NOVEL NON-DUSTING ANTIBIOTIC ANTICOCCIDIAL PREMIX COMPOSITIONS AND A PROCESS FOR THEIR MANUFACTURE

Abstract: The invention provides novel antibiotic, anticoccidial premix compositions which exhibit reduced dusting and lower dermal toxicities and a process for their manufacture.

Description: The invention relates to novel ionophore polyether antibiotic anticoccidial premix compositions as defined in claim 1, comprising 0.25% to 35% on a weight basis of an ionophore polyether antibiotic, or a pharmaceutically or pharmacologically acceptable salt thereof, 0.75% to 35% of a physiologically acceptable alcohol such as benzyl alcohol, phenethyl alcohol and propylene glycol, 0.0% to 10.0% of a vegetable oil such as corn oil, or additional physiologically acceptable alcohol such as propylene glycol, and 30.00% to 99.00% of a sorptive, edible organic carrier such as corncob grits, extracted cornmeal, expanded corn grits, solvent extracted soybean meal, sorghum, or wheat middlings and the like or a sorptive silica or a silicate; process for the manufacture of such premix compositions and animal feed compositions containing the premix. Among the preferred ionophore polyether antibiotics for use in the compositions of the invention are monensin (structure I below), salinomycin (II), narasin (III), lasalocid (IV) and maduramicin (V) and the pharmaceutically and pharmacologically acceptable salts thereof. Antibiotics of structure (V) are disclosed in United States Patent 4,278,663 and United States Patent 4,368,265. These compounds are highly effective anticoccidial agents and the drugs in their pure state are exceedingly toxic by physical contact, ingestion, and inhalation. Providing premixes which do not dust or segregate is highly desirable to minimize human contact with high concentrations of the drug and to help insure even distribution when the premix is mixed with animal feed. EP-A-0 076 059 describes anticoccidial antibiotic feed premix comprising vegetable oil as antidust agent and edible carrier. US-A-4,075,323 describes a feed premix composition comprising ionophore polyether anitbiotics and alcohols. However, the problems of avoiding dust formation and insuring even distribution, when the premix is mixed with animal feed is not addressed in this document. Uniquely, it has been found that antibiotics of structures (I-V) may be applied to edible organic carriers as 10% to 35% solutions in physiologically acceptable alcohols such as benzyl alcohol and phenethyl alcohol and blended to give homogeneous animal feed premix compositions which exhibit reduced drug accumulation in dead spots upon blending into animal feed by as much as a seven-fold factor when compared to the same feed compositions prepared as dry mixes with pure drug as demonstrated in Table I below. Table I represents a summary of the results obtained in Example # which is a segregation study comparing the use of dry pure drug and a premix composition of the invention. Feed Prepared with Premix Feed Prepared with Pure Drug Weight (g) Assay (ppm) Total Drug (mg) Weight (g) Assay (ppm) Total Drug (mg) #1 Neck accumulation 1.82 1085 1.98 8.5 1745 14.8 #2 Bulk sample - 935 - - 1115 - #3 Bottle residue 1.56 1800 2.81 0.80 2300 1.85 The results in Table I indicate that the pure drug when mixed dry with feed has a greater tendency to accumulate in the spots of least movement of processing equipment, the neck of the bottle in this test. Not only did a larger amount of feed accumulate in this spot when the drug was used instead of the 1% premix, 8.5 g vs 1.82 g, but the potency of the accumulated material was also much greater in the case of the pure drug, 1745 ppm vs 1085 ppm. Thus, the actual amount of drug segregating was more than seven times larger for pure drug than for premix. Such highly potent spots could cause toxicity, if ingested, would cause severe drug carry-over into following feed blends, and further indicate that the pure drug separates freely from the feed. This phenomenon could cause dusting problems of highly potent (and toxic) material presenting an inhalation and dermal hazard to operators. These difficulties are readily avoided by the use of a premix composition of the invention in animal feed compositions. The premix is incorporated into the feed by blending or mixing. An additional advantage of handling ionophore polyether antibiotics as a solution in these alcohols is that solutions provide a safe and efficient way to handle materials in closed systems such as pipes and hoses during processing and formulations, avoiding the problems associated with handling solids during these procedures. A further advantage of the compositions of the invention is that once formed, these premix compositions provide a significantly greater margin of safety in handling as illustrated in Table II below which shows the dermal toxicities of premix compositions of formula (I) antibiotic to be at least 100 times less than that of the pure drug or various solutions of the drug. Relative Dermal Toxicities maduramicin Composition LD₅₀ Rabbit Dermal Toxicity Male mg/kg Female mg/kg 1. Pure drug (92% pure) 8.9 3.7 2. Drug 24.8% Benzyl alcohol 75.2% 11.5 14.9 3. Drug 13.0% Benzyl alcohol 37.0% Corn oil 50.0% 37.9 17.3 4. Invention Premix Drug 1.0% Benzyl alcohol 4.0% Corn oil 5.0% Corncob grits 90.0% >4000 >2000 The premix compositions of the invention may be readily prepared by dissolving the pure drug in a physiologically acceptable alcohol optionally diluted with a vegetable oil or additional propylene glycol and feeding the resulting mixture in a fine stream or spray onto the carrier while blending. The mixture is blended until homogeneous, resulting in a dry granular non-dusting premix. Alternatively, the premix compositions of the invention may be prepared from crude biomass material by extraction of the biomass into said physiologically acceptable alcohol and utilizing the alcohol extract directly in the preparation of the premix composition. The invention is further illustrated by the following non-limiting examples. EXAMPLE 1 Preparation of a premix composition The ammonium salt of crude maduramicin (55 g, 1.1% on a weight basis) is dissolved in 385 g, 7.7% on a weight basis, of benzyl alcohol, forming a murky suspension. This suspension is fed in a fine stream into a ribbon blender [28.3 dm³ (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 freeflowing dry granular product results. HPLC assay of this mixture confirms the formula at 0.99%. EXAMPLE 2 Preparation of premix compositions of ionophore polyether antibiotics A. The pure drug or salt thereof is dissolved in the appropriate alcohol and optionally diluted with a vegetable oil or additional propylene glycol. The resulting solution is introduced onto the desired carrier and the mixture is blended until it is homogeneous. B. Biomass material containing an antibiotic is extracted with physiologically acceptable alcohol such as benzyl alcohol, phenethyl alcohol or propylene glycol. Filtration yields an alcohol solution containing the antibiotic which is assayed for drug content. The desired quantity of the solution is then blended onto a carrier and the mixture blended until it is homogeneous. Utilizing these procedures yields the premix compositions listed in Table III below. It should be evident to those versed in the art that these examples are not to be thought of as limiting the applicability to the proportions shown. In particular, various techniques can be used to increase the concentration of active ingredient in the examples using biomass materials by refluxing or by use of more concentrated biomasses up to the limit of the solubility of the given ionophore antibiotic in the selected solvent. EXAMPLE 3 Segregation study The segregation test is performed in a commercially-blended poultry feed, supplemented with 1000 ppm (0.1%) of drug, using the premix prepared in Example 1 in one blend and pure drug with an equivalent amount of corncob grits in the other as indicated in Table IV below. Component A B 1% Premix (from Example 1) 113.4 g - Pure technical drug - 1.26 g Grit-O-Cob - 112 g Poultry feed 1026.6 g 1029.7 g These materials are placed into new 4.5 l (one-gallon) Nalgene dense polyethylene jars and placed on a drum roller for two hours. At the end of the mixing time, the jars are sampled in the horizontal position to remove the material which has accumulated and packed in the neck (#1), then the jars are emptied without shaking or tapping, and a cross-sectional sample taken from the bulk (#2); finally, the empty jar is extracted and assayed for residual drug (#3). The results of this experiment, which are summarized in Table V below, indicate that the pure drug (ca. 90% potency) when mixed dry with feed has a greater tendency to accumulate in the spots of least movement, the neck of the bottle in this test. Not only did a larger amount of feed accumulate in this spot when the drug was used instead of the 1% premix, 8.5 g vs 1.82 g, but the potency of the accumulated material was also much greater in the case of the pure drug, 1745 ppm vs 1085 ppm. Thus, the actual amount of drug segregating was more than seven times larger for pure drug than for premix. Such highly potent spots could cause toxicity, if ingested, would cause severe drug carry-over into following feed blends, and further indicate that the pure drug separates freely from the feed. This phenomenon could cause dusting problems of highly potent (and toxic) material presenting an inhalation and dermal hazard to operators. These difficulties are readily avoided by the use of a suitable premix such as the example cited here. Sample A (Premix) Sample B (Pure Drug) Weight (g) Assay (ppm) Total Drug (mg) Weight (g) Assay (ppm) Total Drug (mg) #1 Neck accumulation 1.82 1085 1.98 8.5 1745 14.8 #2 Bulk sample - 935 - - 1115 - #3 Bottle residue 1.56 1800 2.81 0.80 2300 1.85 EXAMPLE 4 Particle size and potency distribution of non-dusting premix compositions of the invention on different edible carriers Utilizing the procedure of Example 1, premix compositions containing 1% active ingredient are prepared using corncob grits or extracted cornmeal as the edible carrier. The particle size distribution is determined by standard sieve analysis, and the potency of drug within each particle size is determined by high performance liquid chromatography. The results of these experiments are summarized in Table VI below.

Claims: An antibiotic anticoccidial non-dusting dry feed premix composition comprising the following ingredients, all stated in terms of percentage of total weight of feed premix composition: (a) 30.0 % to 99.0 % of a sorptive, edible organic carrier or a sorptive silica or a silicate on which has been sprayed and allowed to dry, (b) a premix solution of 0.25 % to 35 % of an ionophore polyether antibiotic, or a pharmaceutically or pharmacologically acceptable salt thereof, dissolved in from 0.75 % to 35 % of a physiologically acceptable alcohol and 0.0 % to 10.0 % of a vegetable oil or additional physiologically acceptable alcohol. A composition according to Claim 1, wherein the antibiotic is monensin, salinomycin, narasin, lasalocid or maduramicin. A composition according to Claim 2 wherein the physiologically acceptable alcohol is benzyl alcohol, phenethyl alcohol, or propylene glycol and the vegetable oil is corn oil. A composition according to Claim 3 wherein the edible organic carrier is corncob grits, extracted cornmeal, expanded grits, soybean meal, sorghum, or wheat middlings. A composition according to Claim 4 wherein the antibiotic is the ammonium salt of maduramicin on a weight basis of 0.25% to 5% of the composition. In an animal feed composition the improvement which comprises incorporating therein a premix composition as defined in claim 1 to contain about 1.0 ppm to 120 ppm (0.0001% to 0.012%) on a weight basis of the ionophore polyether antibiotic. A process for formulating a non -dusting antibiotic anticoccidial composition as defined in claim 1 comprising, dissolving an ionophore polyether antibiotic or a pharmaceutically or pharmacologically acceptable salt of an ionophore polyether antibiotic in a physiologically acceptable alcohol to form a solution, feeding the solution onto an edible carrier and blending the solution and the carrier into a uniform mixture to form a free-flowing, dry, granular composition. A process according to Claim 7, wherein the salt is the ammonium salt of the antibiotic maduramicin, the alcohol is benzyl alcohol, and the carrier is corncob grits. The process of Claim 8, wherein the benzyl alcohol is diluted with a vegetable oil or propylene glycol.

Inventors: KLOTHEN, IRVING
Applicants: AMERICAN CYANAMID COMPANY
Application year: 1985
Main classification: A23K1
IPC codes: A61K9, A61P33, A61K31, A61K47, C07H15, A23K1