IL22083A - Medicated poultry feed compositions - Google Patents

Description

PATENTS AND DESIGNS ORDINANCE S P E C I F I C A T I O N Τ MνΤtΡΠ ΤΓ ATF !iUiuAiai) " —POU -LTRY n F TEOE TDy,, 1 C τOMPOSITIONS" ' A .M I We, AMERICAN CYANAMID COMPANY, a company organized under the laws of the State of Maine, United States of America of the Township of V/ayne, State of New Jersey, United States of America DO HEREBY DECLARE the nature of this invention and in what manner the same is to be performed to be particularly ascertained in and by the following statement: This invention relates to novel poultry feed compositions containing a tetracycline antibiotic and a potentiating agent therefor which are highly useful in controlling infectious diseases and in accelerating the growth of poultry. More particu-larly, the present invention concerns a poultry feed containing the normally-added, inorganic calcium and phosphate supplements, a tetracycline antibiotic, and an adjuvant which promotes increased absorption of the antibiotic by the blood and tissue of poultry consuming the treated feed.

Although the broad-spectrum antibiotics chlorotetracycline, tetracycline, oxytetracycline, and demethylchlortetracycline have been found to be extremely effective for controlling infectious diseases and for stimulating growth in poultry; nevertheless, due to incomplete absorption thereof by the poultry believed to be due at least in part to the presence of calcium and other metallic cations in the diet, full utilization of such antibiotics has never been achieved.

It is known that the standard sources for calcium and phosphorus in animal diets, particularly poultry diets, are generally calcium carbonate, calcium hydrogen phosphate and bone meal. These materials, while generally considered necessary for normal poultry growth, have been found to markedly lower the blood levels of the tetracycline antibiotics. Since improvement in health is normally related to blood levels of antibiotic, efforts have been made to overcome the deleterious effects of calcium on the blood levels of the antibiotic without eliminating calcium from the diet.

It is generally believed that the calcium ion forms a complex with the tetracycline antibiotics which prevents absorption thereof by the blood. Since such antibiotics are rather expensive, it is most desirable to provide a means by which maximum abosrp-tion of the antibiotic is achieved. Various means, such as a low-calcium diet, have been proposed to accomplish this end but no entirely satisfactory method of solving this problem is presently available. While the low-calcium diet may be used for short periods of time, as, for example, when treating diseased poultry with therapeutic quantities of antibiotic, continued feeding of the low-calcium diet for extended periods of time can result in malformed bone structure and improper poultry growth.

In poultry of large size, such as turkeys, the problem is even more acute than it is with smaller fowl, such as chickens, since the larger birds require substantially more phosphorus and calcium for normal growth than do the smaller ones. According to the National Research Council, turkeys require at least about 1.0% phosphorus and 2.0% calcium whereas chickens require about 0.6% phosphorus and only 1.0% calcium for normal growth. While somewhat lower levels of calcium and phosphorus have been used effectively by poultry growers, the levels cannot be reduced below about 70% of the given values without seriously affecting the growth of the poultry. If these requirements are not met, the larger birds, i.e., turkeys especially, are plagued with serious leg defects which ultimately lead to their loss as marketable birds.

While the calcium requirement for poultry feed could be satisfied by the addition thereto of a selected calcium salt which is free of phosphorus, e.g., calcium sulfate, and which from the standpoint of complexing with the tetracycline antibiotic is less objectionable than other calcium salts, as, for example, calcium carbonate, such addition will in no way satisfy the phosphorus requirement. Phosphorus is essential for normal growth and bone development and it must be supplied in some form. Conventionally, feed supplements such as fish meal, bone meal, meat scraps and dicalcium phosphate have been added to feeds to provide the required phosphorus. These materials are relatively inexpensive and, in addition, furnish other necessary constituents such as minerals, protein and/or vitamins. However, they contain substantial proportions of calcium in a form which readily complexes with the tetracycline antibiotics, i.e., tricalcium phosphate or dicalcium phosphate.

Due to the high cost of antibiotics it is desirable to obtain maximum efficacy for a given amount of antibiotic. Therefore, losses of antibiotic by any means must be prevented if the use thereof is to be practical. To accomplish this end it has been proposed that calcium-free phosphates might be added to the feed. However, it has been found that feeds prepared with such additives are not entirely satisfactory since they are generally too alkaline or acidic, depending upon the additive used, and are not palatable to poultry when the phosphorus requirement is satisfied by the sole addition of such non-conventional phosphates. Some non-conventional phosphates react with the feed, rendering it useless; others are too costly to be practical and do not furnish essential minerals, proteins or vitamins re-quired for normal growth.

It would be most desirable commercially to obtain compositions which would permit? the effectiveness of the tetracycline antibiotics to be appreciably enhanced. It has been found that this most desirable object can be achieved with the novel compositions of the present invention which comprise a tetracycline antibiotic, that is* any antimicrobial! y active, form of the antibiotics tetracycline, chlor-tetracycline, oxytetracycline, demet-lylchl or tetracycline and structually related substances and a novel potentiating agent as described more fully hereinafter.

Thus the invention provides a method of treating poultry fees containing a tetracycline antibiotic and the recommended amounts of calcium and phosphorus supplied from conventional sources whereby the absorption of the antibiotic by the blood and tissue of the poultry consuming the same is significantly increased. Preferably the calcium re-q uirements are supplied by tricalcium phosphate, dicalcium phosphate or a mixture of both. It has been found that such compositions produce, substantially higher- antibiotic blood leyels in poultry from a given amount of antibiotic than has heretofore been possible with fees containing like concentrations of the abovementioned ingredients.

Briefly,; the instart invention comprises a poultry feed which is nutritionally adequate per se and containing phosphorus, calcium, and a tetracycline antibiotic and between about 0. 1% and 0. 6% of a sulfate of a cation carrying a single positive charge. Preferably these are selected from the group consisting of sodium sulfate, sodium bisulfate, potassium sulfate, potassium bisulfate, ammonium sulfate, ammonium bisulfate, sulfuric acid and mixtures thereof, and preferably one present to the extent of between about 0. 35% by weight, of sodium sulfate or 0. 43% potassium sulfate, for each 0. 1% by weight* of calcium present in the feed. Organic sulfates of a cation carrying a single positive charge, such as trimethyl ammonium sulfate, dimethyl ammonium sulfate and the like may also be employed but with less advantage. Furthermore, it has been found that the total concentration of sodium or potassium sulfate should amount to not less than about 7 pounds or more than about 70 pounds per ton of feed.

While sulfates of cations carrying a single positive charge have been found to be effective potentiators for tetracycline antibiotics orally administered, sulfates and bisulfates of cations carrying more than one positive charge generally have been found to produce substantially less desirable results. Some ultivalent metallic sulfates actually inhibit absorption of tetracycline antibiotics while others require reduction in the amount of conventional calcium and phosphorus additiy.es, in the diet to be effective. about 0. 355% of sodium sulfate or 0. 435% potassium sulfate per each 0. 1% of calcium present in a poultry diet containing a tetracycline antibiotic will produce significant increase in antibiotic blood levels for a given concentration of antibiotic in the feed without causing undesirable effects.

Also, the addition of sodium sulfate to poultry feed pre-mixes of concentrates, used for the preparation of potentiated antibiotic fees, has the surprising advantage that it noticeably reduces dusting and improves flowability of the pre -mix materials. In a concentrate comprising a conventional feedstuff dried chlortetracycline fermentation harvest mash solids, an edible oil and a major portion of anhydrous sodium sulfate , no dusting or separation of fines could be observed. In contrast thereto, a similar pre -mix minus the sodium sulfate additive showed noticeable separation or stratification of fines in the lower portions of the mix and considerable dusting.

Pre-mixes or. concentrates included within the scope of the instant invention and useful in supplementing one ton of feed may contain from about 7 to 70 pounds of a sulfate of a cation carrying a single positive charge such as sodium sulfate, potassium sulfate, JL; odium bisulfate, potassium bisulfate, sulfuric acid, ammonium sulfate, ammonium acid sulfate or mixtures thereof; from 10 to iOOO grams of a tetracycline antibiotic, such as tetracycline, oxytetra-cycline, chlortetracycline, demethylchlortetracycline and the like; mixtures of tetracycline antibiotics; from 0. 5 to 3% of edible oil by wfeight of concentrate and an edible feedstuff. Other edible diluents may be added if desired.

Pre- Mixes which are particularly desirable fo supplementing one ton of poultry feed contain, in addition to feedstuff or other inert edible carrier, from about 100 to 500 grams of tetracycline anti-fa iotic, 20 to 40 pounds of a sulfate of a cation carrying a single positive charge and from about 0. 5 to 1. 5% of edible oil by weight of concentrate.

Any of the commercially available and commonly used tetra cycline antibiotics such as tetracycline, chlortetracycline, oxytetracycline, d emethylchlortetracycline, and the like may be used. Chlortetracycline , however, is preferred because of its already wide acceptance as an animal feed additive of choice and because it is more effective than the other tetracycline antibiotics.

Preferably the tetracycline antibiotic is present to the extent of between about 50 and 2000 parts per million based on the weight of the feed with the optimum amount being about 200-400 parts per million.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 Turkeys, 31 days old and of substantially equal size and weight, were randomly divided into 19 groups of ten turkeys each.

These birds were placed in cages and fasted overnight. The following morning a diet of ground yellow corn supplemented with either 200 or 400 ppm of chlortetracycline and selected amounts ofcalcium, phosphorus, and the potentiating agent sodium sulfate, as described in Table I below, was fed to the turkeys ad libitum for three hours. Immediately following the three hour feeding period, the turkeys were bled by cardiac puncture. 1 1/2 ml. of blood was taken from each bird and assayed microbiologically. An average of the results obtained with each group of turkeys is reported in Table I below.

TABLE I Chlortetracycline Blood Levels Obtained From Additio to Ground Yellow Corn Fed to Turkeys Supplement % Inorganic Source Ca++ Phosphorus Ca++ + Phosphorus % NaaS0* 0.01 0.00 None 0.0 0.01 0.00 None 4.93 1.44 0.75 dicalcium phosphate 0.0 1.44 0.75 dicalcium phosphate 4.93 1.44 0.75 CaC03+H3P0^ 0.0 1.44 0.75 CaC03+H3P0^ 4.93 1.44 0.75 CaC03+NaH2P0.H20 0.0 1.44 0.75 CaC03+NaH2P0 .H20 4.93 From the data provided in Table 1 above, it can be readily seen that: (1) the addition of calcium and phosphorus to a poultry diet containing a given amount of chlortetracycline causes severe depression of blood levels in poultry consuming the same. (2) The addition of sodium sulfate to a poultry diet containing given amounts of chlortetracycline, calcium and phosphorus causes a significant increase in the antibiotic blood levels of poultry consuming such diet. That is, the addition of sodium sulfate to the above diets produces as much as a six-fold increase in the antibiotic blood levels for a given amount of antibiotic in the diet.

EXAMPLE 2 Following the procedure set forth in Example I, 31-day old turkeys were divided into 19 groups of ten each, placed in cages and fasted overnight. The following morning they were fed ad libitum a ground corn diet containing 1. calcium ion and 0.75% inorganic phosphorus supplied by 5% fish meal and 5.3% dicalcium phosphate and supplemented with 400 ppm of chlortetracycline hydrochloride.

In addition, the diets of ten groups of turkeys were potentiated with various amounts of sodium sulfate. After three hours feeding, the birds were bled by cardiac puncture and the chlortetracycline blood levels obtained by microbiological assay. The results obtained are shown below.

TABLE II .0 3.30 0.268 .0 3.30 0.355 0.230 .0 3.30 0.71 0.334 .0 3.30 1.065 0.439 .0 3.30 1.42 0.425 .0 3.30 1.775 O.608 .0 3.30 2.13 0.648 .0 3.30 2.485 0.684 .0 3.30 2.84 0.804 .0 3.30 3.195 Ο.828 The additional nine groups of birds were treated in the same manner as those described above but the diet was altered to determine the effect substitution of calcium sulfate and sodium acid phos- phate for equivalent amounts of dicalcium phosphate in the diet would have on the blood levels of the antibiotic. In this series the calcium ion concentration and inorganic phosphorus level were maintained at 1.4% and .75%» respectively. However, dicalcium phosphate was removed in increments from the diet and equivalent quantities of calcium sulfate and sodium acid phosphate were substituted therefor.

After feeding for three hours, the birds were bled by cardiac puncture and the chlortetracycline blood level assays microbiologically. The results obtained are given below.

TABLE III .0 3.04 0.43 0.232 0.266 .0 2.75 0.86 0.464 O.306 .0 2. 6 1.29 Ο.696 Ο. 9 .0 2.17 1.72 Ο.928 0.437 .0 1.88 2.15 I.I60 0.340 .0 1.59 2.58 1.392 0.388 .0 1.30 3.01 1.624 O.630 .0 1.01 3.44 I.856 Ο.496 .0 0.72 3.87 2.Ο88 0.638 On examination of these data it can be seen that ( 1 ) the addition of from 0. 355% to about 3. 2% of sodium sulfate by weight of diet, significantly increased the blood levels of chlortetracycline obtainable" from diets containing such antibiotic and recommend levels of calcium and phosphorus supplied from conventional sources. (2) The use of sodium sulfate as a potentiator for chlortetracycline produced substantially higher blood levels for a given amount of chlortetracycline than can be obtained by substitution of calcium and phosphorus in less objectionable forms than the forms present in conventional additives.

EXAMPLE 3 Twenty-eight day-old chicks were randomly divided into 10 groups of 10 chicks each. These chicks were fasted overnight? and the following morning ad - - libitua a diet of ground corn supplemented with 0.8% calcium and 200 ppm of chlortetracycline. In some tests sodium sulfate was also added to the diet and in others calcium sulfate was substituted for an equivalent amount of calcium carbonate. Three hours after feeding was begun all birds were bled by cardiac puncture. One and one-half milliliters of blood were taken and blood levels of chlortetracycline were determined by microbiological assay.

In the series of tests in which sodium sulfate was added to the diet the calcium content was maintained at 0.8% with calcium carbonate. Sodium sulfate was added to the diet at increments of 0. 355%.

The results obtained are shown below.

TABLE IV S U P P L E M E N T S BLOOD CTC CaC03 CaS04.2H20 NaaS04 meg . per ml 2.00 - 0.15* 2.00 - 0.555 0.186 2.00 - 0.71 0.215 2.00 - ■ 1.065 0.224 2.00 - 1.42 Ο.256 1.75 0. 3 - 0.159 1.50 0.86 - 0.175 1.25 1.29 - 0.195 1.00 1.72 - Ο.23 The calcium ion concentration in the feed containing 200 ppm chlortetracycline was maintained at 0.8%. However, in these tests initially 0.8% or all of - - the calcium in the diet was provided as CaCC^ and then increments of CaSOj, equivalent to 0. 1% Ca++ were substituted for the CaCOj in the diet.

The results of these tests show that the addition of from 0. 355% to 1.42% of calcium sulfate to a chick diet produced a significant potentiation of chlortetracycline blood levels. Substitution of calcium sulfate for dicalcium phosphate produced much less desirable results.

EXAMPLE 4 In these tests six groups of day-old turkey poults, ten turkeys per group, were weighed and placed in cages where they were permitted to feed and drink ad libitum for 21 days. The diet supplied was a standard laboratory turkey diet supplemented with from 0 to 3. 2% by weight of sodium sulfate. The feed provided for each group was weighed and total feed consumption was calculated for the 21-day test period.

At the end of the test period the groups of birds were weighed and their average weight and the average grams of feed per gram gain was determined.

The results of the tests were recorded and appear in Table V below. The diet employed is also provided below.

TABLE V Sodium Sul ate, in Diet Av. Wt. Gms . Feed Per Percent 21 Day3 (grams) Gm. Gain None 4o8 1 .57 0 .2 90 1 .57 0.4 03 1 .54 0 .8 407 1 .57 Met f Ground yellow corn 40.7 Soybean oil meal 45.5 Menhaden fish meal 7.5 GaCOs 2.4 Mcalcium phosphate 2.0 Brewers dried yeast 1.25 Iodized salt 0.250 Magnesium sulfate Ο.Ο25 Vitamin A (10,000 IU/gm.) 0.110 Vitamin D-3 (15,000 ICTJ/gm.) 0.00 Choline chloride - 25$ 0.125 Vitamin supplement 92 0.100 Proferm-20 (Vitamin B12) 0.025 Niacin 0.0044 D-alpha tocopherol acetate 0.00055 Parvo 5~% (folic acid suppleO.OO3O ment) Prom these data, it can he seen that all birds consuming a sodium sulfate supplemented diet gained normally and showed good feed to weight conver sion.

EXAMPLE 5 Following the procedure set forth in Example 4- day-old chicks were divided into groups of ten. The groups of chicks were weighed, placed in standard poultry cages where they were permitted to feed and drink ad libitum for 28 days. The diet employed was a standard commercial chick diet, as described below, supplemented with various concen- trations of sodium sulfate. The feed provided each group of chicks was carefully weighed and the total weight employed for the 28-day test period determined.

On termination of the tests, the groups of chicks were weighed and the average weight per bird, per group calculated. The average grams of feed per gram gain for each chick group was also calculated and the results are recorded in Table VI below. The diet used is likewise set forth below.

TABLE VI Supplemented Diet Gms . Peed Per Avg. Wt. After Supplement Gm. Gain 28 Daya (gram) None 1.695 536 0.2$ Na2S04 1.698 527 0.4$ NaaS04 1.680 535 0.8$ NaaS04 1.644 542 1.6 NaaS04 1.692 536 .2% Na2S04 1.703 553 Diet gm./kg .

Ground yellow corn 514 Soybean oil meal ( %) 300 Menhaden fish meal (60%) 50 Corn gluten meal (4l%) 50 Dehydrated alfalfa meal (17%) 20 Stabilized fat 40 Ground limestone 5 Dicalcium phosphate 12 Sodium chloride Delamix + 2% zinc 1 Vitamin re- ix Prom the data in Table VI, it can be seen that chicks fed a normal diet supplemented with sodium sulfate gained normally and were found to a good feed to weight gain conversion rate.

EXAMPLE 6 Following the procedure set forth in Example 3, twenty-seven day old chicks were divided into groups of twelve chicks each. These groups were fasted overnight. The following morning they were fed ad libitum a ground corn diet containing 200 ppm 0TG.H01 and 0.8% calcium ion as calcium carbonate. Additionally, diets other than the control were supplemented with 1.03% dietary sulfate ion furnished by various sulfate or bisulfate salts. Three hours after feeding was commenced the chicks were bled by cardiac puncture and the blood was assayed microbiologically for CTC. The results obtained are shown in Table VII below where it can be readily seen that the CTC blood levels in chicks consuming diets containing sulfates and bi-sulfates of cations carrying a single positive charge were significantly enhanced, whereas the CTC blood levels in those consuming diets containing sulfates of cations carrying two positive charges were no better than the unpotentiated control.

TABLE VII Chlortetracycline Blood Levels Obtained from Additions to Ground Yellow Corn Fed to Chicks 3 Hours After Feeding Supplement Blood CTC None 0.11 H2S04 0.26 Na2S04 0.17 TTOfi m (Offnt'4) 3 Hours After Feeding Supplement Blood CTC K2S04 0.2 NaHS04.H20 0.24 KHSO4 0.20 (NH )2S04 0.21 MgS04 0.11 MnS04.H2G O.O8

Claims (15)

1. A poultry feed composition comprising a nutrionally balanced diet containing a tetra cycline antibiotic, a source of calcium and a source of phosphorus and as a potentiating agent for said antibiotic an effective amount of sulfate which has a cation carrying a single positive charge.

2. A composition according to Claim 1 in which the sulfate is selec -ed from the group consisting of sodium sulfate, sodium bisulfate, potassium sulfate, potassium bisulfate, ammonium sulfate, sulfuric acid, ammonium acid sulfate and mixtures thereof.

3. A composition according tP Claim 1 in which the amount of sulfate is between about 0. 1% and 0. 6% by weight for each 0. 1% by weight of calcium present in the feed.

4. A composition according to Claim 1 in which the sulfate is sodium sulfate and in which the tetracycline antibiotic is chlortetracycline.

5. A composition according to Claim 1 in which the calcium is present in a form selected from the group consisting of calcium carbonate dicalci m phosphate and tricalcium phosphate.

6. A composition according to Claim 1 which contains at least about 0. 4% phosphorus and 0. 7% calcium by weight of the feed.

7. : A poultry feed concentrate for use in preparing a chlortetracycline potentiated feed comprising minor proportions of a conventional poultry feed; dried chlortetracycline fermentation harvest mash solids and as a potentiating agent therefor a major proportion of a sulfate of a cation carrying a single positive charge.

8. A concentrate according to Claim 7 in which the sulfate is selected from the group consisting of sodium sulfate, sodium bisulfate, potassium sulfate, potassium bisulfate, ammonium sulfate, ammonium bisulfate, sulfuric acid and mixtures thereof.

9. A poultry feed composition comprising a nuitrit ionally balanced diet containing chlortetracycline, more than about 1. 0% by weight of calcium in the feed in a form selected from the group consisting of calcium carbonate, dicalcium phosphate and trica!cium carbonate, dicalcium phosphate and tricalcium phosphate and as a potentiating agent therefor from about 0. 35% to 0. 43% by weight of a sulfate selected from the group consisting of sodium sulfate and potassium sulfate.

10. A method of accelerating the growth rate of poultry eomprising administering orally to poultry a composition comprising a nutritionally balanced diet containin a tetracycline antibiotic, a source of calcium and a source of phosphorus and as a potentiating agent for said antibiotic an effective amount of a sulfate of a cation carrying a single positive charge.

11. A method according to Claim 10 in which the sulfate is selected from the group consisting of sodium sulfate, sodium bisulfate, potassium sulfate, potassium bisulfate, ammonium sulfate, ammonium bisulfate, sulfuric acid and mixtures thereof.

12. A method according o Claim 10 in which the sulfate is present to the extent of between about 0.1% and 0. 6% by weight for each 0. 1% by weight of calcium in the diet.

13. A method according to Claim 10 in which the sulfate is sodium sulfate and in which the tetracycline antibiotic is chlortetracycline.

14. -, A method according to Claim 10 in which the calcium is in a form selected from the group consisting of calcium carbonate, dicalcium phosphate and tricalcium phosphate.

15. A poultry feed composition substantially as hereinbefore described. DATED the % day