Multi-layered granule therapeutics

Abstract

The present disclosure provides multi-layered therapeutics, methods of manufacture thereof, and methods of treatment. More particularly, the disclosure provides compositions formulated for administration to an animal comprising a core particle comprising a first antiparasitic agent and a coating, wherein the coating may comprise a second antiparasitic agent; methods of producing such compositions; and methods of treating and / or preventing parasitic infection in animals in need thereof.

Description

MULTI-LAYERED GRANULE THERAPEUTICSREFERENCE TO RELATED PATENT APPLICATIONS

[0001] This International Patent Application claims priority to U.S. Provisional Patent Application No. 63 / 549,981, filed 5 February 2024, the disclosure of which is herein incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates to multi-layered therapeutics, methods of manufacture thereof, and methods of treatment.BACKGROUND

[0003] Coccidiosis is one of the most destructive and widespread diseases in commercial farming. The infectious disease, which is caused by enteric growth and propagation of protozoan apicomplexa parasites of the genus Eimeria, affects all major livestock species, but is of particular significance in commercial poultry industries. Avian coccidiosis is globally endemic, causes high mortality in birds, and is estimated to cost farmers around $13 billion globally in aggregate cost of losses, treatment, and prevention. See Blake, D., et al. Re-Calculating the Cost of Coccidiosis In Chickens. Vet Res 51, 115 (2020). As of 2023, avian coccidiosis is managed in broiler and egg-laying flocks with combinations of vaccination and chemoprophylaxis. Even with various mitigation strategies in place, an estimated 2 percent of commercial fowl would be expected to die or be culled due to coccidiosis. Id. Although regional prevalence of coccidiosis infection is difficult to measure, recent molecular genetics studies in Australia found evidence of Eimeria parasites in nearly 100 percent of commercial and backyard poultry flocks. See Godwin, R., et al., A Molecular Survey of Eimeria in Chickens Across Australia, Veterinary Parasitology 214 (2015) 16-21.

[0004] Currently, although some poultry vaccines exist for prevention of coccidiosis, there remains significant unmet production challenges with the vaccines. Further, no vaccine yet exists in non-poultry livestock. See Blake, D., et al., Securing poultry production from the ever-present Eimeria challenge, Trends in Parasitology, 30(1) 12-19 (2014); see also Andrews, A., Coccidiosis of Cattle, Merck Veterinary Manual, www.merckvetmanual.com / digestive-system / coccidiosis / coccidiosis-of-cattle. Consequently, in-feed chemoprophylaxis with coccidiostat drugs is a dominant approach to coccidiosis prevention in commercial animal farms.

[0005] The omnipresent coccidiosis risk in commercial animal farming places significant pressure on farmers to refine their approach to prevention and treatment. Safe and effective combination therapies would provide a broader spectrum of protection while mitigating risk of emergent drug resistance. Market forces drive towards an anti-coccidiosis product that is easy-to- produce, homogeneous, consistent, easy-to-use, durable, and highly shelf-stable. In view of these unmet needs, the present disclosure provides multi-layered antiparasitic compositions, methods of manufacture, and methods of disease prevention, disease treatment, and performance improvement.SUMMARY OF THE INVENTION

[0006] The present disclosure provides multi-layered therapeutics, methods of manufacture thereof, and methods of prevention and treatment of a parasitic infection.

[0007] In an aspect, the present disclosure provides a composition formulated for administration to an animal comprising: a core particle having an outer surface, the core particle comprising narasin or a pharmaceutically acceptable salt thereof; and a first layer at least partially covering the outer surface of the core particle, the first layer comprising diclazuril or a pharmaceutically acceptable salt thereof. In any embodiment of the composition, the core particle may further comprise an inert carrier comprising zeolite, a cellulosic material, or both. In any embodiment, the cellulosic material may comprise rice hulls.

[0008] In any embodiment, the pharmaceutically acceptable salt of diclazuril may comprise diclazuril sodium.

[0009] In any embodiment, the composition formulated for administration to an animal comprises a core particle having an outer surface, the core particle comprising narasin or a pharmaceutically acceptable salt thereof; and a first layer at least partially covering the outer surface of the core particle, the first layer comprising diclazuril or a pharmaceutically acceptable salt thereof. In any embodiment of the composition, the core particle may further comprise an inert carrier comprising zeolite, a cellulosic material, or both. In any embodiment, the cellulosic material may comprise rice hulls.

[0010] In any embodiment, the mass ratio of the narasin to the diclazuril may be between about 20: 1 and about 100: 1. In any embodiment, the mass ratio of the narasin to the diclazuril may be between about 30: 1 and about 90: 1. In any embodiment, the mass ratio of the narasin to the diclazuril may be between about 40: 1 and about 80: 1. In any embodiment, the mass ratio of the narasin to the diclazuril may be between about 50: 1 and about 70: 1. In any embodiment, the mass ratio of the narasin to the diclazuril may be about 60: 1. The mass ratio of the narasin to the diclazuril can be 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1,40:1, 41:1, 42:1, 43:1, 44:1,45:1,46:1,47:1,48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1,69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1,86:1, 87:1, 88:1, 89:1, 90:1, 91:1, 92:1, 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, or 100:1.

[0011] The mass ratio of the narasin to the diclazuril can be 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1,42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1,59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1,76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1, 91:1, 92:1,93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, or 100:1.

[0012] In any embodiment, the first layer may comprise from about 0.01 wt% to about 5.0 wt% diclazuril sodium. In any embodiment, the first layer comprises 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, up to about 5 wt% diclazuril, optionally diclazuril sodium.

[0013] In any embodiment, the core particle may comprise from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof. In any embodiment, the core particle may comprise an inert carrier comprising zeolite, a cellulosic material, or both zeolite and a cellulosic material. In any embodiment, the core particle may comprise about 88 wt% to about 92 wt% of an inert carrier comprising zeolite, a cellulosic material, or both zeolite and a cellulosic material. In any embodiment, the composition may comprise about 1 ppm diclazuril sodium. In any embodiment, the composition may comprise about 60 ppm narasin or a pharmaceutically acceptable salt thereof.

[0014] In any embodiment, the composition can comprise between about 40 ppm and about 140 ppm narasin and between about 0.5 ppm and about 2 ppm of diclazuril, between about 50 ppm and about 100 ppm narasin and between about 0.7 ppm and about 1.3 ppm of diclazuril, between about 50 ppm and about 80 ppm narasin and between about 0.7 ppm and about 1 ppm of diclazuril.

[0015] In any embodiment, the composition can comprise between about 40 ppm and about 140 ppm narasin, from about 45 ppm and about 135 ppm narasin, from about 50 ppm and about 130 ppm narasin, from about 55 ppm and about 125 ppm narasin, from about 50 ppm and 80 ppm narasin or a pharmaceutically acceptable salt thereof.

[0016] In any embodiment, the composition can comprise about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117,118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 ppm narasin or a pharmaceutically acceptable salt thereof.

[0017] In any embodiment, the composition can comprise between about 0.5 ppm and about 2 ppm of diclazuril, between about 0.7 ppm and about 1.3 ppm of diclazuril, between about 0.7 ppm and about 1 ppm of diclazuril or a pharmaceutically acceptable salt thereof.

[0018] In any embodiment, the core particle comprises from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof. The core particle can comprise about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, or about 12 wt% narasin or a pharmaceutically acceptable salt thereof. Inany embodiment, the core particle can comprise about 10 wt% narasin or a pharmaceutically acceptable salt thereof.

[0019] In any embodiment, the first layer comprises between about 0.01 and 5.0 wt% diclazuril or a pharmaceutically acceptable salt thereof.

[0020] In any embodiment, the first layer comprises about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1 .8 wt%, about 1 .9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, up to about 5 wt% diclazuril or a pharmaceutically acceptable salt thereof. In any embodiments, the core particle comprises about 0.2 wt% diclazuril or a pharmaceutically acceptable salt thereof.

[0021] In any embodiment, the first layer comprises from about 0.01 wt% to about 5.0 wt% diclazuril, optionally diclazuril sodium. The first layer can comprise 0.01 wt%, about 0.015 wt%, about 0.02 wt%, about 0.025 wt%, about 0.030 wt%, about 0.035 wt%, up to about 0.04 wt% diclazuril, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt% diclazuril, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt% optionally diclazuril sodium. In any embodiment, the firstlayer comprises about 0.01 wt%, about 0.015 wt%, about 0.02 wt%, about 0.025 wt%, about 0.03 wt%, about 0.035 wt%, or about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt% diclazuril, optionally diclazuril sodium.

[0022] In any embodiment, the core particle comprises from about 7 wt% to about 12 wt%, optionally from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof. In any embodiment, the core particle comprises from about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, up to about 12 wt% narasin or a pharmaceutically acceptable salt thereof.

[0023] In any embodiment, the core particle comprises from about 88 wt% to about 92 wt% of an inert carrier.

[0024] In any embodiment, the inert carrier comprises zeolite, a cellulosic material, or both zeolite and a cellulosic material.

[0025] In any embodiment, the core particle comprises about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, or about 2.0 wt% of an anti-dusting oil.

[0026] In any embodiment, the core particle further comprises an inert carrier comprising a zeolite, a cellulosic material, or both a zeolite and a cellulosic material. The zeolite can be a natural zeolite, a synthetic zeolite, or a combination thereof. The zeolite can be clinoptilolite,mordenite, or any combination of clinoptilolite and mordenite. The cellulosic material can comprise rice hulls.

[0027] In any embodiment, the composition can be formulated for administration to an animal selected from the group consisting of a bird, a mammal, or a fish. In any embodiment, the mammal is a cat, dog, pig, horse, cow, donkey, goat, sheep. In any embodiment, the bird is a fowl. In any embodiment, the bird is a chicken, pheasant, guineafowl , turkey, quail, duck, or goose. In any embodiment, the fish is a salmon, trout, tilapia, or catfish.

[0028] In any embodiment, the composition is formulated for oral administration.

[0029] In any embodiment, the pharmaceutically acceptable salt of diclazuril is diclazuril sodium.

[0030] In any embodiment, a feed additive can comprise the composition described herein.

[0031] In any embodiment, an animal feed can comprise the composition described herein.

[0032] In any embodiment, the composition is present in an animal feed an amount of from between about 0.01 wt% and about 15 wt% of the animal feed. In any embodiment, the animal feed comprises the composition in an amount of about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt%, about 2.0 wt%, about 2.5 wt%, about 3.0 wt%, about 3.5 wt%, about 4.0 wt%, about 4.5 wt%, about 5.0 wt%, about 5.5 wt%, about 6.0 wt%, about 6.5 wt%, about 7.0 wt%, about 7.5 wt%, about 8.0 wt%, about 8.5 wt%, about 9.0 wt%, about 9.5 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, or about 15 wt% of the animal feed.

[0033] In any embodiment, the animal feed comprises a ratio of chicken feed:composition at a ratio of about 1 :2000, about 1 : 1500, about 1 : 1000, about 1 :900, about 1 :800, about 1 :700, about 1 :600, about 1:500, about 1 :400, about 1 :300, about 1 :250, about 1 :200, about 1: 150, about 1 : 100, about 1 :50, about 1 :25, or about 1 : 10. In any embodiment, the animal feed comprises a ratio of chicken feed com position at a ratio of about 1 :2000. In any embodiment, the animal feed comprises a ratio of chicken feedcomposition at a ratio of about 1 : 1500. In any embodiment, the animal feed comprises a ratio of chicken feedcomposition at a ratio of about 1 : 1000. In anyembodiment, the animal feed comprises a ratio of chicken feed:composition at a ratio of about 1 :500.

[0034] In any embodiment, the animal feed is grower feed or finisher feed.

[0035] In any embodiment, the animal feed is finisher feed.

[0036] In any embodiment, the core particle may comprise a marumerized particle having an oblong shape profile.

[0037] In any embodiment, the composition may comprise less than about 0.2% of diclazuril degradant R064318.

[0038] In any embodiment, the composition may further comprise a second layer at least partially covering the outer surface of the core particle, the second layer comprising anti-dusting oil. In any embodiment, the composition may further comprise a second layer at least partially covering the outer surface of the core particle, the second layer comprising anti-dusting oil. In any embodiment, the composition may comprise between about 0.01 wt% to about 2.0 wt% antidusting oil. In any embodiment, the composition may further comprise an anti-caking agent. In any embodiment, the anti-caking agent may comprise verxite.

[0039] In any embodiment, the animal for which the composition is formulated may be a bird. In any embodiment, the animal may be a fowl. In any embodiment, the animal may be a chicken. In any embodiment, the animal may be a mammal. In any embodiment, the animal may be a fish. In any embodiment, the animal may be a reptile.

[0040] In any embodiment, the first layer may cover at least 75% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 85% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 90% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 95% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 99% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 99.5% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 99.9% of the outer surface of the core particle. In any embodiment, the first layer may cover about 100% of the outer surface of the core particle.

[0041] In any embodiment, the composition is stable for at least six months at about 25 °C and about 60% relative humidity. In any embodiment, the composition is stable for at least oneyear at about 25 °C and about 60% relative humidity. In any embodiment, the composition is stable for at least two years at about 25 °C and about 60% relative humidity. In any embodiment, the composition is stable for at least six months at about 40 °C and about 75% relative humidity. In any embodiment, the composition is stable for at least one year at about 40 °C and about 75% relative humidity. In any embodiment, the composition may be stable for at least two years at about 40 °C and about 75% relative humidity. In any embodiment, the composition is stable for at least six months at 25 °C and 60% relative humidity. In any embodiment, the composition is stable for at least one year at 25 °C and 60% relative humidity. In any embodiment, the composition is stable for at least two years at 25 °C and 60% relative humidity. In any embodiment, the composition is stable for at least six months at 40 °C and 75% relative humidity. In any embodiment, the composition is stable for at least one year at 40 °C and 75% relative humidity. In any embodiment, the composition may be stable for at least two years at 40 °C and 75% relative humidity. In any embodiment, the composition may be configured such that the composition comprises less than about 0.2% of diclazuril degradant R064318 after six months at 25 °C and 60% relative humidity. In any embodiment, the composition may be configured such that the composition comprises less than about 0.2% of diclazuril degradant R064318 after two years at 25 °C and 60% relative humidity. In any embodiment, the composition may be configured such that the composition comprises less than about 0.2% of diclazuril degradant R064318 after six months at 40 °C and 75% relative humidity. In any embodiment, the composition may be configured such that the composition comprises less than about 0.2% of diclazuril degradant R064318 after one year at 40 °C and 75% relative humidity. In any embodiment, the composition may be configured such that the composition comprises less than about 0.2% of diclazuril degradant R064318 after two years at 40 °C and 75% relative humidity.

[0042] In another aspect, the present disclosure provides a method of preparing an anti- infective composition, the method comprising: applying a coating comprising diclazuril or a pharmaceutically acceptable salt thereof to at least a portion of an outer surface of a granule comprising narasin or a pharmaceutically acceptable salt thereof. In any embodiment, the pharmaceutically acceptable diclazuril salt may be a sodium salt.

[0043] In any embodiment, applying may comprise spraying a diclazuril sodium salt aqueous solution onto the outer surface of the granule. In any embodiment, spraying may occur within a blender chamber. In any embodiment, spraying may occur within a blender chamber, the blender chamber being vacuum evacuated prior to spraying.

[0044] In any embodiment, the method of preparing an anti-infective composition may further comprise preparing the diclazuril sodium salt aqueous solution by mixing diclazuril, an alcohol, and an aqueous base. In any embodiment, the method of preparing an anti -infective composition may further comprise preparing the diclazuril sodium salt aqueous solution by mixing diclazuril, an alcohol, and an aqueous base in an intermediate tank. In any embodiment, preparing may further comprise an aqueous base that is not degassed. In any embodiment, preparing may further comprise degassing the aqueous base. In any embodiment, preparing may further comprise removing oxygen from the aqueous base. In any embodiment, preparing may further comprise drawing a vacuum to remove oxygen from the intermediate tank prior to mixing the aqueous base. In any embodiment, preparing may further comprise a nitrogen purge to remove oxygen from the intermediate tank prior to mixing the aqueous base.

[0045] In any embodiment, the method may further comprise applying the coating to an outer surface of a diluent particle. In any embodiment, the diluent particle may comprise zeolite, cellulosic material, or zeolite and cellulosic material. In any embodiment, the diluent particle may comprise zeolite or rice hulls.

[0046] In any embodiment, the method may further comprise heating or cooling the blender chamber so that a jacket in contact with the granules is at a temperature between about 10 °C and about 150 °C, optionally between about 20 °C and about 140 °C, optionally between about 30 °C and about 130 °C, optionally between about 40 °C and about 120 °C, optionally between about 40 °C and about 100 °C, between about 50 °C and about 110 °C, optionally between about 50 °C to about 100 °C, optionally between about 50 °C and about 90 °C, optionally between about 60 °C and about 100 °C, optionally between about 60 °C and about 90 °C, or between about 60 °C to about 80 °C.

[0047] In any embodiment, the applying may comprise spraying at a rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 10,000 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 1,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 7,000 g / min, optionally from about 7,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 5,000 g / min to about 2,500 g / min, optionally from about 2,500 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, optionally from about 500 g / min to about 250 g / min, optionally from about 250 g / min to about 150 g / min, optionally from about 100 g / min to about 250 g / min, optionally from about 120 g / min to about 230 g / min, optionally from about 130 g / min to about 220 g / min, or optionally from about 140 g / min to about 200 g / min. In any embodiment, the applying may comprise a spray duration of about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, or about 60 minutes. In any embodiment, the applying may comprise spraying from about 1 minute to about 60 minutes, optionally from about 5 minutes to about 60 minutes, optionally from about 5 minutes to about 50 minutes, optionally from about 5 minutes to about 45 minutes, optionally from about 5 minutes to about 40 minutes, optionally from about 5 minutes to about 35 minutes, optionally from about 5 minutes to about 30 minutes, optionally from about 5 minutes to about 25 minutes, optionally from about 5 minutes to about 20 minutes, optionally from about 5 minutes to about 15 minutes, optionally from about 5 minutes to about 10 minutes, optionally from about 2 minutes to about 45 minutes, optionally from about 2 minutes to about 35 minutes, optionally from about 2 minutes to about 30 minutes, optionally from about 2 minutes to about 25 minutes, optionally from about 2 minutes to about 20 minutes, optionally from about 2 minutes to about 15 minutes, or from about 2 minutes to about 10 minutes.

[0048] In any embodiment of the method, the aqueous base may be an aqueous hydroxide. In any embodiment, the aqueous hydroxide may be at a concentration from about 0.1 M to about 5 M, from about 0.3 M to about 2 M, from about 0.5 M to about 1.5 M, from about 0.5 M to about1.0 M, or may be about 1 M. In any embodiment, the aqueous base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide or a mixture thereof.

[0049] In any embodiment, mixing diclazuril, the alcohol, and the aqueous base in the intermediate tank may include a first step of mixing the diclazuril with the alcohol and a second step of adding the aqueous base, wherein the aqueous base is added at a rate of greater than 1 minute and less than 60 minutes at a temperature from about 5 °C to about 50 °C.

[0050] In any embodiment of the method, the method may further comprise applying an antidusting oil to the anti-infective composition. In any embodiment, the method may further comprise applying an anti-caking agent to the anti-infective composition. In any embodiment, the anti-caking agent may be verxite.

[0051] In any embodiment of the method, the anti-infective composition may comprise between about 7 - 15% (wt / wt) narasin or pharmaceutically acceptable salt thereof and between about 0.01- 5.0% (wt / wt) diclazuril or pharmaceutically acceptable salt thereof. In any embodiment of the method, the anti-infective composition may comprise between about 7 - 12% (wt / wt) narasin or pharmaceutically acceptable salt thereof and between about 0.01- 2.0% (wt / wt) diclazuril or pharmaceutically acceptable salt thereof. In any embodiment of the method, the anti -infective composition may comprise between about 7 - 10% (wt / wt) narasin or pharmaceutically acceptable salt thereof and between about 0.01- 2.0% (wt / wt) diclazuril or pharmaceutically acceptable salt thereof.

[0052] In any embodiment of the method, the granule may comprise about 10 wt% narasin or a pharmaceutically acceptable salt thereof, and the antiprotozoal agent may comprise about 0.02 wt% diclazuril sodium in aqueous solution. In any embodiment of the method, the granule may comprise about 10 wt% narasin or a pharmaceutically acceptable salt thereof, and the antiprotozoal agent may comprise about 0.05 wt% diclazuril sodium in aqueous solution. In any embodiment of the method, the granule may comprise about 10 wt% narasin or a pharmaceutically acceptable salt thereof, and the antiprotozoal agent may comprise about 0.5 wt% diclazuril sodium in aqueous solution. In any embodiment of the method, the granule may comprise about 10 wt% narasin or a pharmaceutically acceptable salt thereof, and the antiprotozoal agent may comprise about 2.0 wt% diclazuril sodium in aqueous solution. In anyembodiment, a portion of the outer surface of the granule may comprise substantially all of the outer surface of the granule.

[0053] In still another aspect, the present disclosure provides a process for preparing a combination antiparasitic particle composition, the process comprising: coating a batch of granules, the granules comprising narasin or a pharmaceutically acceptable salt thereof, with an aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof.

[0054] In any embodiment of the process may further comprise forming the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof, wherein the forming comprises: dissolving solid diclazuril or a pharmaceutically acceptable salt thereof in an alcohol solvent, thereby generating a diclazuril-alcohol solution; removing O2 from atmosphere exposed to the diclazuril-alcohol solution; blanketing the diclazuril-alcohol solution in inert gas; and adding aqueous hydroxide to the diclazuril-alcohol solution, wherein the aqueous hydroxide comprises sodium hydroxide, potassium hydroxide, ammonium hydroxide, or a mixture thereof. In any embodiment, the alcohol solvent comprises a straight chain or branched chain C1-C6 alcohol. In any embodiment, the alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol and hexanol. In any embodiment, the alcohol solvent comprises ethanol, n-propanol or isopropanol. In any embodiment, the alcohol solvent comprises ethanol. In any embodiment, the alcohol solvent comprises isopropanol or isopropyl alcohol.

[0055] In any embodiment of the process, the aqueous hydroxide may be at a concentration from about 0.1 M to about 5.0 M, from about 0.1 M to about 4.0 M, from about 0.1 M to about 3.0 M, from about 0.1 M to about 2.0 M, from about 0.1 M to about 1.5 M, from about 0.1 M to about 1.0 M, from about 0.5 M to about 2.5 M, from about 1.0 M to about 3.0 M, or from about 1.0 M to about 2.5 M. In any embodiment, the aqueous hydroxide may be added at a rate of greater than 1 minute and less than 60 minutes at a temperature from about 5 °C to about 50 °C.

[0056] In any embodiment of the process, the granules may further comprise an inert carrier comprising zeolite, cellulosic material, or a combination of zeolite and cellulosic material. In any embodiment the granules may further comprise an inert carrier comprising rice hulls.

[0057] In any embodiment, the process may further comprise forming the batch of granules, wherein the forming comprises: mixing an inert carrier comprising rice hulls with narasin or apharmaceutically acceptable salt thereof in a vacuum blender; removing O2 from atmosphere in the vacuum blender; and setting a pressure inside the vacuum blender to under about 150 mBar.

[0058] In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 50 g / min, optionally from about 20,000 g / min to about 10,000 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 1,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 7,000 g / min, optionally from about 7,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 5,000 g / min to about 2,500 g / min, optionally from about 2,500 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, optionally from about 500 g / min to about 250 g / min, optionally from about 250 g / min to about 150 g / min, optionally from about 300 g / min to about 150 g / min, optionally from about 100 g / min to about 250 g / min, optionally from about 120 g / min to about 230 g / min, optionally from about 130 g / min to about 220 g / min, optionally from about 140 g / min to about 200 g / min, optionally from about 300 g / min to about 50 g / min, or optionally from about 100 g / min to about 50 g / min.

[0059] In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 50 g / min, optionally from about 20,000 g / min to about 10,000 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 1,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 7,000 g / min, optionally from about 7,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 5,000 g / min to about 2,500 g / min, optionally from about 2,500 g / min to about 1,000 g / min, optionally from about 1,000 g / min toabout 500 g / min, and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 10,000 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 1,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 7,000 g / min, optionally from about 7,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 5,000 g / min to about 2,500 g / min, optionally from about 2,500 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution under vacuum. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 10,000 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 1,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 7,000 g / min, optionally from about 7,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 5,000 g / min to about 2,500 g / min, optionally from about 2,500 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution without the use of vacuum.

[0060] In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 500 g / min to about 100 g / min, optionally from about 500 g / min to about 250 g / min, optionally from about 250 g / min to about 150 g / min, optionally from about 300 g / min to about 150 g / min, optionally from about 100 g / min to about 250 g / min, optionally from about 120 g / min to about 230 g / min, optionally from about 130 g / min to about 220 g / min, optionally from about 140 g / min to about 200 g / min, or optionally from about 100 g / min to about 50 g / min, or optionally from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 500 g / min to about 100 g / min, optionally from about 500 g / min to about 250 g / min, optionally from about 250 g / min to about 150 g / min, optionally from about 300 g / min to about 150 g / min, optionally from about 100 g / min to about 250 g / min, optionally from about 120 g / min to about 230 g / min, optionally from about 130 g / min to about 220 g / min, optionally from about 140 g / min to about 200 g / min, or optionally from about 100 g / min to about 50 g / min, or optionally from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution under vacuum. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 500 g / min to about 100 g / min, optionally from about 500 g / min to about 250 g / min, optionally from about 250 g / min to about 150 g / min, optionally from about 300 g / min to about 150 g / min, optionally from about 100 g / min to about 250 g / min, optionally from about 120 g / min to about 230 g / min, optionally from about 130 g / min to about 220 g / min, optionally from about 140 g / min to about 200 g / min, or optionally from about 100 g / min to about 50 g / min, or optionally from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution without the use of vacuum. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable saltthereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution. In any embodiment, the coating may comprise spraying from about 1 minute to about 60 minutes, optionally from about 5 minutes to about 60 minutes, optionally from about 5 minutes to about 50 minutes, optionally from about 5 minutes to about 45 minutes, optionally from about 5 minutes to about 40 minutes, optionally from about 5 minutes to about 35 minutes, optionally from about 5 minutes to about 30 minutes, optionally from about 5 minutes to about 25 minutes, optionally from about 5 minutes to about 20 minutes, optionally from about 5 minutes to about 15 minutes, optionally from about 5 minutes to about 10 minutes, optionally from about 2 minutes to about 45 minutes, optionally from about 2 minutes to about 35 minutes, optionally from about 2 minutes to about 30 minutes, optionally from about 2 minutes to about 25 minutes, optionally from about 2 minutes to about 20 minutes, optionally from about 2 minutes to about 15 minutes, optionally from about 2 minutes to about 10 minutes.

[0061] In any embodiment of the process, the process may further comprise coating the granules in anti-dusting oil. In any embodiment, the process may further comprise coating the granules in anti-caking agent. In any embodiment, the anti-caking agent may comprise verxite. In any embodiment, the verxite may comprise verxite granules, verxite flakes, and / or verxite grits.

[0062] In any embodiment of the process, the combination antiparasitic particle composition may comprise from about 7 wt% to about 12 wt% narasin, optionally from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof and from about 0.01 wt% to about 5.0 wt% diclazuril sodium. In any embodiment of the process, the combination antiparasitic particle composition may comprise from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof and from about 0.01 wt% to about 2.0 wt% diclazuril sodium.

[0063] In yet another aspect, the present disclosure provides a method of preventing and / or treating a coccidian infection in a fowl, the method comprising administering to the fowl atherapeutically effective amount of an embodiment of the composition formulated for administration to an animal provided in the present disclosure.

[0064] In still another aspect, the present disclosure provides the use of a therapeutically effective amount of an embodiment of composition formulated for administration to an animal provided in the present disclosure for manufacture of a medicament for treatment of a coccidian infection in a fowl.

[0065] In any embodiment, a method of preventing and / or treating a coccidian infection in an animal can comprise administering to the animal a therapeutically effective amount of the composition described herein.

[0066] In any embodiment, a method of preventing and / or treating a coccidian infection in an animal can comprise administering to the animal a therapeutically effective amount of the feed additive described herein.

[0067] In any embodiment, a method of preventing and / or treating a coccidian infection in an animal can comprise administering to the animal a therapeutically effective amount of the animal feed described herein.

[0068] In any embodiment, the animal can be a non-human animal. The animal can be a bird, a mammal, or a fish. The mammal can be a cat, dog, pig (swine), horse, cow, donkey, goat, or sheep. The bird can be a fowl. The bird can be a chicken, turkey, quail, duck, guineafowl, or goose. The fish can be a salmon, trout, tilapia, or catfish.

[0069] In any embodiment, the coccidian infection is an Eimeria species. The Eimeria species can be E. Brunetti , E. necatrix, E. tenella, E. acervulina, E. maxima, E. mitis, E. praecox, or any combination thereof. The Eimeria species can be E. acervulina, E. maxima, E. tenella, or any combination thereof.

[0070] In any embodiment, the composition is administered orally.

[0071] In any embodiment, the composition can be admixed with an animal feed.

[0072] In any embodiment, the composition can be administered for at least 1, 2, 3, 4, 5, 6, 7,8, 9, or 10 feed cycles.

[0073] In any embodiment, the composition can be administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive grow cycles in a finisher feed, optionally at least 3 consecutive grow cycles.

[0074] In any embodiment, the therapeutically effective amount of the composition described herein can be used for manufacture of a medicament for treatment of a coccidian infection in an animal.

[0075] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0076] The above-mentioned and other features and advantages of the various embodiments of the present disclosure, and the manner of attaining them, will become more apparent and better understood by reference to the following accompanying non-limiting drawings, wherein:

[0077] Fig. l is a flowchart of an embodiment of a method of producing a layered composition according to the present disclosure.

[0078] Fig. 2 is an exemplary non-scale illustration of an apparatus configured to facilitate methods of producing a layered composition according to the present disclosure.

[0079] Figs. 3A-3G are exemplary non-scale illustrations depicting an exemplary series of process steps carrying out a method according to the present disclosure. Accordingly to the exemplary series, Fig. 3A illustrates dry formulation ingredients are added to the blending and mixed therein; Fig. 3B illustrates aqueous solution preparation, where the solution preparation tank is purged with N2 gas, and then specified amounts of ethanol and diclazuril salt are charged, and while mixing, a hydroxide solution is added at a controlled rate to facilitate dissolution; Fig. 3C illustrates that vacuum pulls on the blending containing the dry ingredients; Fig. 3D illustrates that the diclazuril solution is sprayed over time onto the dry materials in the blender, as the blender jacket is heated; Fig. 3E illustrates that after diclazuril solution addition, the blender is maintained under vacuum and heated jacket during mixing; Fig. 3F illustrates that anti-dusting oil is added while the blender is mixing, and after addition of the oil the vacuum is released and blender jacked cooled; and Fig. 3G illustrates that the formulated composition is fed to a hopper, and then onto packaging processes.

[0080] Fig. 4 is an illustrative diagram of an apparatus for making the composition of the present disclosure.

[0081] Fig. 5 is an illustrative diagram focusing on management of the wet ingredients for making the composition of the present disclosure.

[0082] Fig. 6 is an illustrative diagram of an Eimeria (coccidiosis-causing parasite) lifecycle.

[0083] Figs. 7A-7C are data tables for experiments in which chickens were artificially challenged with ionophore-tolerant Eimeria. “Gigaban” as used in Figs. 7A-7C refers to an embodiment the composition of the present disclosure comprising 1 ppm diclazuril + 60 ppm narasin. Fig. 7A shows average daily growth according to weight gain measured in grams. Fig. 7B shows feed conversion rate (FCR), which is calculated by dividing total feed intake by total weight gain. Fig. 7C shows lesion scoring totals. Lesion scoring for all experiments is undertaken by opening and scoring for lesions of cocci diosis at three sites: the duodenum (from the pyloric junction to the most distal point of insertion of the duodenal mesentery), upper half of the jejunum, and lower half of the jejunum on a scale of 0 to 4, according the method described in Johnson J., Reid W. M. Anticoccidial drugs: Lesion scoring techniques in battery and floor pen experiments with chickens. Exp. Parasitol. 1970; 28:30-36, which is incorporated by reference in its entirety herein.

[0084] Figs. 8A-8B show data from emergent anticoccidial drug resistance challenge experiments. Birds were treated with compositions of the present disclosure for five consecutive grow outs. Resistance to narasin or diclazuril was not observed, as measured by drug efficacy in treatment (Fig. 8A) and oocyst counts (Fig. 8B).

[0085] Figs. 9A-9E are bar graphs showing experimental results of experiments testing compositions of the present disclosure as compared with a single drug alone on the metrics of average daily weight gain (Fig. 9A), feed conversion (Fig. 9B), lesion score following A. acervulina challenge (Fig. 9C), lesion score following E. maxima challenge (Fig. 9D), and lesion score following A. tenella challenge (Fig. 9E). Lesion scoring was evaluated in accordance with Johnson et al., supra.

[0086] Figs 10A-10G are bar graphs showing experimental results of another set of experiments testing compositions of the present disclosure as compared with a single drug alone.

[0087] Figs. 11 A-l IB show data indicating compositions of the present disclosure offer superior feed conversion efficiency over salinomycin alone when used during the same feeding phase.

[0088] Figs. 12A-E show scanning electron microscopy (SEM) images of exemplary uncoated narasin from a first bottle.

[0089] Figs. 13A-E show scanning electron microscopy (SEM) images of exemplary uncoated narasin from a second bottle.

[0090] Figs. 14A-E show scanning electron microscopy (SEM) images of exemplary uncoated narasin from a third bottle.

[0091] Figs. 15A-E show scanning electron microscopy (SEM) images of exemplary narasin coated in accordance with an exemplary process disclosed herein, from a first bottle.

[0092] Figs. 16A-E show scanning electron microscopy (SEM) images of exemplary narasin coated in accordance with an exemplary process disclosed herein, from a second bottle.

[0093] Figs. 17A-E show scanning electron microscopy (SEM) images of exemplary narasin coated in accordance with an exemplary process disclosed herein, from a third bottle.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0094] The embodiments of the present invention described below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices of the present invention.

[0095] While illustrative examples of the disclosure have been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only certain examples have been shown and described and that all changes and modifications that come within the spirit of the claimed invention are desired to be protected. It should be understood that while the use of words such as preferable, preferably, preferred or more preferred utilized in the description above indicates that the feature so described may be more desirable, it nonetheless may not be necessary and examples lacking the same may be contemplated as within the scope of the invention, the scope being defined by the claims that follow. In reading the claims, it is intended that when words such as “a,” “an,” “at least one,” or “at least one portion” are used there is no intention to limit the claim to only one item unless specifically stated to the contrary in the claim. When thelanguage “at least a portion” and / or “a portion” is used the item can include a portion and / or the entire item unless specifically stated to the contrary.

[0096] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any one of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0097] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). The term “about,” as used herein when referring to a measurable value such as an amount of dose, time, temperature, enzymatic activity or other activity and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0098] Following from the above description and invention summaries, it should be apparent to those of ordinary skill in the art that, while the methods and apparatuses herein described constitute exemplary embodiments of the present invention, the invention contained herein is not limited to this precise embodiment and that changes may be made to such embodiments without departing from the scope of the invention as defined by the claims. Additionally, it is to be understood that the invention is defined by the claims and it is not intended that any limitations or elements describing the exemplary embodiments set forth herein are to be incorporated into the interpretation of any claim element unless such limitation or element is explicitly stated. Likewise, it is to be understood that it is not necessary to meet any or all of the identified advantages or objects of the invention disclosed herein in order to fall within the scope of any claims, since the invention is defined by the claims and since inherent and / or unforeseen advantages of the present invention may exist even though they may not have been explicitly discussed herein.

[0099] As used herein, the term “alcohol solvent” means a straight chain or branched chain aliphatic alcohol, optionally a C1-C6 alcohol, optionally methanol, ethanol, propanol, butanol, pentanol, or hexanol. Branched chain alcohols include but are not limited to isopropyl alcohol, isobutyl alcohol, tert-butyl alcohol and the like.

[0100] As used herein, “pharmaceutically acceptable salt” means a pharmacologically active salt homolog of a therapeutic, which is generally safe, non-toxic, neither biologically nor otherwise undesirable, and includes that which is acceptable for veterinary and / or human therapeutic uses.

[0101] As used herein, “parasite” refers to any organism that lives on and / or in a host organism and gets sustenance from and / or at the expense of its host organism. Parasites may be, but are not limited to, bacteria, archaea, protozoa (including, e.g., amoebae, mastigophora, ciliophoran, sporozoa, toxoplasma, apicomplexa, etc.), helminths (including, e.g., flatforms, acanthocephalins, nematodes, etc.), and ectoparasites. The apicomplexan genus Eimeria is an exemplary parasite.

[0102] As used herein, “coccidiosis” refers to enteric infection (i.e., infection of the intestinal tract) caused by protozoans of the apicomplexa phylum. Unless context otherwise dictates, the term “coccidiosis” usually refers to non-human animal infections caused by apicomplexans of the genus Eimeria. Coccidiosis may affect any livestock animal, including, but not limited to, pigs (also referred to as swine, including sows), sheep (including lambs), goats, chickens (including broilers and egg-laying hens), guineafowl, turkeys, cows (including calves and dairy cows), rabbits, and horses. Species of coccidiosis-causing parasite known to infect fowl include (but are not necessarily limited to) hemorrhagic-type Eimeria species E. brunetti, E. necatrix, and E. tenella, and malabsorptive-type Eimeria species A. acervulina, E. maxima, E. mitis, and E. praecox. Although prevalence of Eimeria is not generally known, and likely varies according to local conditions and farming practices, a recent survey in Australia found DNA evidence of infection of at least one of the above species in nearly 100 percent of tested commercial and backyard flocks. See Godwin, R., et al., A Molecular Survey of Eimeria in Chickens Across Australia, Veterinary Parasitology 214 (2015) 16-21. Broken down by individual Eimeria species, among other results the survey found E. acervulina in nearly 70 percent of commercial flocks, and E. maxima in nearly 60 percent of commercial flocks.

[0103] As illustrated in Fig. 6, the Eimeria parasite life cycle, in summary, proceeds with (1) ingestion by animal host of a sporulated oocyst (which may be colloquially called a “spore”), initiating endogenous phases of the life cycle; (2) in avian Eimeria, the spore wall is disrupted during passage through the animal’s crop or gizzard, releasing sporocysts; (3) exposure to digestive enzymes allows sporozoite cells to escape the sporocyst; (4) the sporozoite inhabits intestinal epithelium cells, transitions to trophozoite stage before undergoing asexual fission (i.e., schizogony), and offspring rupture and leave the host cell; (5) first-generation asexual offspring invade another epithelial cell, engaging a second round of asexual fission; (6) after a finite- number of asexual fissions, o. Eimeria cells differentiate into gametes as the sexual phase begins, forming uninucleate macrogametes (typically described as “female”), or biflagellated microgametes (typically described as “male”); (7) mature microgametes leave the host cell and enter neighboring host cells, fertilizing macrogametes to form zygotes; (8) after fertilization, the zygote forms a tough cell wall, enters the intestinal lumen, and is excreted into the environment to initiate the exogenous phase; and (9) the oocyst undergoes sporulation in the environment. The sporulated oocyst is now infectious, waiting to be ingested by a new host animal.

[0104] Diclazuril is a pure synthetic benzeneacetonitrile derivative effective in treating parasitic diseases including coccidiosis, toxoplasmosis, protozoal myeloencephalitis, and other diseases in fowl (chickens for fattening, hens reared for laying, guineafowls and turkeys for fattening) and rabbits, with an IUPAC name (±)-2,6-dichloro-alpha-(4-chlorophenyl)-4-(4,5- dihydro-3,5-dioxo-l,2,4-triazine-2-(3H)-yl)benzeneacetonitrile, and CAS No. 101831-37-2.

[0105] Narasin, also sometimes called 4-m ethyl salinomycin, is salinomycin-family antiparasitic and antibacterial agent with an IUPAC name (2R)-2-[(2R,3S,5S,6R)-6- [(2S,3S,4S,6R)-6-[(3S,5S,7R,9S,10S,12R,15R)-3-[(2R,5R,6S)-5-ethyl-5-hydroxy-6-methyloxan- 2-yl]-15-hydroxy-3,10,12-trimethyl-4,6,8-trioxadispiro[4.1.57.35]pentadec-13-en-9-yl]-3- hydroxy-4-methyl-5-oxooctan-2-yl]-3,5-dimethyloxan-2-yl]butanoic acid and CAS No. 55134-13-9. Narasin is generally produced through fermentation of bacteria species Streptomyces aureofaciens strain NR.R.L 5758 or Streptomyces aureofaciens strain NR.R.L 8092.

[0106] Livestock farmers, including poultry farmers, have a substantial interest in prevention, mitigation, and treatment of coccidiosis in their animals. Coccidia (Eimeria) are the most common enteric parasites found in commercial poultry with E. acervulina, E. maxima, and E. tenella being the three species most commonly found in broiler chicken production.Coccidiosis can be costly to broiler producers as a result of decreased performance with respect to Feed Conversion Ratios, and weight gain, and / or increased mortality. (Feed conversion is calculated by dividing total feed intake by total weight gain, thereby measuring the efficiency of animal growth per unit of feed ingested.) Control of coccidiosis continues to be an issue despite availability of a number of anticoccidial drugs and vaccines.

[0107] Currently available treatments present significant drawbacks. Eimeria vaccines, among other problems, are difficult to produce and therefore supplies are limited and costs relatively high. Various approaches to in-feed chemoprophylaxis are used around the world. While strategies differ in broiler chickens and egg-laying hens, farmers face difficulties with drug resistance, requiring rotation of drug between flocks. Further, many governments require withdrawal of coccidiostat drugs prior to slaughter, thereby increasing risk of infection in older animals. To limit selection of drug-resistant strains, shuttle and rotation programs have been introduced in which different coccidiostats are alternately used, either within a single flock or in a series of consecutive flocks. See Vermeulen, AN, Control of Coccidiosis in Chickens by Vaccination, Veterinary Parasitology, 100 (2001) 13-30.

[0108] Rotation programs of anticoccidial drugs or vaccines are commonly used to minimize the occurrence of resistance, and the present disclosure provides compositions and methods oftreatment which slow or mitigate the resistance development and lessen the need for rotational programs.

[0109] Further, the combination of diclazuril and narasin results in surprising and unexpected improved performance and intestinal integrity (reduction in gastrointestinal injury) over either diclazuril or narasin alone. For example, diclazuril (1 ppm) is effective against narasin resistant Eimeria, Narasin (60 ppm) is effective against diclazuril resistant Eimeria, and Narasin + diclazuril (1 ppm diclazuril + 60 ppm narasin) is effective against both narasin-resistant and diclazuril-resistant Eimeria and the growth performance in infected birds is comparable to the growth performance in non-infected birds. In experiments on embodiments of the composition of the present disclosure, no signs of anticoccidial resistance increasing were observed, as measured by oocyst counts in litter (after use in grower / finisher feed) after the first and third grow out- cycles in floor pen conditions in the presence of field isolates. This was shown and measured by no statistically significant reduction in anticoccidial performance indicators (e.g., lesion score).

[0110] Additionally, the formulation process of coating aqueous diclazuril over solid narasin-containing granule overcomes previous difficulties in producing a safe, effective, shelfstable diclazuril + narasin combination or diclazuril + salinomycin combination in-feed therapeutic product that fowl would eat.

[0111] Faced with these challenges, the present disclosure provides multi-layered therapeutics, methods of manufacture thereof, and methods of treatment of coccidiosis.

[0112] In an aspect, the present disclosure provides a composition formulated for administration to an animal comprising: a core particle having an outer surface, the core particle comprising narasin or a pharmaceutically acceptable salt thereof; and a first layer at least partially covering the outer surface of the core particle, the first layer comprising diclazuril or a pharmaceutically acceptable salt thereof. In any embodiment of the composition, the core particle may further comprise an inert carrier comprising zeolite, a cellulosic material, or both. In any embodiment, the cellulosic material may comprise rice hulls.

[0113] In any embodiment, the zeolite may be a natural zeolite, a synthetic zeolite, or a combination thereof. In any embodiment, the zeolite may comprise clinoptilolite, mordenite, or any combination of clinoptilolite and mordenite.

[0114] In any embodiment, the pharmaceutically acceptable salt of diclazuril may comprise diclazuril sodium.

[0115] In any embodiment, the mass ratio of the narasin to the diclazuril may be between about 20: 1 and about 100: 1. In any embodiment, the mass ratio of the narasin to the diclazuril may be between about 30: 1 and about 90: 1. In any embodiment, the mass ratio of the narasin to the diclazuril may be between about 40: 1 and about 80: 1. In any embodiment, the mass ratio of the narasin to the diclazuril may be between about 50: 1 and about 70: 1. In any embodiment, the mass ratio of the narasin to the diclazuril may be about 60: 1.

[0116] In any embodiment, the first layer comprises from about 0.01 wt% to about 5.0 wt% diclazuril, optionally diclazuril sodium. The first layer can comprise 0.01 wt%, about 0.015 wt%, about 0.02 wt%, about 0.025 wt%, about 0.030 wt%, about 0.035 wt%, up to about 0.04 wt% diclazuril, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt% diclazuril, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt% optionally diclazuril sodium. In any embodiment, the first layer may comprise from about 0.01 wt% to about 0.2 wt% diclazuril sodium. For example, the first layer may comprise about 0.01 wt%, about 0.015 wt%, about 0.02 wt%, about 0.025 wt%, about 0.030 wt%, about 0.035 wt%, 0.04 wt%, about 0.045 wt%, about 0.05 wt%, about 0.055 wt%, about 0.06 wt%, about 0.065 wt%, 0.07 wt%, about 0.075 wt%, about 0.08 wt%, about 0.085 wt%, about 0.09 wt%, about 0.1 wt%, 0.11 wt%, about 0.115 wt%, about 0.12 wt%, about 0.125 wt%, about 0.130 wt%, about 0.135 wt%, 0.14 wt%, about 0.145 wt%, about 0.15 wt%, about 0.155 wt%, about 0.16 wt%, about 0.165 wt%, 0.17 wt%, about 0.175 wt%, about 0.18 wt%, about 0.185 wt%, about 0.19 wt%, up to about 0.2 wt% diclazuril sodium.

[0117] In any embodiment, the core particle may comprise from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof. For example, the core particle may comprise about 8 wt%, about 8.5% wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, up to about 12 wt% narasin or a pharmaceutically acceptable salt thereof. It should be appreciated that pharmaceutically acceptable homologs of narasin known in the art, such as deoxynarasin may be used without departing from the contemplated scope of the disclosure.

[0118] In any embodiment, the core particle may comprise an inert carrier comprising zeolite, a cellulosic material, or both zeolite and a cellulosic material. In any embodiment, the core particle may comprise about 88 wt% to about 92 wt% of an inert carrier comprising zeolite, a cellulosic material.

[0119] In any embodiment, the composition may comprise about 1 ppm diclazuril sodium. In any embodiment, the composition may comprise about 60 ppm narasin or a pharmaceutically acceptable salt thereof.

[0120] In any embodiment, the core particle may comprise a marumerized particle. “Marumerization”, also sometimes referred to as “spheronization” more or less interchangeably, refers to processes of manufacture of products comprising small granules, typically of a size range of around 0.4mm to 3.0mm in diameter, though granules may be smaller or larger. Typically, a marumerized particle is produced by an extrusion process. In any embodiment, the core particle may have an oblong shape profde. In any embodiment, the core particle may comprise a marumerized particle having an oblong shape profile. In any embodiment, the core particle may be of a shape selected from any one of: barrel, cylindrical, cardioid, disc, corpuscular, crescent, conic, dome, ellipsoid, helicoid, hemispherical, spherical, spheroid, hyperboloid, lozenge, lunar, oblate, oblong, ovular, paraboloid, prolate, rhomboid, scalloped, semicircular, semielliptical, spall, stellate, teardrop, torus, triangular, tubular, vermiculate, and wafer.

[0121] In any embodiment, the composition may comprise less than about 0.2% of diclazuril degradant R064318.

[0122] In any embodiment, the composition may further comprise a second layer at least partially covering the outer surface of the core particle, the second layer comprising anti-dustingoil. In any embodiment, the composition may comprise between about 0.01 wt% to about 2 wt% anti-dusting oil. For example, the composition may comprise about 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.15 wt%, 0.2 wt%, 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, 0.8 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt%, 1 wt%,1.01 wt%, 1.05 wt%, 1.1 wt%, 1.15 wt%, 1.2 wt%, 1.25 wt%, 1.3 wt%, 1.35 wt%, 1.4 wt%, 1.45 wt%, 1.5 wt%, 1.55 wt%, 1.6 wt%, 1.65 wt%, 1.7 wt%, 1.75 wt%, 1.8 wt%, 1.85 wt%, 1.9 wt%,1.95 wt%, or 2.0 wt% anti-dusting oil.

[0123] The second layer may cover at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5%, at least 99.9%, or about 100% of the outer surface of the core particle. The anti-dusting oil may form a distinct second layer atop the first layer, or may form an emulsion with the first layer, or a form a second layer atop the first layer that is also partially emulsified with the first layer. In any embodiment, the composition may further comprise an anti-caking agent.

[0124] In any embodiment, the anti-caking agent may comprise verxite. “Verxite” refers to hydrobiotite mineral that has been thermally expanded to form lightweight granules having high internal porosity. Other suitable anti-caking agents may include, but are not limited to, silicon dioxide, tricalcium phosphate, mannitol, powdered cellulose, magnesium stearate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate(s), calcium silicate, magnesium silicate, talc, aluminum silicate, stearic acid, polydimethylsiloxane, iron ammonium citrate, yellow prussiate of soda (YPS), and any combination thereof.

[0125] In any embodiment, the animal for which the composition is formulated may be a bird. In any embodiment, the animal may be a fowl, including chicken, pheasant, goose, duck, guineafowl, and turkey. In any embodiment, the animal may be a chicken. In any embodiment, the animal may be a non-human animal. In any embodiment, the animal may be a mammal. In any embodiment, the animal may be a non-human mammal, including, e.g., pig, cow, horse, camel, llama, alpaca, goat, sheep, rabbit, ferret, mink, stoat, mouse, and rat. In any embodiment, the animal may be a fish. The fish can be a salmon, trout, tilapia, or catfish. In any embodiment, the animal may be a reptile.

[0126] In any embodiment, the first layer may cover at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or more of the outer surface of the core particle. In any embodiment, the first layer may cover at least 85% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 90% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 95% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 99% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 99.5% of the outer surface of the core particle. In any embodiment, the first layer may cover at least 99.9% of the outer surface of the core particle. In any embodiment, the first layer may cover about 100% of the outer surface of the core particle.

[0127] In any embodiment, the composition is stable for at least six months at 25 °C and 60% relative humidity. In any embodiment, the composition is stable for at least one year at 25 °C and 60% relative humidity. In any embodiment, the composition is stable for at least two years at 25 °C and 60% relative humidity. In any embodiment, the composition may be stable for at least two years at 40°C and 75% relative humidity. In any embodiment, the composition may be configured such that the composition comprises less than about 0.2% of diclazuril degradant R064318 after six months at 25 °C and 60% relative humidity. In any embodiment, the composition may be configured such that the composition comprises less than about 0.2% of diclazuril degradant R064318 after two years at 40°C and 75% relative humidity.

[0128] In another aspect, the present disclosure provides a method of preparing an anti- infective composition, the method comprising: applying a coating comprising diclazuril or a pharmaceutically acceptable salt thereof to at least a portion of an outer surface of a granule comprising narasin or a pharmaceutically acceptable salt thereof.

[0129] In any embodiment, the pharmaceutically acceptable diclazuril salt may be a sodium salt.

[0130] In any embodiment, applying may comprise spraying a diclazuril sodium salt aqueous solution onto the outer surface of the granule. In any embodiment, spraying may occur within a blender chamber. In any embodiment, the blender chamber may be vacuum evacuated prior to spraying. The vacuum evacuation may be to an atmosphere of from about 0.1 in Hg to perfectvacuum (i.e., 29.92 in Hg). The vacuum evacuation may be to an atmosphere of from about 5 in Hg to about 29 in Hg, from about 18 in Hg to about 29 in Hg, from about 21 in Hg to about 29 in Hg, or from about 22 in Hg to about 28 in Hg. In an embodiment, the atmosphere may be at about 22 in Hg. In another embodiment, the atmosphere may be at about 28 in Hg. In an embodiment, the atmosphere may be at about 20 mBar.

[0131] In any embodiment, the method of preparing an anti-infective composition may further comprise preparing the diclazuril sodium salt aqueous solution by mixing diclazuril, an alcohol, and an aqueous base. In any embodiment, the method of preparing an anti-infective composition may further comprise preparing the diclazuril sodium salt aqueous solution by mixing diclazuril, an alcohol, and an aqueous base in an intermediate tank. In any embodiment, preparing may further comprise an aqueous base that is not degassed. In any embodiment, preparing may further comprise degassing the aqueous base. In any embodiment, preparing may further comprise removing oxygen from the aqueous base. In any embodiment, preparing may further comprise drawing a vacuum to remove oxygen from the intermediate tank prior to mixing the aqueous base. In any embodiment, preparing may further comprise a nitrogen purge to remove oxygen from the intermediate tank prior to mixing the aqueous base.

[0132] In any embodiment, the method may further comprise heating or cooling the blender chamber so that a jacket in contact with the granules is at a temperature between about between about 10 °C and about 150 °C, between about 50 °C to about 100 °C, or between about 60 °C to about 80 °C. For example, the jacket in contact with the granules may be at a temperature of about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C, about 90 °C, about 95 °C, about 100 °C, about 105 °C, about 110 °C, about 115 °C, about 120 °C, about 125 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, or about 150 °C.

[0133] In any embodiment, the applying may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof at a substantially fixed spray rate from about 100 g / min to about 250 g / min, from about 120 g / min to about 230 g / min, from about 140 g / min to about 200 g / min. For example, the spray rate may be about 100 g / min, about 105 g / min, about 110 g / min, about 115 g / min, about 120 g / min, about 125 g / min, about 130 g / min, about135 g / min, about 140 g / min, about 145 g / min, about 150 g / min, about 155 g / min, about 160 g / min, about 165 g / min, about 170 g / min, about 175 g / min, about 180 g / min, about 185 g / min, about 190 g / min, about 195 g / min, about 200 g / min, about 205 g / min, about 210 g / min, about 215 g / min, about 220 g / min, about 225 g / min, about 230 g / min, about 235 g / min, about 240 g / min, about 245 g / min, about 250 g / min, or even more.

[0134] In any embodiment, the applying may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof at a rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 10,000 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 1,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 7,000 g / min, optionally from about 7,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 5,000 g / min to about 2,500 g / min, optionally from about 2,500 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, optionally from about 500 g / min to about 250 g / min, optionally from about 250 g / min to about 150 g / min, optionally from about 100 g / min to about 250 g / min, optionally from about 120 g / min to about 230 g / min, optionally from about 130 g / min to about 220 g / min, or optionally from about 140 g / min to about 200 g / min.

[0135] In any embodiment, the applying may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof for a duration from about 1 minute to about 60 minutes, optionally from about 5 minutes to about 60 minutes, optionally from about 5 minutes to about 50 minutes, optionally from about 5 minutes to about 45 minutes, optionally from about 5 minutes to about 40 minutes, optionally from about 5 minutes to about 35 minutes, optionally from about 5 minutes to about 30 minutes, optionally from about 5 minutes to about 25 minutes, optionally from about 5 minutes to about 20 minutes, optionally from about 5 minutes to about 15 minutes, optionally from about 5 minutes to about 10 minutes, optionally from about 2 minutes to about 45 minutes, optionally from about 2 minutes to about 35 minutes, optionally from about 2 minutes to about 30 minutes, optionally from about 2 minutes to about25 minutes, optionally from about 2 minutes to about 20 minutes, optionally from about 2 minutes to about 15 minutes, or from about 2 minutes to about 10 minutes.

[0136] In any embodiment of the method, the aqueous base may be an aqueous hydroxide. In any embodiment, the aqueous hydroxide may be at a concentration from about 0. 1 M to about 5 M, from about 0.3 M to about 2 M, or may be about 1 M. For example, the aqueous hydroxide may be at a concentration of exactly 0.1 M, about 0.1 M, about 0.5 M, about 1 M, about 1.5 M, about 2 M, about 2.5 M, about 3 M, about 3.5 M, about 4 M, about 4.5 M, about 4.9 M, about 5 M, or exactly 5 M. In any embodiment, the aqueous base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide and a mixture thereof.

[0137] In any embodiment, mixing diclazuril, the alcohol, and the aqueous base in the intermediate tank may include a first step of mixing the diclazuril with the alcohol and a second step of adding the aqueous base, wherein the aqueous base is added at a rate of greater than 1 minute and less than 60 minutes at a temperature from about 5 °C to about 50 °C.

[0138] In any embodiment of the method, the method may further comprise applying an antidusting oil to the anti-infective composition. In any embodiment, the method may further comprise applying an anti-caking agent to the anti-infective composition. In any embodiment, the anti -caking agent may be verxite.

[0139] In any embodiment of the method, the anti-infective composition may comprise between about 7 - 15% (wt / wt) narasin or pharmaceutically acceptable salt thereof and between about 0.01-5.0% (wt / wt) diclazuril or pharmaceutically acceptable salt thereof.

[0140] In any embodiment of the method, the granule may comprise about 10 wt% narasin or a pharmaceutically acceptable salt thereof, and the antiprotozoal agent may comprise about 2 wt% diclazuril sodium in aqueous solution. In any embodiment, the portion of the outer surface of the granule may comprise at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5%, at least 99.9%, or about 100% of the outer surface of the granule. In any embodiment, the portion of the outer surface of the granule may comprise substantially all ofthe outer surface of the granule. In any embodiment, the diclazuril sodium in aqueous solution may be applied to from about 80% to about 100% of the outer surface of the granule.

[0141] In any embodiment, the granule may comprise an inert carrier. In any embodiment, the inert carrier may comprise zeolite, cellulosic material, or a combination thereof. In any embodiment, the inert carrier may comprise rice hulls. In any embodiment, the zeolite may be a natural zeolite, a synthetic zeolite, or a combination thereof. In any embodiment, the zeolite may comprise clinoptilolite, mordenite, or any combination of clinoptilolite and mordenite.

[0142] In any embodiment, the method may further comprise applying an anti-dusting oil to the granules. The spray of the diclazuril aqueous solution and / or spray of the anti-dusting oil may be, without limitation, via any one of an aerosol propellant spray, atomized spray, film-forming spray, ordinal spray, metered dose spray, electrostatic spray, and / or ultrasonic spray.

[0143] In any embodiment, the anti-dusting oil may comprise a mineral oil, e.g., CAS number 8042-47-5, and may be free or substantially free of alkylphenol ethoxylates (including, e.g., nonylphenol ethoxylates), and / or free of silicon compounds. The anti-dusting oil may form a distinct second layer atop the first layer, or may form an emulsion with the first layer, or a form a second layer atop the first layer that is also partially emulsified with the first layer. In any embodiment, the method may further comprise applying an anti-caking agent to the granules. In any embodiment, the anti-caking agent may be verxite.

[0144] In still another aspect, the present disclosure provides a process for preparing a combination antiparasitic particle composition, the process comprising: coating a batch of granules, the granules comprising narasin or a pharmaceutically acceptable salt thereof, with an aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof.

[0145] In any embodiment of the process may further comprise forming the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof, wherein the forming comprises: dissolving solid diclazuril or a pharmaceutically acceptable salt thereof in an alcohol solvent, thereby generating a diclazuril-alcohol solution; removing O2 from atmosphere exposed to the diclazuril-alcohol solution; blanketing the diclazuril-alcohol solution in inert gas; and adding aqueous hydroxide to the diclazuril-alcohol solution, wherein the aqueous hydroxide comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, ammonium hydroxide, or a mixture thereof. In any embodiment, the inert gas maycomprise helium, neon, argon, krypton, xenon, N2, or any combination thereof. In any embodiment, the inert gas may be N2.

[0146] In any embodiment of the process, the aqueous hydroxide may be at a concentration from about 0. 1 M to about 5 M. For example, the aqueous hydroxide may be at a concentration of exactly 0.1 M, about 0.1 M, about 0.5 M, about 1 M, about 1.5 M, about 2 M, about 2.5 M, about 3 M, about 3.5 M, about 4 M, about 4.5 M, about 4.9 M, about 5 M, or exactly 5 M. In any embodiment, the aqueous hydroxide may be added over any suitable time interval, including, for example, less than 1 minute, about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or even more. The aqueous hydroxide may be added at a suitable temperature, including, for example, less than 10 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, or higher. In any embodiment, the aqueous hydroxide may be added at a rate of greater than 1 minute and less than 60 minutes at a temperature from about 5 °C to about 50 °C.

[0147] In any embodiment of the process, the granules may further comprise an inert carrier comprising zeolite, cellulosic material, or a combination of zeolite and cellulosic material. In any embodiment the granules may further comprise an inert carrier comprising rice hulls. In any embodiment, the zeolite may be a natural zeolite, a synthetic zeolite, or a combination thereof. In any embodiment, the zeolite may comprise clinoptilolite, mordenite, or any combination of clinoptilolite and mordenite.

[0148] In any embodiment, the process may further comprise forming the batch of granules, wherein the forming comprises: mixing an inert carrier comprising rice hulls with narasin or a pharmaceutically acceptable salt thereof in a vacuum blender; removing O2 from atmosphere in the vacuum blender; and setting a pressure inside the vacuum blender to under about 150 mBar. In any embodiment, the pressure inside the vacuum may be set to under about 150 mBar, about 145 mBar, about 140 mBar, about 135 mBar, about 130 mBar, about 125 mBar, about 120 mBar, about 115 mBar, about 110 mBar, about 105 mBar, about 100 mBar, about 95 mBar, about 90 mBar, about 85 mBar, about 80 mBar, about 75 mBar, about 60 mBar, about 55 mBar, about 50mBar, about 45 mBar, about 40 mBar, about 35 mBar, about 30 mBar, about 25 mBar, about 20 mBar, about 15 mBar, about 10 mBar, about 5 mBar, or less.

[0149] In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 50 g / min, optionally from about 20,000 g / min to about 10,000 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 1,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 7,000 g / min, optionally from about 7,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 5,000 g / min to about 2,500 g / min, optionally from about 2,500 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 10,000 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 1,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 7,000 g / min, optionally from about 7,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 5,000 g / min to about 2,500 g / min, optionally from about 2,500 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution under vacuum. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate fromabout 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 10,000 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 1,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 10,000 g / min to about 7,000 g / min, optionally from about 7,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 5,000 g / min to about 2,500 g / min, optionally from about 2,500 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution without the use of vacuum.

[0150] In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution under vacuum. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution without the use of vacuum.

[0151] For example, the substantially fixed spray rate may be about 50 g / min, about 55 g / min, about 60 g / min, about 65 g / min, about 70 g / min, about 75 g / min, about 80 g / min, about 85 g / min, about 90 g / min, about 95 g / min, about 100 g / min, about 105 g / min, about 110 g / min, about 115 g / min, about 120 g / min, about 125 g / min, about 130 g / min, about 135 g / min, about140 g / min, about 145 g / min, about 150 g / min, about 155 g / min, about 160 g / min, about 165 g / min, about 170 g / min, about 175 g / min, about 180 g / min, about 185 g / min, about 190 g / min, about 195 g / min, about 200 g / min, about 205 g / min, about 210 g / min, about 215 g / min, about 220 g / min, about 225 g / min, about 230 g / min, about 235 g / min, about 240 g / min, about 245 g / min, about 250 g / min, about 255 g / min, about 260 g / min, about 275 g / min, about 280 g / min, about 285 g / min, about 290 g / min, about 295 g / min, or about 300 g / min. The temperature may be, for example, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C, about 90 °C, or about 95 °C.

[0152] In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution. In any embodiment, the coating may comprise spraying from about 1 minute to about 60 minutes, optionally from about 5 minutes to about 60 minutes, optionally from about 5 minutes to about 50 minutes, optionally from about 5 minutes to about 45 minutes, optionally from about 5 minutes to about 40 minutes, optionally from about 5 minutes to about 35 minutes, optionally from about 5 minutes to about 30 minutes, optionally from about 5 minutes to about 25 minutes, optionally from about 5 minutes to about 20 minutes, optionally from about 5 minutes to about 15 minutes, optionally from about 5 minutes to about 10 minutes, optionally from about 2 minutes to about 45 minutes, optionally from about 2 minutes to about 35 minutes, optionally from about 2 minutes to about 30 minutes, optionally from about 2 minutes to about 25 minutes, optionally from about 2 minutes to about 20 minutes, optionally from about 2 minutes to about 15 minutes, optionally from about 2 minutes to about 10 minutes. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueoussolution under vacuum. In any embodiment, the coating may comprise spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution without the use of vacuum.

[0153] In any embodiment of the process, the process may further comprise coating the granules in anti-dusting oil. In any embodiment, the process may further comprise coating the granules in anti-caking agent. In any embodiment, the anti-caking agent may be verxite.

[0154] In any embodiment of the process, the combination antiparasitic particle composition may comprise from about 7 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof and about 0.01 wt% to about 5.0 wt% diclazuril sodium. In any embodiment of the process, the combination antiparasitic particle composition may comprise from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof and about 0.5 wt% to about 2.0 wt% diclazuril sodium. In any embodiment of the process, the combination antiparasitic particle composition may comprise from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof and about 0.01 wt% to about 2.0 wt% diclazuril sodium.

[0155] In yet another aspect, the present disclosure provides a method of preventing or treating a coccidian infection in a fowl, the method comprising administering to the fowl a therapeutically effective amount of an embodiment of the composition formulated for administration to an animal provided in the present disclosure. In any embodiment, the coccidian may be an Eimeria species. In any embodiment, the species may be E. brunetti, E. necatrix, E. tenella, E. acervulina, E. maxima E. mitis, E. praecox, or any combination thereof. In any embodiment, the coccidian may be E. acervulina, E. maxima, E. tenella, or any combination thereof.

[0156] In any embodiment of the method of preventing or treating a coccidian infection in a fowl, the composition may be administered for at least three consecutive grow cycles in grower feed without emergence of any Eimeria strain resistant to diclazuril, resistant to narasin, or resistant to both diclazuril and narasin. In any embodiment of the method of preventing or treating a coccidian infection in a fowl, the composition may be administered for at least threeconsecutive grow cycles in finisher feed without emergence of any Eimeria strain resistant to diclazuril, resistant to narasin, or resistant to both diclazuril and narasin.

[0157] In still another aspect, the present disclosure provides the use of a therapeutically effective amount of an embodiment of composition formulated for administration to an animal provided in the present disclosure for manufacture of a medicament for treatment of a coccidian infection in a fowl. In any embodiment, the coccidian may be an Eimeria species. In any embodiment, the species may be E. brunetti, E. necatrix, E. tenella, E. acervulina, E. maxima, E. mitis, E. praecox, or any combination thereof.

[0158] Additional embodiments, features, and advantages of the disclosure will be apparent from the detailed description and through practice of the disclosure.

[0159] Embodiments may be further understood, without limitation, by reference to the following clauses:

[0160] Clause 1. A composition formulated for administration to an animal comprising: a core particle having an outer surface, the core particle comprising narasin or a pharmaceutically acceptable salt thereof; and a first layer at least partially covering the outer surface of the core particle, the first layer comprising diclazuril or a pharmaceutically acceptable salt thereof.

[0161] Clause 2. The composition of clause 1, wherein the mass ratio of the narasin to the diclazuril is between about 20: 1 and about 100:1, optionally between about 30:1 and about 90: 1, optionally between about 40: 1 and about 80: 1, optionally between about or about 50: 1 and optionally about 70: 1, or about 60: 1.

[0162] Clause 3. The composition of clause 2, wherein the composition comprises between about 40 ppm and about 140 ppm narasin and between about 0.5 ppm and about 2 ppm of diclazuril, optionally between about 50 ppm and about 100 ppm narasin and between about 0.7 ppm and about 1.3 ppm of diclazuril, optionally between about 50 ppm and about 80 ppm narasin and between about 0.7 ppm and about 1 ppm of diclazuril.

[0163] Clause 4. The composition of any one of clauses 1-3, wherein the core particle comprises from about 7 wt% to about 12 wt% narasin, optionally from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof.

[0164] Clause 5. The composition of any one of clauses 1-4, wherein the core particle comprises from about 88 wt% to about 92 wt% of an inert carrier comprising zeolite, a cellulosic material, or both zeolite and a cellulosic material.

[0165] Clause 6. The composition of any one of clauses 1-5, wherein the core particle comprises a marumerized particle having an oblong shape profile.

[0166] Clause 7. The composition of any one of clauses 1-6, wherein the first layer comprises between about 0.01 and 5.0 wt% diclazuril or a pharmaceutically acceptable salt thereof.

[0167] Clause 8. The composition of any one of clauses 1-7, wherein the first layer comprises between about 0.01 and 2.0 wt% diclazuril or a pharmaceutically acceptable salt thereof.

[0168] Clause 9. The composition of any one of clauses 1-8, wherein the composition comprises less than about 0.2% of diclazuril degradant R064318.

[0169] Clause 10. The composition of any one of clauses 1-9, further comprising a second layer at least partially covering the outer surface of the core particle, the second layer comprising an anti-dusting oil.

[0170] Clause 11. The composition of clause 10 comprising between about 0.01 wt% to about 2 wt% of the anti-dusting oil.

[0171] Clause 12. The composition of any one of clauses 1-11, wherein the core particle further comprises an inert carrier comprising a zeolite, a cellulosic material, or both a zeolite and a cellulosic material.

[0172] Clause 13. The composition of clause 5-12, wherein the cellulosic material is rice hulls.

[0173] Clause 14. The composition of any one of clauses 1-13, wherein the animal is selected from the group consisting of a bird, a mammal, or a fish.

[0174] Clause 15. The composition of any one of clauses 1-14, wherein composition is stable for at least six months at 25 °C and 60% relative humidity.

[0175] Clause 16. The composition of any one of clauses 1-15, wherein composition is stable for at least two years at 40 °C and 75% relative humidity.

[0176] Clause 17. The composition of clause 1-16, wherein the composition is configured such that the narasin or a pharmaceutically acceptable salt thereof and the diclazuril or a pharmaceutically acceptable salt thereof are assayable at least about 90% of an original potency after 2 years.

[0177] Clause 18. The composition of clause 1-17, wherein the composition is configured such that the composition comprises less than about 0.2% of diclazuril degradant, R064318 after six months at 25 °C and 60% relative humidity.

[0178] Clause 19. The composition of clause 1-18, wherein the composition is configured such that the composition comprises less than about 0.2% of diclazuril degradant, R064318 after two years at 40 °C and 75% relative humidity.

[0179] Clause 20. A method of preparing an anti-infective composition, the method comprising: applying a coating comprising diclazuril or a pharmaceutically acceptable salt thereof to at least a portion of an outer surface of a granule comprising narasin or a pharmaceutically acceptable salt thereof.

[0180] Clause 21. The method of clause 20, wherein applying comprises spraying a diclazuril sodium salt aqueous solution onto the outer surface of the granule.

[0181] Clause 22. The method of clause 21, wherein the spraying occurs within a blender chamber, the blender chamber being vacuum evacuated prior to spraying.

[0182] Clause 23. The method of any one of clauses 20-21, wherein the method further comprises preparing the diclazuril sodium salt aqueous solution by mixing diclazuril, an alcohol, and an aqueous base in an intermediate tank.

[0183] Clause 24. The method of clause 23, wherein preparing further comprises degassing the aqueous base. The method of clause 23, wherein preparing further comprises removing oxygen from the aqueous base.

[0184] Clause 25. The method of clause 24, wherein preparing further comprises drawing a vacuum to remove oxygen from the intermediate tank prior to mixing the aqueous base. The method of clause 24, wherein preparing further comprises a nitrogen purge to remove oxygen from the intermediate tank prior to mixing the aqueous base.

[0185] Clause 26. The method of clause 23, wherein preparing further comprises an aqueous base that is not degassed.

[0186] Clause 27. The method of any one of clauses 20-26, wherein the method further comprises applying the coating to an outer surface of a diluent particle.

[0187] Clause 28. The method of clause 27, wherein the diluent particle comprises zeolite or rice hulls.

[0188] Clause 29. The method of any one of clauses 22-28, further comprising heating or cooling the blender chamber so that a jacket in contact with the granules is between about 10 °C and about 150 °C, between about 20 °C and about 140 °C, between about 30 °C and about 130 °C, between about 40 °C and about 120 °C, between about 50 °C to about 100 °C, between about 60 °C and about 90 °C, or between about 60 °C to about 80 °C.

[0189] Clause 30. The method of any one of clauses 20-29, wherein the applying comprises spraying at a rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, from about 100 g / min to about 250 g / min, from about 120 g / min to about 230 g / min, from about 130 g / min to about 220 g / min, from about 140 g / min to about 200 g / min. The method of any one of clauses 20-29, wherein the spraying comprises spraying from about 1 minute to about 60 minutes, optionally from about 5 minutes to about 60 minutes, optionally from about 5 minutes to about 50 minutes, optionally from about 5 minutes to about 45 minutes, optionally from about 5 minutes to about 40 minutes, optionally from about 5 minutes to about 35 minutes, optionally from about 5 minutes to about 30 minutes, optionally from about 5 minutes to about 25 minutes.

[0190] Clause 31. The method of any one of clauses 23-30, wherein the aqueous base is an aqueous hydroxide.

[0191] Clause 32. The method of any one of clauses 23-31, wherein the aqueous base is at a concentration from about 0.1 M to about 5 M, from about 0.3 M to about 2 M, or about 1 M.

[0192] Clause 33. The method of any one of clauses 23-32, wherein the aqueous base is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide and a mixture thereof.

[0193] Clause 34. The method of any one of clauses 23-33, wherein mixing diclazuril, the alcohol, and the aqueous base in the intermediate tank includes a first step of mixing the diclazuril with the alcohol and a second step of adding the aqueous base, wherein the aqueous base is added at a rate of greater than 1 minute and less than 60 minutes at a temperature from about 5 °C to about 50 °C.

[0194] Clause 35. The method of any one of clauses 20-34, further comprising applying an anti-dusting oil to the anti -infective composition.

[0195] Clause 36. The method of any one of clauses 20-35, further comprising applying an anti-caking agent to the anti-infective composition.

[0196] Clause 37. The method of clause 36 wherein the anti-caking agent is verxite.

[0197] Clause 38. The method of any one of clauses 20-37, wherein the anti-infective composition comprises between about 7 - 15% (wt / wt) narasin or pharmaceutically acceptable salt thereof and between about 0.01 - 2.0% (wt / wt) diclazuril or pharmaceutically acceptable salt thereof.

[0198] Clause 39. A process for preparing a combination antiparasitic particle composition, the process comprising: coating a batch of granules, the granules comprising narasin or a pharmaceutically acceptable salt thereof, with an aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof.

[0199] Clause 40. The process of clause 39, further comprising forming the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof, wherein the forming comprises: dissolving solid diclazuril or a pharmaceutically acceptable salt thereof in an alcohol solvent, thereby generating a diclazuril-alcohol solution; removing O2 from atmosphere exposed to the diclazuril-alcohol solution; blanketing the diclazuril-alcohol solution in inert gas; and adding aqueous hydroxide to the diclazuril-alcohol solution, wherein the aqueous hydroxide comprises sodium hydroxide, potassium hydroxide, ammonium hydroxide, or a mixture thereof.

[0200] Clause 41. The process of any one of clauses 39-40, wherein the granules further comprise an inert carrier comprising zeolite, cellulosic material, or a combination of zeolite and cellulosic material.

[0201] Clause 42. The process of any one of clauses 39-41, wherein the granules further comprise an inert carrier comprising rice hulls.

[0202] Clause 43. The method of any one of clauses 39-42, further comprising forming the batch of granules, wherein the forming comprises: mixing an inert carrier comprising rice hulls with narasin or a pharmaceutically acceptable salt thereof in a vacuum blender; removing O2 from atmosphere in the vacuum blender; and setting a pressure inside the vacuum blender to under about 150 mBar.

[0203] Clause 44. The method of any one of clauses 39-43, wherein the coating comprises: spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 50 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, optionally from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution under vacuum. The method of any one of clauses 39-43, wherein the coating comprises: spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 50 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, optionally from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution without the use of vacuum.

[0204] Clause 45. The method of any one of clauses 39-43, wherein the coating comprises spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes. The method of any one of clauses 39-43, wherein the coating comprises spraying the aqueoussolution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution under vacuum. The method of any one of clauses 39-43, wherein the coating comprises spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes and at a temperature from about 20 °C to about 95 °C, optionally from about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution without the use of vacuum.

[0205] Clause 46. The method of any one of clauses 39-45, further comprising coating the granules in anti-dusting oil.

[0206] Clause 47. The method of any one of clauses 39-46, further comprising coating the granules in anti-caking agent.

[0207] Clause 48. The method of clause 47 wherein the anti-caking agent is verxite.

[0208] Clause 49. The method of any one of clauses 39-48, wherein the combination antiparasitic particle composition comprises from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof and about 0.01 wt% to about 2.0 wt% diclazuril sodium.

[0209] Clause 50. A method of preventing and / or treating a cocci dian infection in a nonhuman animal, the method comprising administering to the non-human animal a therapeutically effective amount of the composition of any one of clauses 1-19.

[0210] Clause 51. The method of clause 50, wherein the non-human animal is a non-human mammal, a bird, a fish, or a reptile.

[0211] Clause 52. The method of clause 50, wherein the bird is a fowl.

[0212] Clause 53. The method of clause 50, wherein the non-human mammal is a cat, dog, pig, horse, cow, donkey, goat, or sheep.

[0213] Clause 54. The use of a therapeutically effective amount of the composition of any one of clauses 1-19 for manufacture of a medicament for treatment of a coccidian infection in a non-human animal.

[0214] Clause 55. The use of clause 54, wherein the non-human animal is a non-human mammal, a bird, a fish, or a reptile.

[0215] Clause 56. The use of clause 55, wherein the bird is a fowl.

[0216] Clause 57. The use of clause 55, wherein the non-human mammal is a cat, dog, pig, horse, cow, donkey, goat, or sheep.

[0217] Clause 58. A feed additive comprising the composition of any one of clauses 1-19.

[0218] Clause 59. An animal feed comprising the composition of any one of clauses 1-19.

[0219] Clause 60. The animal feed of clause 59, wherein the composition is present in an amount of from between about 0.01 wt% and 15wt% of the animal feed.EXAMPLES EXAMPLE 1 FORMULATION OF SOLUBLE DICLAZURIL SALT FOR LAYER FORMATION

[0220] Diclazuril was synthesized by reaction of (±)-4-amino-2,6-dichloro-a-(4- chlorophenyl)benzeneacetonitrile monohydrochloride with dibutyl AyV'-(l,3-dioxo-l,3- propanediyl) biscarbamate at a molar ratio of 1.000 : 1.052. The reaction product was crystalized to form diclazuril, which is highly insoluble in water. The low aqueous solubility and other properties of diclazuril present significant difficulties with regard to getting the compound into sprayable solution usable in a multi-layer composition.

[0221] Since diclazuril is practically insoluble in water and has relatively low solubility in other commonly used solvents such as ethanol, dissolution experiments were needed to generate a proper solution that can be sprayed as a layer on narasin without negatively affecting the quality of the narasin. Extensive experimentation was conducted to establish an appropriate salt form of diclazuril for making the core particle / shell product.

[0222] It was advantageously discovered that for making a coating layer, a solution with a salt of diclazuril can be formed by reacting diclazuril with an aqueous hydroxide, such as, e.g., forming diclazuril sodium by reacting diclazuril with sodium hydroxide. The sodium salt of diclazuril dissolves readily in water. It was determined that the moles of sodium hydroxide to moles of diclazuril should be at least about 1 : 1 for completing the acid-base reaction and thus salt formation.

[0223] During experiments establishing which salts would be most advantageous, it was seen that the process of converting crystalline diclazuril into diclazuril salt generates degradation byproducts. Treatment with alkaline hydroxides is understood to have caused a ketone group to replace the methyl-nitrile group of diclazuril, generating undesirable degradation product R064318, 2-[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]-l,2,4-triazine-3,5(27 / ,47y)-dione.Extensive experimentation revealed conditions favorable for diclazuril salt formation while minimizing formation of R064318.Diclazuril degradant species R064318, 2-[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]-l,2,4- triazine-3,5(2 / / ,4 / / )-dione

[0224] One experiment was to screen different normalities of alkaline hydroxide (e.g., sodium hydroxide) at varying mole equivalents with respect to diclazuril and varyingtemperatures at the time of alkaline hydroxide addition. Sodium hydroxide (NaOH) was selected as the hydroxide, with a goal of converting crystalline diclazuril into diclazuril sodium salt. Changing the normality of the sodium hydroxide solution varied the amount of water in the final formulation. The amount of excess sodium hydroxide required was tested by varying the normality of the sodium hydroxide solution and volume added. In one such experiment, sixteen different formulations, described in Table 1 below, were prepared to screen for potential issues before performing a second DoE to optimize the parameters.Table 1. Test solutions for Salt Solution Screening

[0225] The target concentration of the solution was kept fixed at 6.5% diclazuril and a target solution volume of 100 m . The amount of isopropyl alcohol (also known as IPA or 2-propanol) varied between solution makeups to account for volume differences. The parameters for the experiment were based upon preliminary experiments conducted. The initial work showed that complete dissolution was a challenge utilizing a 1 : 1 mole:mole ratio of diclazuril to sodium hydroxide.

[0226] Physical observation of test solutions found that five of them were fully soluble and had little to no visible particles. The only samples showing complete dissolution were samplesthat utilized the 1 N sodium hydroxide solution. The addition of sodium hydroxide at a lower concentration will lead those samples to have more water present in the solution. It was expected that the difference in water content was influencing the solubility of the sodium salt of diclazuril.

[0227] The solutions that were fully solubilized were diluted in A,A-dimethyacetamide (DMA) for injection on High Performance Liquid Chromatography (HPLC) for potency and impurity analysis. The undiluted solutions were kept under N2 and reanalyzed at 24 hours and 96 hours to check for additional degradation over time.

[0228] From the HPLC analysis of the amount of degradation product / related substances (e g., degradation product RS064318), the physical observation of color trends with the formation of degradation product. Darker color solutions had more degradation product. While none of the studied conditions met the desired 0.2 % degradant level, the data indicated potential trends with temperature and degradation product formation that were used for the design of the next solution designed experiment with narrower range on sodium hydroxide concentration, molar ratio of diclazuril to sodium hydroxide, and temperature.

[0229] In another experiment focused on testing IN and 2N sodium hydroxide at 1.02 and 1.05 moles equivalents with respect to Diclazuril. Table 2, below, outlines the eight different formulations that were prepared. The target concentration of the solution was kept fixed at 6.5% and a target solution volume of 100 mL. Hence, the amount of IP A varied between solution make up to account for the volume differences. In this experiment, no nitrogen overlay was utilized and the NaOH solution was slowly added to the isopropanol + diclazuril mixture over a short period of time (about 30 seconds). The temperature upon addition of NaOH was also tested at 37 °C and 50 °C.Table 2. Test solutions for second Salt Solution Screening

[0230] The solutions were diluted with A,A-dimethyacetamide (DMA) for injection on High Performance Liquid Chromatography (HPLC) for potency and impurity analysis (data shown in Table 3, below).Table 3. HPLC Results from experiment, with peak areas calculated at 214nm versus total area

[0231] The solutions prepared in 1 N sodium hydroxide were fully soluble, but the 2 N sodium hydroxide conditions did not stay soluble. After 15 minutes the solutions prepared with 2 N sodium hydroxide began to show precipitation. The HPLC analysis showed that all conditions had higher than the desired amount of diclazuril degradant, R064318 (greater than 0.2 %). The analysis also showed that there were higher levels of degradants present when 1.05 molar equivalents of sodium hydroxide were used to form the sodium salt of diclazuril. Further it was seen that the color and present degradants were higher with the higher temperature conditions. Since all solutions prepared had a degradant level above the target value of 0.2%, a thorough investigation of the transferred analytical method from Basel initiated. The area of focus was the formation of primary degradant observed. The specific initial focus of the investigation was with the diluent used to prepare the samples prior to the HPLC analysis, and to determine if the diluent was facilitating the formation of degradant.

[0232] The diluents selected to screen were; Dimethylacetamide (DMA), Dimethylformamide (DMF), Dimethylformamide-Hydrochloric Acid 2500:1 v / v (DMF-HC1), and Dimethylformamide with 2.5 mg / mL Butylated Hydroxytoluene (DMF-BHT). Thescreening was conducted by preparing two diclazuril solutions, one at 37 °C and one at 50 °C, and diluting aliquots of the same solution with the four different diluents for HPLC analysis.

[0233] When looking at the different degradant amounts from the use of different diluents, it was found that it was important to utilize the actual concentration of the degradant (R064318) and not just compare the peak areas, as the peak areas give a result over 2x that of the actual concentration as calculated from use of the reference standard. The analysis of the impact of diluents on different solution conditions was then looked at in terms of the actual concentrations of diclazuril and the degradation product R064318. The amount of degradant (R064318) did appear to be impacted by the diluent used for HPLC analysis. To verify that this was a reaction and not a difference in solubility of the degradant in the diluent system, a spiking study was conducted. The spiking study was conducted by adding a known amount of the R064318 degradant standard into a solution of diclazuril. The spiking study showed for the limited size of the study that there was not a significant difference in recovery from the different diluent systems. Then a non-spiked study was conducted with the preparation of diclazuril in each of the diluent systems.

[0234] This study showed that the use of DMF and DMF-BHT produced conditions that cause the formation of the diclazuril degradant product (R064318). Further, the investigation into diluents showed that DMA was the correct diluent to use when preparing materials for analysis. Overall the study showed that a slight molar excess of sodium hydroxide to form the sodium salt of diclazuril at lower temperature formed less of the degradant product R064318. The study also showed that the amount of degradant R064318 should be determined using a standard curve and not estimated by peak area. The estimation from peak area over estimates the content by roughly 2.2 times the actual content. A follow up experiment will focus in on deeper understanding on the required molar excess of sodium hydroxide and temperature.

[0235] The third diclazuril salt solution study was focused on producing the diclazuril solution with less than 0.2 % of the diclazuril degradant (R064318). The process was executed with the use of nitrogen purging of diclazuril and denatured ethanol solution prior to the addition of sodium hydroxide, and the sodium hydroxide was added slowly to make the diclazuril salt solution using an inert gas overlay, in this case nitrogen.

[0236] The experimentation focused on four different solution preparations: (1) 10% diclazuril with 1.01 molar equivalents NaOH heated to 37 °C; (2) 10% diclazuril with 1.02 molar equivalents NaOH heated to 37 °C; (3) 10% diclazuril with 1.02 molar equivalents NaOH prepared at room temperature; and (4) 10% diclazuril with 1.05 molar equivalents NaOH heated to 37 °C.

[0237] The solution with 1.05 molar equivalents of sodium hydroxide was included as an experimental control. These conditions had been included in previous experimental designs that were not as focused at reducing the exposure of the diclazuril solution from oxygen allowing for better comparison of the effects of the study to the previous studies. The experimental process for each of the conditions was to first weigh up the glass bottle, lid, and stir bar. Then by weight add the targeted amount of diclazuril. Then add the 2-propanol by weight. A nitrogen purge system was arranged with glassware.

[0238] The solution was then heated to the desired temperature and sodium hydroxide solution was then added in a dropwise manner. This allowed for controlled addition rate of the sodium hydroxide solution. At the end of the addition time, the final weight of bottle, lid, stir bar and solution were measured to determine the expected final concentration. Each of the four solutions of diclazuril sodium salt solutions was diluted into two different matrices (DMA and DMF-HCL) and analyzed with two different injection volumes (2 and 5 microliters) into the analytical method. The samples were then analyzed for the content of the degradation product R064318.

[0239] The multiple dilution matrices were utilized to make sure the dilution process was not causing the formation of the degradant (R064318). The physical observation showed that the DMA led to a final solution that was slightly pale yellow in color and had higher levels of R064318. The solutions diluted with DMF-HC1 resulted in lower R064318 with a clear and colorless solution. Further analytical analysis utilized DMF-HC1 with a 2500 to 1 dilution and 2 microliter injection volume.

[0240] The analysis of the diclazuril content by HPLC for the four solutions showed that it was possible to make the 10% solution of diclazuril. The review of the degradation product showed that (1) temperature was important, and room temperature was better than heated; (2) thediluent for preparing analysis samples mattered; (3) there was no statistical difference between 1.01 and 1.02 molar equivalents of sodium hydroxide in solution formation.

[0241] Based on these experiments, it was determined that the optimal approach would be using 1 N sodium hydroxide with 1.02 molar ratio to diclazuril, conducting the reaction at room temperature, not utilizing overage of diclazuril, and using DMF-HC1 with 2500-to-l dilution ratio to prepare analysis samples.EXAMPLE 2GRANULE INERT CARRIER OPTIMIZATION

[0242] A series of solution optimization studies were executed and resulted in a solution makeup process that allows for formation of diclazuril salt without formation of significant formation of degradation products such as R064318, and optimal spray application conditions.

[0243] The composition of the present disclosure may be formed by dissolving diclazuril in a solution and spraying onto a mixture of narasin granules and an inert carrier, such as zeolite or rice hulls, in a heated vacuum blender with to target a narasin potency of 10% and diclazuril potency of 0.2%. Early formulation screens were conducted to identify the appropriate inert carrier to mix with narasin granules and were narrowed down to zeolite and rice hulls. Narasin granule potency ranges from 13-16% so a dilution step is required to target the 10% inclusion rate. Following these early formulation screenings, a series of experiments were executed to identify optimal composition manufacture processes and requirements.

[0244] A first experiment was executed to investigate type of diluent, anti-caking agent, solution spray rate, and solution size. (Note: the solution studies were executed after the execution of this study; hence, why the molar excess of NaOH used in this study was 1.06.) Solution size can affect homogeneity as well as the rate the solution is sprayed onto the narasin / carrier mixture. In addition, lumping can be an issue with this type of medicated feed so an anti-caking agent (verxite) was added at either 1% or 3%. Finally, two carriers were investigated zeolite and rice hulls. Other parameters remained constant for all batches in this experiment: diclazuril potency of 0.2% with 9% overage, narasin potency of 10%, sodium hydroxide moral excess of 1.06 with solution prepared without nitrogen gas overlay, batch size of 40 kilograms, and no anti-dusting oil used. On average, formulations with rice hulls showed better homogeneity than zeolite and with the 9% overage, the target of 2 mg / g was achieved forthe majority of the batches. Dustiness and lumping were also measured. Dustiness performance was better for rice hulls than zeolite for all batches. Most batches showed no lumping.

[0245] The data from the experimentation was considered to complete a qualitative assessment of suitability of the two different carriers. After a thorough head-to-head analysis of rice hulls versus zeolite, it was concluded that the optimal diluent was rice hulls and thus, rice hulls were chosen for future optimization studies. In addition, two batches were placed in stability analyses. All the stability studies were conducted at two different conditions 25 °C and 60% relative humidity and 40 °C and 75% relative humidity. Both of the formulations with rice hulls put onto stability demonstrated acceptable stability.

[0246] The conclusions from this study were that anti -caking agent could be used but no anti-caking agent was required, the product had a low dust index, the solution size did not have a significant effect on the homogeneity of the premix, the rate of the solution spray did not have a significant impact on the premix homogeneity, narasin and diclazuril had acceptable homogeneity, and both of the active ingredients (narasin and diclazuril) are stable for 24 months in these formulations.EXAMPLE 3DICLAZURIL SOLUTION APPLICATION

[0247] A series of solution experiments were executed and resulted in a robust solution makeup process that allows for the formation of diclazuril salt without the significant formation of the R064318 degradant. Additionally, there were studies being executed testing an even lower inclusion rate of diclazuril of 0.1% versus the original target of 0.2%. For this reason, an experimental was developed to investigate the effect of solution size on homogeneity while investigating jacket temperature. Additionally the experimentation would be evaluating if an overage would be needed to meet target potency. It was found during the preparation of the diclazuril salt solution for the low inclusion rate of 0.61% and the solution size of 4% batches, incomplete dissolution of diclazuril was observed due to the low water content in these solution. Therefore, for these formulations, the sodium hydroxide solution concentration was decreased to 0.5N to increase the amount of water during the solution preparation step. Furthermore, an additional batch was also added to the study that included adding diclazuril as a powder without preparing a solution. This was added to investigate the homogeneity of adding the diclazurilwithout a spray step. Controlled parameters in these experiments included maintaining sodium hydroxide at 1.02 moral excess, batch size of 50 kilograms, and fixed spray rate.

[0248] Batches were tested with diclazuril content of 0.01% and 0.02%; at diclazuril overage of 0% and 10%; and at blender jacket heat temperatures of 60 °C and 80 °C. After the blending of the different conditions for the experiment, the samples were analyzed. Confirmation batches met preliminary specifications for the multi-layered composition.

[0249] Two formulations — those were 0.02% diclazuril, 0% diclazuril overage, and 80 °C blend temperature, and 0.02% diclazuril, 10% diclazuril overage, and 80 °C blend temperature — were found to have optimal overall performance, and were selected for long-term stability testing at 25 °C and 60% relative humidity and at 40 °C and 75% relative humidity for 24 months in foil-lined bags and paper bags. Test batches showed strong long-term stability for both active ingredients. As previously observed, there was no significant increase in the level degradation product R064318 at 25 °C and 60% relative humidity or at 40 °C and 75% relative humidity. In addition, this study had two packaging configurations that were being tested. Even with moisture incursion into the product using a paper bag (no foil lined), the product remains stable.EXAMPLE 4NARASIN MANUFACTURING PROCESS

[0250] Narasin (and pharmaceutically acceptable homologs) are products of fermentation of Streptomyces aureofaciens strains NRRL 5758 and / or NRRL 8092 (or derivative strains therefrom). Narasin is produced in submerged fermentation in aerated tanks. The fermentation system is maintained under controlled conditions of aeration, agitation, pH, and temperature. The broth medium is harvested and narasin extracted through a series of evaporation, centrifugation, and distillation steps. The narasin product is dried, pellet milled, size screened, blended into homogeneous lots, and packaged.EXAMPLE 5MULTI-LAYER COMPOSITION MANUFACTURE PROCESS

[0251] Diclazuril, as described elsewhere in the present disclosure, is not soluble in water, and thus to be dissolved in a sprayable solution must first be converted into diclazuril salt. (See Figs. 1, 5.)

[0252] Thus, according to one exemplary formulation of the multi-layered composition, in step 1, granulated dry narasin, rice hulls or zeolite carrier, and recycled material (not more than 10 percent from previous batches) are added to a vacuum blender. (Fig. 3 A.) A preliminary moisture content is measured for determination of later drying endpoint.

[0253] In step 2, the aqueous diclazuril solution is prepared. (Fig. 3B.) First, the solution preparation tank is purged with nitrogen gas. Then, required amounts of ethanol and diclazuril are charged. While mixing the diclazuril and ethanol, sodium hydroxide solution is added at a controlled rate to produce diclazuril sodium and facilitate diclazuril dissolution.

[0254] In step 3, vacuum is pulled on the blender containing the blended dry ingredients of step 1, thereby removing O2 and allowing for establishment of an inert-gas atmosphere using, e.g., nitrogen. (Fig. 3C.)

[0255] In step 4, the diclazuril solution is sprayed at a controlled rate onto the blend of dry materials while the blender is mixing, the blender jacket is heated, under vacuum, and under nitrogen atmosphere. (Fig. 3D.)

[0256] In step 5, after the completion of the diclazuril solution addition, the blender mixing continues, and blender is maintained under vacuum and heated jacket. The product temperature is monitored and the loss-on-drying (“LOD”) is monitored to determine the drying endpoint. (Fig. 3E.)

[0257] In step 6, anti-dusting oil is added to the product while blender is mixing. After addition of the anti-dusting oil, the vacuum is released, blender jacket cooled, and product released into a hopper. (Fig. 3F.)

[0258] In step 7, the formulated product is fed from the hopper to bagging. The material is bagged and weighed and samples are taken and tested. The bagged product is stacked on pallets and stored in a warehouse until released for distribution. (Fig. 3G.)EXAMPLE 6PREVENTION OF PARASITIC INFECTION IN ANIMALS IN NEED THEREOF

[0259] In an example, the multi-layered composition is a 10 wt% narasin granule on rice hull carrier coated in 0.02 wt% diclazuril sodium. A 40kg batch of the multi-layered composition is bagged and shipped to a commercial poultry farm raising flocks of broiler chickens.

[0260] From day 1 of hatching and up to day of slaughter, the multi-layered composition is mixed into un-medicated chicken feed at a ratio of 1 :2000, about 1 : 1500, about 1 : 1000, about 1 :900, about 1 :800, about 1 :700, about 1:600, about 1 :500, about 1 :400, about 1 :300, about 1 :250, about 1 :200, about 1 : 150, about 1 : 100, about 1 :50, about 1 :25, or about 1 : 10. The flock is fed the mixed feed up to the day of slaughter.

[0261] The combination of narasin and diclazuril sodium prevents the chickens from being infected with protozoan parasites such as Eimeria, thereby preventing avian coccidiosis.EXAMPLE 7TREATMENT OF PARASITIC INFECTION IN ANIMALS IN NEED THEREOF

[0262] In an example, the multi-layered composition is a 10 wt% narasin granule on rice hull carrier coated in 0.02 wt% diclazuril sodium. A 40kg batch of the multi-layered composition is bagged and shipped to a commercial poultry farm raising flocks of broiler chickens. The batch is shelf-stable and kept on-site until needed.

[0263] Broiler chickens become infected with avian coccidiosis caused by an Eimeria sp. parasite. The multi-layered composition is mixed into un-medicated chicken feed at a ratio of 1 :200. The flock is fed the 1 :200 mixed feed, thereby treating the individuals with active protozoan parasite infection and preventing transmission of infection to healthy individuals.EXAMPLE 8EFFICACY AGAINST DRUG RESISTANT EMERIA STRAINS

[0264] Separate groups of chickens were challenged with diclazuril resistant Eimeria and narasin resistant Eimeria. A negative control group was not challenged.

[0265] Diclazuril 1 ppm was effective in treating narasin resistant Eimeria, and narasin 60 ppm was effective in treating diclazuril resistant Eimeria. (Figs. 7A-7C.) Combination diclazuril 1 ppm + narasin 60 ppm (labeled as “Gigaban” in Figs. 7A-7C) was effective in treating both narasin resistant Eimeria and diclazuril resistant Eimeria.EXAMPLE 9NO SIGNS OF EMERGENT DRUG RESISTANT EIMERIA IN CHICKENS TREATEDWITH COMBINATION THERAPEUTIC

[0266] Test groups of about 4,000 chickens infected with Eimeria were divided into an experimental group and an untreated control group. The experimental groups were treated with narasin + diclazuril for five consecutive feed cycles. The narasin + diclazuril combination therapeutic maintained efficacy in all measured outputs, e.g, average daily weight gain, feed conversion efficiency, E. acervulina lesion score, E. maxima lesion score, and E. tenella lesion score. (Fig. 8A.) As further measured by oocyst counts, no resistance to narasin or diclazuril emerged after five growth cycles. (Fig. 8B.)EXAMPLE 10EFFICACY OF COMBINATION THERAPEUTIC SUPERIOR TO NARASIN ALONE

[0267] As shown in Figs. 9A-9E, combination therapeutic is superior to narasin alone. The average daily weight gain was higher than that observed with narasin alone for all combinations tested. For instance, the average daily weight gain was about 37% higher than that observed with only narasin when a combination therapeutic comprising 60ppm Narasin + Ippm diclazuril was administered (Figure 9A). Similarly, the average daily weight gain was about 28% higher than that observed with only narasin when a combination therapeutic comprising 50ppm Narasin + Ippm diclazuril was administered, and about 32% higher than that observed with only narasin when a combination therapeutic comprising 70ppm Narasin + Ippm diclazuril was administered (Figure 9A).

[0268] Further, the feed efficiency, and the average lesion scores were all lower than that observed with narasin alone for all combinations tested (Figures 9B-9E).EXAMPLE 11 EFFICACY OF COMBINATION THERAPEUTIC SUPERIOR TO SALINOMYCIN ALONE

[0269] Efficacy of diclazuril 1 ppm + narasin 50 ppm (Interban 50 / 1) as measured by feed conversion efficiency was superior to that of salinomycin (Sacox) when used during the same feeding phase. (Figs. 11A-1 IB) For instance, the feed conversion efficiency for day 21 to 28 was 1.813 for Sacox as compared to 1.6041 for Interban.EXAMPLE 12EFFICACY OF COMBINATION THERAPEUTIC IS SUPERIOR TO EITHER INDIVIDUAL DRUG ALONE

[0270] As shown in Figs. 10A-10B, the efficacy of combination therapeutic is superior to either individual drug alone. As shown in Figure 10A, the average daily weight gain was about 26% higher than that observed with only narasin when a combination therapeutic comprising 40ppm Narasin + 0.8ppm diclazuril was administered.EXAMPLE 13 SEM CHARACTERIZATION

[0271] Exemplary uncoated narasin (SEM images in Figs. 12A-E, 13A-E, and 14A-E) and exemplary narasin coated in accordance with an exemplary process disclosed herein (SEM images in Figs. 15A-E, 16A-E, and 17A-E) were characterized using scanning electron microscopy (SEM).

[0272] The study was performed according to the ISO quality standard.

[0273] A spatula tip of each sample bottle was transferred onto double sided carbon tape and sputtered with an 8 nm platinum-layer. Images were collected with 5 keV at 40,000x, 10,000x, l,000x, 500x and lOOx magnification.

[0274] Instruments and Equipment:

[0275] Image Analysis Software: Image analysis software Imagic ims Client Lab Image Management and archiving system Version V20H2.

[0276] Scanning electron microscope: Nova NanoSEM 230, FEI Company.

[0277] Sputter coater: 328UHR, Cressington.

[0278] To ensure reproducibility, three batches of samples were analyzed for exemplary uncoated narasin (SEM images in Figs. 12A-E, 13A-E, and 14A-E) and exemplary narasin coated in accordance with an exemplary process disclosed herein (SEM images in Figs. 15A-E, 16A-E, and 17A-E). Fig. 12A shows an SEM image of the exemplary uncoated narasin, and Figs. 12B-E shows a magnified view of Fig. 12A. Fig. 13A shows an SEM image of the exemplary uncoated narasin, and Figs. 13B-E shows a magnified view of Fig. 13A. Fig. 14A shows an SEM image of the exemplary uncoated narasin, and Figs. 14B-E shows a magnifiedview of Fig. 14A. Figs. 12A-E, 13A-E, and 14A-E images show uncoated narasin particles. Fig. 15A shows an SEM image of the exemplary coated narasin, and Figs. 15B-E shows a magnified view of Fig. 15 A. Fig. 15A shows an SEM image of the exemplary coated narasin, and Figs. 15B-E shows a magnified view of Fig. 15 A. Fig. 16A shows an SEM image of the d exemplary coated narasin, and Figs. 16B-E shows a magnified view of Fig. 16A. Figs. 12A-E, 13A-E, and 14A-E images show the structure of the uncoated narasin particles. Figs. 14A-E, 15A-E, and 16A-E images show the homogenous shell-like structure of diclazuril coating the narasin particles.

Claims

WHAT IS CLAIMED IS:

1. A composition formulated for administration to an animal comprising: a core particle having an outer surface, the core particle comprising narasin or a pharmaceutically acceptable salt thereof; and a first layer at least partially covering the outer surface of the core particle, the first layer comprising diclazuril or a pharmaceutically acceptable salt thereof.

2. The composition of claim 1, wherein the mass ratio of the narasin to the diclazuril is between about 20:1 and about 100:1, between about 30:1 and about 90:1, between about 40: 1 and about 80: 1, between about or about 50: 1 and about 70: 1, or about 60: 1.

3. The composition of claim 1 or 2, wherein the mass ratio of the narasin to the diclazuril is20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1,36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1,52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1,68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1,84:1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1, 91:1, 92:1, 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, or 100:1.

4. The composition of any one of claims 1-3, wherein the composition comprises between about 40 ppm and about 140 ppm narasin and between about 0.5 ppm and about 2 ppm of diclazuril, between about 50 ppm and about 100 ppm narasin and between about 0.7 ppm and about 1.3 ppm of diclazuril, between about 50 ppm and about 80 ppm narasin and between about 0.7 ppm and about 1 ppm of diclazuril.

5. The composition of any one of claims 1-4, wherein the composition comprises between about 40 ppm and 140 ppm narasin, 45 ppm and 135 ppm narasin, 50 ppm and 130 ppm narasin, 55 ppm and 125 ppm narasin, 50 ppm and 80 ppm narasin or a pharmaceutically acceptable salt thereof.

6. The composition of any one of claims 1-5, wherein the composition comprises about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 ppm narasin or a pharmaceutically acceptable salt thereof.

7. The composition of any one of claims 1-6, wherein the composition comprises between about 0.5 ppm and about 2 ppm of diclazuril, between about 0.7 ppm and about 1.3 ppm of diclazuril, between about 0.7 ppm and about 1 ppm of diclazuril or a pharmaceutically acceptable salt thereof.

8. The composition of any one of claims 1-7, wherein the core particle comprises from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof.

9. The composition of any one of claims 1-8, wherein the core particle comprises about 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 wt% narasin or a pharmaceutically acceptable salt thereof.

10. The composition of any one of claims 1-9, wherein the core particle comprises about 10 wt% narasin or a pharmaceutically acceptable salt thereof.

11. The composition of any one of claims 1-10, wherein the first layer comprises between about 0.01 and 5.0 wt% diclazuril or a pharmaceutically acceptable salt thereof.

12. The composition of any one of claims 1-11, wherein the first layer comprises about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.

9. 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 wt% diclazuril or a pharmaceutically acceptable salt thereof.

13. The composition of any one of claims 1-12, wherein the first layer comprises from about 0.01 wt% to about 2.0 wt% diclazuril, optionally diclazuril sodium.

14. The composition of any one of claims 1-13, wherein the first layer comprises about 0.01 wt%, about 0.05 wt%, about 0.10 wt%, about 0.15 wt%, about 0.20 wt%, about 0.25 wt%, about 0.30 wt%, about 0.35 wt%, about 0.40 wt%, about 0.45 wt%, about 0.50 wt%, about 0.55 wt%, about 0.60 wt%, about 0.65 wt%, about 0.70 wt%, about 0.75 wt%, about 0.80 wt%, about 0.85 wt%, about 0.90 wt%, about 0.95 wt%, about 1.0 wt%, about 1.10 wt%, about 1.15 wt%, about 1.20 wt%, about 1.25 wt%, about 1.30 wt%, about 1.35 wt%, about 1.40 wt%, about 1.45 wt%, about 1.50 wt%, about 1.55 wt%, about 1.60 wt%, about 1.65 wt%, about 1.70 wt%, about 1.75 wt%, about 1.80 wt%, about 1.85 wt%, about 1.90 wt%, about 1.95 wt%, or about 2 wt% diclazuril, optionally diclazuril sodium.

15. The composition of any one of claims 1-14, wherein the first layer comprises 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, up to about 2 wt% diclazuril, optionally diclazuril sodium.

16. The composition of any one of claims 1-15, wherein the core particle comprises about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof.

17. The composition of any one of claims 1-16, wherein the core particle comprises from about 8 wt%, about 8.5% wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, up to about 12 wt% narasin or a pharmaceutically acceptable salt thereof.

18. The composition of any one of claims 1-17, wherein the core particle comprises about 8 wt%, about 8.5% wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, or about 12 wt% narasin or a pharmaceutically acceptable salt thereof.

19. The composition of any one of claims 1-18, wherein the core particle comprises from about 88 wt% to about 92 wt% of an inert carrier.

20. The composition of claim 19, wherein the inert carrier comprises zeolite, a cellulosic material, or both zeolite and a cellulosic material.

21. The composition of any one of claims 1-20, wherein the core particle comprises a marumerized particle having an oblong shape profile.

22. The composition of any one of claims 1-21, wherein the composition comprises less than about 0.2 wt% of diclazuril degradant R064318 2-[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]- l,2,4-triazine-3,5(2 / / ,4 / / )-dione .

23. The composition of any one of claims 1-22, wherein the core particle further comprises a second layer at least partially covering the outer surface of the core particle, the second layer comprising an anti-dusting oil.

24. The composition of any one of claims 1-23, wherein the core particle comprises between about 0.01 wt% to about 2 wt% of an anti-dusting oil.

25. The composition of any one of claims 1-24, wherein the core particle comprises about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2.0 wt% of an anti-dusting oil.

26. The composition of any one of claims 1-25, wherein the core particle further comprises an inert carrier comprising a zeolite, a cellulosic material, or both a zeolite and a cellulosic material.

27. The composition of any one of claims 1-26, wherein the zeolite is a natural zeolite, a synthetic zeolite, or a combination thereof.

28. The composition of any one of claims 1-27, wherein the zeolite is clinoptilolite, mordenite, or any combination of clinoptilolite and mordenite.

29. The composition of any one of claims 1-28, wherein the cellulosic material comprises rice hulls.

30. The composition of any one of claims 1-29, wherein the animal is selected from the group consisting of a bird, a mammal, or a fish.

31. The composition of claim 30, wherein the mammal is a cat, dog, pig, horse, cow, donkey, goat, or sheep.

32. The composition of claim 30, wherein the bird is a fowl.

33. The composition of claim 30, wherein the bird is a chicken, pheasant, guineafowl, turkey, quail, duck, or goose.

34. The composition of claim 30, wherein the fish is a salmon, trout, tilapia, or catfish.

35. The composition of any one of claims 1-34, wherein the composition is stable for at least six months at 25 °C and 60% relative humidity.

36. The composition of any one of claims 1-35, wherein the composition is stable for at least one year at 25 °C and 60% relative humidity.

37. The composition of any one of claims 1-36, wherein the composition is stable for at least two years at 25 °C and 60% relative humidity.

38. The composition of any one of claims 1-37, wherein the composition is stable for at least six months at 40 °C and 75% relative humidity.

39. The composition of any one of claims 1-38, wherein the composition is configured such that the narasin or a pharmaceutically acceptable salt thereof and the diclazuril or a pharmaceutically acceptable salt thereof are assayable at least about 90% of an original potency after 2 years.

40. The composition of any one of claims 1-39, wherein the composition is configured such that the composition comprises less than about 0.2% of diclazuril degradant, R064318, after two years at 25 °C and 60% relative humidity.

41. The composition of any one of claims 1-40, wherein the composition is configured such that the composition comprises less than about 0.2% of diclazuril degradant, R064318, after two years at 40 °C and 75% relative humidity.

42. The composition of any one of claims 1-41, wherein the composition is formulated for oral administration.

43. The composition of any one of claims 1-42, wherein the pharmaceutically acceptable salt of diclazuril is diclazuril sodium.

44. A feed additive comprising the composition of any one of claims 1-43.

45. An animal feed comprising the composition of any one of claims 1-43.

46. The animal feed of claim 45, wherein the composition is present in an amount of from between about 0.01 wt% and 15 wt% of the animal feed.

47. The animal feed of claim 45 or 46, wherein the composition is present in an amount of about 0.01 wt% , about 0.02wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 1.5 wt%, about 2.0 wt%, about 2.5 wt%, about 3.0 wt%, about 3.5 wt%, about 4.0 wt%, about 4.5 wt%, about 5.0 wt%, about 5.5 wt%, about 6.0 wt%, about 6.5 wt%, about 7.0 wt%, about 7.5 wt%, about 8.0 wt%, about 8.5 wt%, about 9.0 wt%, about 9.5 wt%, about 10.0 wt%,about 11.0 wt%, about 12.0 wt%, about 13.0 wt%, about 14.0 wt%, or about 15.0 wt% of the animal feed.

48. The animal feed of claim 45, wherein the animal feed comprises a ratio of chicken feed:composition at a ratio of about 1 :2000, about 1 :1500, about 1 :1000, about 1 :900, about 1 :800, about 1 :700, about 1 :600, about 1 :500, about 1 :400, about 1 :300, about 1 :250, about 1 :200, about 1 : 150, about 1 : 100, about 1 :50, about 1 :25, or about 1 : 10.

49. The animal feed of any one of claims 45-48, wherein the feed is grower feed or finisher feed.

50. The animal feed of any one of claims 45-49, wherein the feed is finisher feed.

51. A method of preparing an anti-infective composition, the method comprising: applying a coating comprising diclazuril or a pharmaceutically acceptable salt thereof to at least a portion of an outer surface of a granule comprising narasin or a pharmaceutically acceptable salt thereof.

52. The method of claim 51, wherein applying comprises spraying a diclazuril sodium salt aqueous solution onto the outer surface of the granule.

53. The method of claim 52, wherein the spraying occurs within a blender chamber, the blender chamber being vacuum evacuated prior to spraying.

54. The method of any one of claims 51-53, wherein the method further comprises preparing the diclazuril sodium salt aqueous solution by mixing diclazuril, an alcohol, and an aqueous base in an intermediate tank.

55. The method of claim 54, wherein preparing further comprises an aqueous base that is not degassed.

56. The method of claim 54, wherein preparing further comprises removing oxygen from the aqueous base.

57. The method of claim 56, wherein preparing further comprises a nitrogen purge to remove oxygen from the intermediate tank prior to mixing the aqueous base.

58. The method of claims 56 or 57, wherein preparing further comprises drawing a vacuum to remove oxygen from the intermediate tank prior to mixing the aqueous base.

59. The method of any one of claims 51-58, wherein the method further comprises applying the coating to an outer surface of a diluent particle.

60. The method of claim 59, wherein the diluent particle comprises zeolite or rice hulls.

61. The method of any one of claims 51-60, wherein the method further comprises heating or cooling the blender chamber so that a jacket in contact with the granules is between about 10 °C and about 150 °C, between about 20 °C and about 140 °C, between about 30 °C and about 130 °C, between about 40 °C and about 120 °C, between about 50 °C to about 100 °C, between about 60 °C and about 90 °C, or between about 60 °C to about 80 °C.

62. The method of any one of claims 51-61, wherein the applying comprises spraying at a rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, optionally from about 100 g / min to about 250 g / min, optionally from about 120 g / min to about 230 g / min, optionally from about 130 g / min to about 220 g / min, optionally from about 140 g / min to about 200 g / min.

63. The method of any one of claims 51-61, wherein the applying comprises spraying from about 1 minute to about 60 minutes, optionally from about 5 minutes to about 60 minutes, optionally from about 5 minutes to about 50 minutes, optionally from about 5 minutes to about 45 minutes, optionally from about 5 minutes to about 40 minutes, optionally fromabout 5 minutes to about 35 minutes, optionally from about 5 minutes to about 30 minutes, optionally from about 5 minutes to about 25 minutes, optionally from about 5 minutes to about 20 minutes, optionally from about 5 minutes to about 15 minutes, optionally from about 5 minutes to about 10 minutes, optionally from about 2 minutes to about 45 minutes, optionally from about 2 minutes to about 35 minutes, optionally from about 2 minutes to about 30 minutes, optionally from about 2 minutes to about 25 minutes, optionally from about 2 minutes to about 20 minutes, optionally from about 2 minutes to about 15 minutes, or from about 2 minutes to about 10 minutes.

64. The method of any one of claims 51-63, wherein the aqueous base is an aqueous hydroxide.

65. The method of any one of claims 51-64, wherein the aqueous base is at a concentration from about 0.1 M to about 5 M, from about 0.3 M to about 2 M, or about 1 M.

66. The method of any one of claims 51-65, wherein the aqueous base is sodium hydroxide, potassium hydroxide, ammonium hydroxide or a mixture thereof.

67. The method of any one of claims 51-66, wherein mixing diclazuril, the alcohol, and the aqueous base in the intermediate tank includes a first step of mixing the diclazuril with the alcohol and a second step of adding the aqueous base, wherein the aqueous base is added at a rate of greater than 1 minute and less than 60 minutes at a temperature from about 5 °C to about 50 °C.

68. The method of any one of claims 51-67, wherein the method further comprises applying an anti-dusting oil to the anti-infective composition.

69. The method of any one of claims 51-68, wherein the method further comprises applying an anti-caking agent to the anti-infective composition.

70. The method of claim 69, wherein the anti-caking agent is verxite.

71. The method of any one of claims 51-70, wherein the anti-infective composition comprises between about 7 - 15% (wt / wt) narasin or pharmaceutically acceptable salt thereof and between about 0.01 - 2% (wt / wt) diclazuril or pharmaceutically acceptable salt thereof.

72. A method for preparing a combination antiparasitic particle composition comprising: coating a batch of granules, the granules comprising narasin or a pharmaceutically acceptable salt thereof, with an aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof.

73. The method of claim 72, wherein the method further comprises forming the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof, wherein the forming comprises: dissolving solid diclazuril or a pharmaceutically acceptable salt thereof in an alcohol solvent, thereby generating a diclazuril-alcohol solution; removing oxygen from the atmosphere exposed to the diclazuril-alcohol solution; blanketing the diclazuril-alcohol solution in inert gas; and adding aqueous hydroxide to the diclazuril-alcohol solution, wherein the aqueous hydroxide comprises sodium hydroxide, potassium hydroxide, ammonium hydroxide, or a mixture thereof.

74. The method of claim 72, wherein the method further comprises forming the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof, wherein the forming comprises: dissolving solid diclazuril or a pharmaceutically acceptable salt thereof in an ethanol solvent, thereby generating a diclazuril-alcohol solution; removing oxygen from the atmosphere exposed to the diclazuril-alcohol solution; blanketing the diclazuril-alcohol solution in inert gas; and adding aqueous hydroxide to the diclazuril-alcohol solution, wherein the aqueous hydroxide comprises sodium hydroxide, potassium hydroxide, ammonium hydroxide, or a mixture thereof.

75. The method of any one of claims 72 -74, wherein the granules further comprise an inert carrier comprising zeolite, cellulosic material, or a combination of zeolite and cellulosic material.

76. The method of any one of claims 71-75, wherein the granules further comprise an inert carrier comprising rice hulls.

77. The method of any one of claims 71-76, wherein the method further comprises forming the batch of granules, wherein the forming comprises: mixing an inert carrier comprising rice hulls with narasin or a pharmaceutically acceptable salt thereof in a vacuum blender; removing oxygen from the atmosphere in the vacuum blender; and setting a pressure inside the vacuum blender to less than about 150 mBar.

78. The method of any one of claims 71-77, wherein the coating comprises: spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, optionally from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C optionally about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution.

79. The method of any one of claims 71-76, wherein the coating comprises: spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 13,000g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, optionally from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C optionally about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution under vacuum.

80. The method of any one of claims 71-76, wherein the coating comprises: spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray rate from about 20,000 g / min to about 100 g / min, optionally from about 20,000 g / min to about 15,000 g / min, optionally from about 15,000 g / min to about 10,000 g / min, optionally from about 15,000 g / min to about 13,000 g / min, optionally from about 13,000 g / min to about 10,000 g / min, optionally from about 10,000 g / min to about 5,000 g / min, optionally from about 5,000 g / min to about 1,000 g / min, optionally from about 1,000 g / min to about 500 g / min, optionally from about 500 g / min to about 100 g / min, optionally from about 50 g / min to about 300 g / min and at a temperature from about 20 °C to about 95 °C optionally about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution without the use of vacuum.

81. The method of any one of claims 71-76, wherein the coating comprises spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes, optionally from about 5 minutes to about 30 minutes, at a temperature from about 20 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution.

82. The method of claim 82, wherein the coating comprises spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes, optionally from about 5 minutes to about 30 minutes, and at a temperature from about 20 °C to about 95 °C,optionally about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution under vacuum.

83. The method of claims 81 or 82, wherein the coating comprises spraying the aqueous solution of diclazuril or a pharmaceutically acceptable salt thereof onto the granules at a substantially fixed spray duration from about 1 minute to about 60 minutes, optionally from about 5 minutes to about 30 minutes, and at a temperature from about 20 °C to about 95 °C, optionally about 45 °C to about 95 °C; and at least partially evaporating the solvent of the aqueous solution without the use of vacuum.

84. The method of any one of claims 71-83, wherein the method further comprises coating the granules in anti-dusting oil.

85. The method of any one of claims 71-84, wherein the method further comprises coating the granules in anti-caking agent.

86. The method of claim 85, wherein the anti-caking agent is verxite.

87. The method of any one of claims 71-85, wherein the combination antiparasitic particle composition comprises from about 8 wt% to about 12 wt% narasin or a pharmaceutically acceptable salt thereof and about 0.01 wt% to about 2 wt% diclazuril sodium.

88. A method of preventing and / or treating a coccidian infection in an animal comprising administering to the animal a therapeutically effective amount of the composition of any one of claims 1-43, feed additive of claim 44, or animal feed of any one of claims 45-49.

89. The method of claim 88, wherein the animal is a non-human animal.

90. The method of claim 88 or 89, wherein the animal is a bird, a mammal, or a fish.

91. The method of claim 89, wherein the mammal is a cat, dog, pig, horse, cow, donkey, goat, or sheep.

92. The method of claim 89, wherein the bird is a fowl.

93. The method of claim 89, wherein the bird is a chicken, pheasant, turkey, quail, duck, guineafowl, or goose.

94. The method of claim 89, wherein the fish is a salmon, trout, tilapia, or catfish.

95. The method of any one of claims 88-94, wherein the coccidian infection is an Eimeria species.

96. The method of claim 95, wherein the Eimeria species is E. brunetti, E. necatrix, E. tenella, E. acervulina, E. maxima, E. mitis, E. praecox, or any combination thereof.

97. The method of claim 96, wherein the Eimeria species is E. acervulina, E. maxima, E. tenella, or any combination thereof.

98. The method of any one of claims 88-97, wherein the composition is administered orally.

99. The method of any one of claims 88-98, wherein the composition is admixed with an animal feed.

100. The method of any one of claims 88-99, wherein the composition is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 feed cycles.

101. The method of any one of claims 88-100, wherein the composition is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 consecutive grow cycles in a finisher feed, optionally at least 3 consecutive grow cycles.

102. Use of a therapeutically effective amount of the composition of any one of claims 1-39 for manufacture of a medicament for treatment of a coccidian infection in an animal.

103. The use of claim 102, wherein the animal is a non-human animal.

104. The use of claim 102 or 103, wherein the animal is a bird, a mammal, a fish, or a reptile.

105. The use of claim 104, wherein the mammal is a cat, dog, pig, horse, cow, donkey, goat, or sheep.

106. The use of claim 102, wherein the bird is a fowl.

107. The use of claim 104, wherein the bird is a chicken, pheasant, turkey, quail, duck, guineafowl, or goose.

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