CA1271359A - Non-dusting antibiotic anticoccidial premix compositions and a process for their manufacture - Google Patents

Abstract

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

:1~ 7~ 3 NOVEL, NON--DUS'I'LNG AN'l'lBIOT[C, AN'[':[COCCIDIAL
~_ ___ _ _ _ _ PRE.MIX COMPOSITIONS AND APROCESS ~'OR T~IEIR MANUFAC'rURE

'I`he invention rela-tes to novel ionophore polye-ther antibiotic anticoccidial premix compositions 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, 0.0% to 10.0% of a vegetable oil or additional alcohol, and 30.00% to 99.00% of a sorptive, edible organic carrier or a sorptive silica or a silicate; process for the manufacture of such premix com-posi-tions and animal feed compositions containing the premix.
The premix may be a solution of the ionophore polyether antibiotic anticoccidial and the alcohol.
In one aspect, the invention provides an antibiotic anticoccidial feed premix composition 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, 0.0% to 10.0% of a vegetable oil, or additional alcohol, and 30.00% to 99.00% of a sorptive, edible organic carrier or a sorptive silica or a silicate.
In another aspect, the invention provides an antibiotic anticoccidial liquid feed premix solution comprising 0.25% to 35%
on a weight basis oE an ionophore polyetherantibiotic or a phar-maceutically or pharmacologically acceptable salt thereof, 55% to 99.75% of a physiologically acceptable alcohol and 0.0% to 10.0%
of a vegetable oil.

,~B, i .`. ~ ', ~ t.~3 ~[n a :~ur-ther aspeet, -the :Lnven-tion p:rovides an an-tibio-tic an-ticoeciclial non-dusti.ny dry feecl prem:ix compo-sition comprising -the following ingredients, all stated in terms of percentage of -total weight of feed premix composition: -(a) 30.0% to 99.00% of a sorptive, edible organlc carrier or a sorpti,ve si]ica or a silicate on which has been sprayed and allowed to clry.
(b) a premix solution of 0.25% to 35% of an ionophore polyether antibiotic, or a pharmaceutically or pharmaeologically 10 aeeeptable salt thereof, 0.75% to 35% of a phsiologieally aeeeptable aleohol, provided that the rati.o of sai.d antibiotic or salt thereof to said aleohol is between about 1:10 and about 3:'10, and 0.0% to '10.0% of a vegetable oil or additional physiologieally aceeptable aleohol.
In yet a further aspeet, the invention provides a proeess for formulating a non-dusting antibiotie antieoeeidial eomposition eomprising the steps of:
(a) dissolving an ionophore polyether antibiotie or a pharmaeeutieally or pharmaeologieally aeeeptable salt of an ionophore polyether antibiotie in a physiologieally aeeeptable aleohol, provided that the ratio of said antibiotie to said aleohol is between about 1:10 and about 3:10 to form a solution;
(b) feeding the solution of step (a) onto 30.0% to 99% of a sorptive, edible earrier and (e) blending the solution of step (a) and the earrier of step (b) into a uniform mixture allowing the solution of step (a) to dry to form a free-f]owing, dry, granular eomposition.

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Among -the preferred alcohols are benzyl alcohol, phene-thyl a:Lcohol and propylene glycol. ~ preEerred vegetable oil is corn oil. Among the preferred organic carr:iers are corncob grits, extracted cornmeal, expanded corn grits, solvent extracted soybean meal, sorghum, or wheat middlings and the like.
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 10 acceptable salts thereof.

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Sal ino~cin (II) ta30CCN .
~yC~I CH a~ C CHCI~,CH, ,L 1 1 1 H,C ~
Narasin (III) ! ~-OR ' .... _ .. ,,,,~, ,,,. ,, ,,,,,, ,,,,,,,, ,,eN~
Lasalocid (IV) OCII~ ~O~
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Antibiotics oE structure (V) are disclosed in United States Patent 4,278,663 and Un;ted States Patent 4,368,265. These compounds are highly effective anti-coccidial 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.
Uniquely, it has been found that antibiotics of structures ~I-V) may be applied to edible organic carriers as 10% to 35% solutions in physiologicallg acceptable alcohols such as benzyl alcohol and phenethyl alcohol and blended to give homogeneous animal feed premix compo-sitions 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 com-positions prepared as dry mixes with pure drug as demon-strated in Table I below.
Table I repd~esents a summary of the resultsobtained in Example ~ which is a segregation study com-paring the use of dry pure drug and a premix composition of the invention.

TABLE I

Feed Prepared Feed Prepared with Premix with Pure Drug Total Total Weight Assay Drug ~ t ~ ug (g) (ppm) (mg) (g) (ppm) (mg) #1 Nkck accumulation 1.82 1085 1.98 8.5 1745 14.8 #2 Bulk sample - 935 - - 1115 #3 Eottle residue 1.56 1800 2.81 0.80 2300 1.85 35~

The results in Table I indicate that the pure drug when mixed dry with Eeed 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 5 did a larger amount of Eeed 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 prem;x. 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 o 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 prohlems asso-ciated 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 hand-ling as illustrated in Table II below which shows thedermal 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.

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TABLE II
Relative Dermal Toxicities maduramicin LDso Rabbit Dermal Toxicity Composition Male mg/kg Female m~/k~

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~/O>4000 >2000 The premix compositions of the invention may be readily prepared by dissolving the pure drug in a physio-logically 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. Al~erna-tively, the premix compositions of the invention may be prepared from crude biomass ma~erial 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 fol-lowing non-limiting examples.

~;~'7~ 3 EXAMPLE l Preparation of a premix composition The ammonium salt o crude maduramicin (55 g, 1.1% on a weight basis) is dissolved in 385 g, 7.7% on a

5 weight basis, of benzyl alcohol, forming a murky suspen-sion. This suspension is fed in a fine stream into a ribbon blender (one cubic foot capacity) holding 4,/i60 g, 89.2% on a weight basis of granular corncob (Grit-0-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 un~il uniform, about ten minutes, and a freeflowing dry granular product results. HPLC assay of this mixture confirms the formula at 0.99%.

15 Preparation of premix compositions of ionophore poly-ether 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 tbe mixture is blended until it is homogeneous.
B. Biomass material containing an antibiotic is extracted with physiologically acceptable al-cohol such as benzyl alcohol, phenethyl al-cohol 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 on~o a carrier and the mixture blended until it is homogeneous. Utilizing these procedures yields the premix compositions listed in Table III
below.

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TABLE III
Premix compositions of ionophore polyether antibiotics grams 5 1. Monesin sodium (93%) 4.3 8enzyl alcohol 11.7 25% Monesin Solution 16.0 2. 25% Monesin solution 4.0 Corn cob grits 40/60 mesh26.0 3.33% Monesin premix 30.0 This dry premix is useful at 6 lb/ton of feed to supply 90 g of monesin per ton o feed when mixed into a complete feed.

3. 25% Monesin Solution 5.2 Fumed silica 1.8 20% Monesin premix 7.0 This dry premix is useful at 1 lblton to supply 90 g monesin per ton of feed when mixed into a complete feed.

4. 25% Monesin solution 2.0 Expanded corn grits, 30 mesh- 3.0 10% Monesin premix 5.0 This premix can be used at 2 lb/ton to supply 90 g monesin to a ton of feed when mixed into such feed.

7~ 3 ~9 TABLE III (Continued) grams 5. Monesin biomass (10% active) 100.0 Benzyl alcohol _ .0 Monesin Extract (ca. 11% a.i.) 85.0 (Recovered 38) This extract could be analyzed, diluted to exactly 10%
for instance and used directly to spray into mixed animal feed at the rate of 2 lb/ton to supply 90 g monesin per ~on.

6. Monesin Extract 11% 5.0 Fumed silica 2.0 Monesin premix 7.8% 7.0 This premix can be used at 2.5 g/ton to supply 90 g monesin.

7. Monesin biomass 25~L active 5.0 Benzyl alcohol 5.0 Monesin extract 20% 6.25 (Recovered 3)

8. Monesin ext~act 20% 2.0 Corn cob grits 11.33 Monesin Premix 3% 13.3 This premix can be used at 9 lb/ton to supply 120 g monesin.
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9. Monesin extract 11% 15.0 Hi-Sil (silica) 7.0 Monesin premix 7.5% 22.0 1 ~ 71;~

-10-TABLE III (Continued) grams 10. Salinomycin sodium 100% 0.22 Benzyl alcohol 0.20 Salinomycin solution 52.4%0.42 Corn cob grits 40/60 mesh 2.91 Salinomycin premix 6.6% 3.33 Two pounds of this premix supply 60 g salinomycin to medicate a ton of feed.

11. Salinomycin sodium 100% 0.085 Propylene glycol SUP 0.100 Salinomycin solution 46% 0.185 Propylene glycol USP 0.015 Corn cob grits 1.100 Salinomycin premix 6.5% 1.300

12. Salinomycin hiomass 5.5% a.i. 100.0 Benzyl alcohol 75.0 Salinomycin extract ca. 8%82.0 (Recovered 50.5)

13. Salinomycin ext.ract 8% 6.5 Verxite (mixed silicates) 10.3 Salinomycin premix 4.3% 16.8 This free-flowing premix can be used at 3 lb/ton to supply 60 g salinomycin to a ton of feed.

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TABLE III (Continued) grams

14. Narasin biomass (10% a.i.)50.0 Benzyl alcohol 25.0_ Narasin extract ca. 16.5% 30.0 (recovered 13.5)

15. Lasalocid sodium 0.11 Ben~yl alcohol 0.61 Propylene glycol 0.20 Lasalocid solution 12% 0.92 It should be evident to those versed in the art that these examples are not to be thought of as limiting the applica-bility to the proportions shown. In particular, varioustechniques 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 anti-biotic in the selected solvent.

~ ~ 7~ 3 S~3 EXAM~LE 3 Se~re~ation study The segregation test is performed in a com-mercially-blended poultry feed, supplemented with 1000 S 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.

TABLE IV
Component A B
-1% Prem;x (from Example 1) 113.4 g Pure technical drug - 1.26 g Grit-0-Cob~ - 112 g Poultry feed 1026.6 g 1029.7 g 2~

.

These materials are placed into new 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 grea~er in the case of the pure drug7 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 pre-senting 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.

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TABL,E V

S~mple A (Premix) Sample B (Pure Dru~) Total Total Wb ght ~ y Dru~ Weight say Dru~
(g) (ppm) (mg) (g) (ppm) (mg) #1 Neck accumulation 1.82 1085 1.98 ~.5 1745 14.8 #2 Bulk sample - 935 - - 1115 #3 Bottle residue1.561800 2.81 0.80 2300 1.85 Pa ticle size and ~otency distribution of non-dusting premlx compositions of the invention on dif~erent edible carriers Utilizing the procedure of Example 1, premix compositions containing 1% active ingredient are pre-pared using corncob grits or extracted cornmeal as theedible carrier. The particle size distribution is de-termined 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.

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Claims (11)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. 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, 0.75% to 35% of a physiologically acceptable alcohol, provided that the ratio of said antibiotic or salt thereof to said alcohol is between about 1:10 and about 3:10, and 0.0% to 10.0% of a vegetable oil or additional physiologically acceptable alcohol.

2. A composition according to Claim 1, wherein the anti-biotic is monensin, salinomycin, narasin, lasalocid or maduramicin.

3. A composition according to Claim 2 wherein the physio-logically acceptable alcohol is benzyl alcohol, phenethyl alcohol, or propylene glycol and the vegetable oil is corn oil.

4. A composition according to claim 3 wherein the edible organic carrier is corncob grits, extracted cornmeal, expanded grits, soybean meal, sorghum, or wheat middlings.

5, 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.

6. In an animal feed composition, the improvement which comprises incorporating therein a premix composition comprising 30%
to 99% of a sorptive, edible organic carrier or a sorptive silica or a silicate on which has been sprayed and allowed to dry a solution of 0.25% to 35% on a weight basis of the premix composition of an ionophore polyether antibiotic or a pharmaceutically or pharma-cologically acceptable salt thereof, 0.75% to 35% of a physio-logically acceptable alcohol, provided that the ratio of said antibiotic to said alcohol is between about 1:10 and 3:10, and 0.0%
to 10% of a vegetable oil or additional physiologically acceptable alcohol.

7. A process for formulating a non-dusting antibiotic anticoccidial composition comprising the steps of:
(a) dissolving an ionophore polyether antibiotic or a pharmaceutically or pharmacologically acceptable salt of an ionophore polyether antibiotic in a physiologically acceptable alcohol, provided that the ratio of said antibiotic to said alcohol is between about 1:10 and about 3:10 to form a solution;
(b) feeding the solution of step (a) onto 30.0% to 99% of a sorptive, edible carrier and (c) blending the solution of step (a) and the carrier of step (b) into a uniform mixture allowing the solution of step (a) to dry to form a free-flowing, dry, granular composition.

8. 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.

9. The process of Claim 8, wherein the benzyl alcohol is diluted with a vegetable oil or propylene glycol.

10. An antibiotic anticoccidial liquid feed premix solution comprising 0.25% to 35% on a weight basis of an ionophore polyether antibiotic or a pharmaceutically or pharmacologically acceptable salt thereof, 55% to 99.75% of a physiologically acceptable alcohol and 0.0% to 10.0% of a vegetable oil.

11. An antibiotic anticoccidial feed premix composition 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, 0.0% to 10.0% of a vegetable oil, or additional alcohol, and 30.00%
to 99.00% of a sorptive, edible organic carrier or a sorptive silica or a silicate.