MONENSIN WATER DISPERSIBLE GRANULES BY WET GRANULATION

Abstract

The present disclosure provides a water dispersible granule formulation comprising from about 5% to about 80% (w/w) of monensin; from about 1% to about 20% (w/w) of one or more surfactants; from about 1% to about 30% (w/w) of one or more binders; from about 1% to about 90% (w/w) of one or more fillers; and water up to about 2% (w/w). The present disclosure also provides a process for the preparation of a water dispersible monensin granule formulation. The present disclosure further provides a method of administering a therapeutically effective amount of a water dispersible monensin granule formulation to an animal.

Claims

1. A water dispersible granule formulation comprising from about 5% to about 80% (w/w) of monensin; from about 1% to about 20% (w/w) of one or more surfactants selected from alkyl sulphates, sodium lauryl sulphate, sulphonates, sodium dodecylbenzene sulphonate, carboxylates, dioctyl sodium sulfosuccinate, quaternary ammonium salts, benzalkonium chloride, alkyl betaines, cocamidoalkyl betaines, polyoxyethylene glycol sorbitan alkyl esters, alkyl polyglucoside, polysorbates, alkoxylates, and combinations thereof; from about 1% to about 30% (w/w) of one or more one binders selected from lignosulphonates, sodium lignosulphonate, and combinations thereof; from about 1% to about 90% (w/w) of one or more fillers selected from lactose monohydrate, glucose, sucrose, sugars, mannitol, modified sugars, celluloses, magnesium silicate monohydrate, amorphous alumina silicate, and combinations thereof; and water up to about 2% (w/w); wherein the formulation does not comprise a disintegrant.

2. The formulation of claim 1, comprising from about 35 to about 55% (w/w) of monensin, from about 1% to about 5% (w/w) of alkyl polyglucoside, from about 5% to about 15% (w/w) of sodium lignosulphonate, from about 20% to about 40% (w/w) of magnesium silicate monohydrate, and from about 10% to about 30% (w/w) of amorphous alumina silicate.

3. The formulation of claim 1, comprising monensin at about 43% (w/w), alkyl polyglucoside at about 1% (w/w), sodium lignosulphonate at about 8% (w/w), and magnesium silicate monohydrate at about 18% (w/w), and amorphous alumina silicate at about 27% (w/w).

4.-6. (canceled)

7. A method of treatment comprising providing a therapeutically effective amount of a water dispersible granule formulation to a volume of drinking water of an animal; wherein the water dispersible granule formulation comprises: from about 35 to about 55% (w/w) of monensin, from about 1% to about 5% (w/w) of alkyl polyglucoside, from about 5% to about 15% (w/w) of sodium lignosulphonate, from about 20% to about 40% (w/w) of magnesium silicate monohydrate, and from about 10% to about 30% (w/w) of amorphous alumina silicate.

8.-10. (canceled)

11. The method of claim 7, wherein the treatment further comprises increasing milk production efficiency.

12. The method of claim 7, wherein the treatment further comprises treating or preventing ketosis.

13. The method of claim 7, wherein the treatment further comprises treating or preventing bloat.

Description

[0069] Non-limiting examples of the formulations of the present disclosure will now be described, and the formulations in each of these examples can be prepared by the processes described hereinabove.

EXAMPLE 1

[0070]

TABLE-US-00001 Concentration Component Function of Component (% w/w) Monensin Sodium Milled Ionophore Antibiotic 43.48 Agnique PG 8107 Surfactant/Wetting Agent 2.00 (1.4 dry) Ultrazine NA Binder/Disperser 12.00 Talc SF 15 Filler/Anticaking 24.12 agent/Lubricant/Helps Dispersion Harborlite 200 Filler/Helps dispersion 18.00 * Granulation water is utilized in the batch as a granulating aid/medium at 28.0 Granulation Water Parts per Hundred (PPH).

EXAMPLE 2

[0071]

TABLE-US-00002 Concentration Component Function of Component (% w/w) Monensin Sodium Milled Ionophore Antibiotic 43.48 Agnique PG 8107 Surfactant/Wetting Agent 2.00 (1.4 dry) Ultrazine NA Binder/Disperser 10.00 Talc SF 15 Filler/Anticaking 26.12 agent/Lubricant/Helps Dispersion Harborlite 200 Filler/Helps dispersion 18.00 * Granulation water is utilized in the batch as a granulating aid/medium at 27.5 Granulation Water Parts per Hundred (PPH).

EXAMPLE 3

[0072]

TABLE-US-00003 Concentration Component Function of Component (% w/w) Monensin Sodium Milled Ionophore Antibiotic 43.48 Agnique PG 8107 Surfactant/Wetting Agent 2.00 (1.4 dry) Ultrazine NA Binder/Disperser 9.00 Talc SF 15 Filller/Anticalking 27.12 agent/Lubricant/Helps Dispersion Harborlite 200 Filler/Helps dispersion 18.00 * Granulation water is utilized in the batch as a granulating aid/medium at 28.0 Granulation Water Parts per Hundred (PPH).

EXAMPLE 4

[0073]

TABLE-US-00004 Concentration Component Function of Component (% w/w) Monensin Sodium Milled Ionophore Antibiotic 43.48 Agnique PG 8107 Surfactant/Wetting Agent 2.00 (1.4 dry) Ultrazine NA Binder/Disperser 8.00 Talc SF 15 Filler/Anticaking 28.12 agent/Lubricant/Helps Dispersion Harborlite 200 Filler/Helps dispersion 18.00 * Granulation water is utilized in the batch as a granulating aid/medium at 29.5 Granulation Water Parts per Hundred (PPH).

EXAMPLE 5

[0074]

TABLE-US-00005 Concentration Component Function of Component (% w/w) Monensin Sodium Milled Ionophore Antibiotic 43.48 Agnique PG 8107 Surfactant/Wetting Agent 2.00 (1.4 dry) Ultrazine NA Binder/Disperser 7.00 Talc SF 15 Filler/Anticaking 29.12 agent/Lubricant/Helps Dispersion Harborlite 200 Filler/Helps dispersion 18.00 * Granulation water is employed in the batch as a granulating aid/medium at 32.0 Granulation Water Parts per Hundred (PPH).

EXAMPLE 6

[0075]

TABLE-US-00006 Concentration Component Function of Component (% w/w) Monensin Sodium Milled Ionophore Antibiotic 43.48 Agnique PG 8107 Surfactant/Wetting Agent 1.40 Ultrazine NA Binder/Disperser 8.50 Talc SF 15 Filler/Anticaking 27.62 agent/Lubricant/Helps Dispersion Harborlite 200 Filler/Helps dispersion 18.00 Residual Water Water is removed during the Approx. 1 manufacturing process (drying) although some residual water will remain

[0076] The above example formulations are suitable for addition to the drinking water system of animals to be treated, or they can be mixed with water or milk to provide a drench formulation.

Study 1: Compatibility

[0077] Studies can be conducted to test the compatibility of the formulation of Example 1 with various materials that are often added to the drinking water of dairy cattle. The materials that can be tested include zinc sulphate heptahydrate, magnesium chloride hexahydrate, copper sulphate pentahydrate, and Bloatenz Plus. These studies illustrate that the formulation of Example 1 demonstrates desireable compatibility with all the salts and Bloatenz Plus. The compatibility is demonstrated by none of the mixtures showing any signs of flocculation, excessive precipitation, or other adverse reaction. The magnesium chloride solution appears to provide some buoyancy to the granules and dispersed particles in the initial stales of the trial.

Study 2: Process Development

[0078] A 1.3 kg laboratory batch of the formulation of Example 1 is prepared via a laboratory Grantrol granulator for use in a short term (2 months) stability study and compatibility testing program. The Grantrol granulator process is a process by which a continuously fed granulator is used to convert an intimate water wet mixture of technical grade active ingredient, surfactants or other ingredients where applicable into granules of consistent size and density during a single pass.

[0079] The Ultrazine NA and Agnique PG 8107 are applied in solution with part of the water used for granulation in the proportions set out in TABLE 1.

TABLE-US-00007 TABLE 1 Ingredient % w/w Ultrazine NA 36.00 Agnique PG 8107 6.00 Water 50 deg. C. 58.00

[0080] The dry ingredients are blended and the surfactant solution is added at the rate of 33.33 g/100 g dry and thoroughly blended. Water is added incrementally and blended until a damp evenly colored pre-mix of appropriate consistency is formed. The damp premix is passed through the granulator twice for stress processing. The quantity of water is about right on first pass, but marginally too much at second pass. It granulates at a fast rate. The extrudates are cohesive and break down well. The wet granules are dried at 45 C. and screened through a 0.750 mm and 1.7 mm screens. There is very little oversize or fines produced, normally less than about 5%, and more preferably, less than about 4.6% by weight. 1.24 kg is recovered after losses to granulator and screening. Time to disperse at 20 C. is 65 seconds, which is well within specification and the visual quality of the suspension is excellent. The results are provided in TABLE 2.

TABLE-US-00008 TABLE 2 Test Results Time to disperse 65 seconds Suspensibility 82% total solids Wet sieve residue 150 m 0.003% (% w/w retained, 75 m 0.055% cumulative) 45 m 0.660% Bulk density Loose 501.5 g/L Tapped 575.5 g/L pH 7.37 Assay 433 mg/g (43.3% w/w) LOD 1.1% Resistance to Attrition 99.1% Wettabillity Without swirling 40 seconds With swirling 4-5 seconds

[0081] A 5 kg batch of the formulation of Example 1 is manufactured to test the manufacturing process before progressing to a larger scale batch. The viscous liquid formed by dissolving all of the Ultrazine NA in a substantial part of the granulation water may not be able to be sprayed effectively through the preferred nozzles of the pilot plant blender liquid delivery system. Allowing only 3kg additional water per 100 kg dry pre-mix does not provide adequate flexibility for adjustment of water level in the commercial process as may be required to compensate in variations in particle size and absorptive capacity of powder raw materials as well as the ambient conditions (temperature and humidity).

[0082] A trial batch of 45 kg of the formulation of Example 6 can be produced. For instance, all raw materials are pre-weighed as specified in TABLE 3. Next, 1.00 kg of distilled water (ambient) and Agnique PG 8107 can be added to a clean 20 L pail. Using a mechanical stirrer with an impellor, the Agnique PG 8107 is dispersed. Then, the Harborlite 200, Ultrazine NA, Talc Superfine 15, and monensin sodium milled, as specified in TABLE 3, are added to an interrupted ribbon blender. Next, the interrupted ribbon blender is turned on and blended for approximately 5 minutes. While blending, 1.80 kg of Agnique PG 8107 Solution is pumped into the interrupted ribbon blender through spray nozzles. Next, the Agnique PG 8107 Solution container, lines, and nozzles are flushed with approximately 9 kg distilled water into the interrupted ribbon blender while blending. Additional distilled water may be added if necessary. Blending of the ingredients is continued until a homogenous mix is achieved. At the completion of blending, the damp premix is transferred onto a blender conveyor. Next, the granulator is filled with premix, the premix is passed through the granulator and a conditioner/compactor, and the premix is put in a dryer container. Then, the dryer container is placed into the fluid bed dryer, and the premix is dried at 50 C. until the outlet temperatures reach 50 C. At completion of drying, the dryer and shake socks are turned off, the drying trolley is removed, and the granules are examined for the presence of dust. Next, the container is removed from the dryer and wheeled around to the container discharge hopper. The hopper is fully discharged into a storage hopper. Sieving is commenced and the product is filled into 20 L pails until the hopper is empty.

TABLE-US-00009 TABLE 3 Ingredient Amount Required (kg) Agnique PG 8107 2.00 Harborlite 200 8.10 Uttrazine NA 3.83 Tale Superfine 15 12.43 Monensin Sodium Milled 19.57

[0083] The following can be concluded from this trial batch. The product granulates well through the Jackson & Crockett No. 4 Granulator with no agglomeration occurring. This indicates the amount of Ultrazine at 8.5% (w/w) and quantity of water used was acceptable. However, the formation of a few agglomerates in the conditioner did indicate slightly too much water had been used. Their formation could have been compensated for if the residence time in the conditioner had been reduced. A setting of 3.5 on the fluid bed dryer appears acceptable and does not cause excessive dust formation. The monensin homogeneity within the blended damp premix is considered to be acceptable indicating the ribbon blender is capable of producing a homogeneous blend prior to granulation. The monensin homogeneity within the final dried product is considered to be acceptable indicating the processing that occurs post the ribbon blender does not have a negative impact on homogeneity. The vibratory sieve screen sizes used appeared suitable for the removal of dust and agglomerates without the loss of good product. It is recommended that the amount of water should be reduced by approximately 300 g for a 45 kg batch.

Study 3: Stability

[0084] Accelerated stability trials are carried out to determine the acceptable shelf life of a water dispersible monensin granule formulation of the present disclosure comprising about 43% (w/w) active monensin. A 1.3 kg laboratory batch of the formulation described in Example 1 is placed on a 60 day 54 C. accelerated stability study. The study is designed to test how stable the formulation is under extreme conditions. All results comply with the tentative stability specifications or targets indicating that the formulation is stable and could survive longer periods under less extreme conditions. The results are provided in TABLE 4.

[0085] Assuming the product produced commercially has a starting content of 400 mg/g monensin sodium, the results indicate the product will still be within the tentative stability specification at the end of shelf life as the reduction is less than 15% of the 0 day result (i.e., within 85 to 115% of 0 days). The assumption above is that 60 days at 54 C. is equivalent to 36 months at 30 C.

TABLE-US-00010 TABLE 4 Tentative Stability 30 days @ 60 days @ Test Specification 0 days 54 C. 54 C. Time to disperse NMT 90 65 60 70 (seconds) seconds Suspensibility NLT 60% active 82 81 76 (% total solids) suspended Suspensibility NLT 60% active (% active) suspended Target Wet sieve 150 m 0.3% max 0.003 0.006 0.004 residue 75 m 2.0% max 0.055 0.067 0.076 (% w/w 45 m 3.0% max 0660 0.683 0.687 retained, cumulative) Monensin 340 to 460 mg/g 433 391 388 Sodium (mg/g) Monensin Target: 85 to 100 90.3 89.6 Sodium(as % 115% of 0 days of 0 days) Wettability Target 40 NT 25 without swirling NMT 12.0 (seconds) seconds Wettability with Target 4-5 NT 5-6 swirling NMT 120 (seconds) seconds LOD (% w/w) NMT 30% w/w 1.1 0.9 0.8

[0086] The 45 kg trial batch of the formulation described in Example 1 is placed on a 14 days 54 C. accelerated stability study. All results comply with the tentative stability specifications or targets and are comparable to the 60 day study above. The results are provided in TABLE 5.

TABLE-US-00011 TABLE 5 Tentative Stability 0 14 days @ Test Specification days 54 C. Time to disperse (seconds) NMT 90 seconds 75 85 Suspensibility (% total NLT 60% active 81 75 solids) suspended Target Wet sieve 150 m up to 0.3% max 0.004 0.009 residue (% w/w 75 m up to 2.0% max 0.006 0.019 retained, 45 m up to 3.0% max 0.030 0.287 cumulative) Wettability without Target 25 15 swirling (seconds) NMT 120 seconds Wettability with swirling Target 2 3 (seconds) NMT 120 seconds