm. 7. An improved poultry feedstuff composition accord ing to Claim 6, wherein said subtherapeutic doses of maduramicin and nicarbazin are maduramicin in amounts of 2.5 ppm to 5.0 ppm and nicarbazin in amounts of 1.50 ppm to 25 ppm. 8. A method for controlling and preventing coccidiosis in poultry, said method characterized by: orally administering to poultry a coccidiosis-controlling-and-prevent- ing-amount of a composition containing maduramicin and nicarbazin, wherein said maduramicin and nicarbazin are synergistically effective in controlling and preventing coccidiosis in poultry and are present in said composition in combined subtherapeutic doses; wherein said subtherapeutic doses of maduramicin are in amounts of 1.00 ppm to 8.00 ppm and said subtherapeutic doses of nicarbazin are in amounts of 1.50 ppm to 125 ppm. 9. A method according to Claim 8, wherein said subtherapeutic doses of maduramicin and nicarbazin are maduramicin in amounts of 1.25 ppm to 5.00 ppm and nicarbazin in amounts of 1.5 ppm to 50 ppm. 10. A method according to Claim 9, wherein said subtherapeutic doses of maduramicin and nicarbazin are maduramicin in amounts of 2.50 ppm to 5.00 ppm and nicarbazin in amounts of 1.50 ppm to 25 ppm. 11. An improved method for controlling and preventing coccidiosis in poultry by orally administering to poultry a coccidiosis-controll ing-and-preventing-amount of a composition containing nicarbazin, said improvement characterized by: orally administering to poultry a coccidiosis-controlling-andpreventing-amount of a composition also containing maduramicin, said maduramicin and nicarbazin synergistically effective for controlling and preventing coccidiosis at combined subtherapeutic doses; wherein said subtherapeutic doses of maduramicin are in amounts of 1.00 ppm to 8.00 ppm and said subtherapeutic doses of nicarbazin are in amounts of 1.50 ppm to 125 ppm. 12. An improved method according to Claim 11, wherein said subtherapeutic doses of maduramicin and nicarbazin are maduramicin in amounts of 1.25 ppm to 5.00 ppm and nicarbazin in amounts of 1.50 ppm to 50 ppm. 13. An improved method according to Claim 12, wherein said subtherapeutic doses of maduramicin and nicarbazin are maduramicin in amounts of 2.50 ppm to 5.00 ppm and nicarbazin in amounts of 1.50 ppm to 25 ppm.

Inventors: KANTOR, SIDNEY
Applicants: AMERICAN CYANAMID COMPANY
Application year: 1985
Main classification: A23K1
IPC codes: A23K1, A61K31, A61P33