USOO8227427B2

(12) United States Patent (10) Patent No.: US 8,227,427 B2 Coracci Neto et al. (45) Date of Patent: Jul. 24, 2012

(54) VETERINARIAN COMPOSITION (52) US. Cl...... 514/27; 514/368 COMPRISING AN ORGANIC SALT 0F (58) Field of Classi?cation Search ...... 513/71; LEVAMISOLE IN COMBINATION WITH AT 548/155; 514/27, 368 LEAST ONE AVERMECTIN AND/OR See application ?le for complete search history. MILBEMYCIN (75) Inventors: Dolivar Coracci Neto, Sertaozinho (56) References Cited (BR); Nelson Henriques Fernandes Filho, Jaboticabal (BR); Ricardo da FOREIGN PATENT DOCUMENTS Silva Sercheli, Jaboticabal (BR) BR PI0505716 A 9/2007 GB 2150024 A 6/1985 (73) Assignee: NPA—Nucleo de Pesquisas Aplicadas WO 00/74489 A1 12/2000 Ltda., Jaboticabal (BR) WO 2004/009080 A1 1/2004 OTHER PUBLICATIONS ( * ) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 International Search Report. U.S.C. 154(b) by 575 days. Analytical Report Characterization of Pharmaceutical Input Aurixazol (Feb. 20, 2010). (21) App1.No.: 12/097,683 Primary Examiner * Elli Peselev (22) PCT Filed: Dec. 18, 2006 (74) Attorney, Agent, or Firm * Laurence P. Colton; Smith Risley Tempel Santos LLC (86) PCT No.: PCT/BR2006/000282 § 371 (0X1)’ (57) ABSTRACT (2), (4) Date: Nov. 3, 2008 Veterinarian composition comprising an organic salt of (87) PCT Pub. No.: WO2007/068073 levamisole in combination With at least one avermectin and/ or milbemycin. A veterinarian formulation comprising of organ PCT Pub. Date: Jun. 21, 2007 ics salts of levamisole, more speci?cally to the levamisole salt of 2,6-diiodo-4-nitrophenol and the levamisole salt of 4-hy (65) Prior Publication Data droxy-3-iodo-5-nitrobenzonitrile With avermectins and mil US 2009/0075918 A1 Mar. 19, 2009 bemycins and its use in treatment of helminthiasis in mam mals, in particular in bovines, sWines, caprines, equines, (51) Int. Cl. ovines, canines and felines. A61K 31/70 (2006.01) A61K 31/425 (2006.01) 13 Claims, No Drawings US 8,227,427 B2 1 2 VETERINARIAN COMPOSITION Milbemycins are similar to avermectins in their structure, COMPRISING AN ORGANIC SALT OF because they have a 16 membered ring structures. However, it LEVAMISOLE IN COMBINATION WITH AT does not have a disaccharidic sub unit and there are constitu LEAST ONE AVERMECTIN AND/OR ent differences. Milbemycin used in the association are MILBEMYCIN selected from the group consisting of moxidectin, milbemy cin and milbemycin oxime. STATEMENT OF RELATED APPLICATIONS Considering these aspects, it is known that levamisole salt of 2,6-diiodo-4-nitrophenol, as well as levamisole salt of This patent application is the United States PCT Chapter II 4-hydroxy-3-iodo-5-nitrobenzonitrile, both combine the National Phase of PCT/BR2006/000282, having an Interna action of levamisole against nematodes, for example, Hae tional Filing Date of 18 Dec. 2006, which claims priority on monchus contorlus, Oslerlagia spp., Trichoslrongylus spp. Brazilian Patent Application No. PI 0506279-9, having a (example: Trichoslrongylus axei), Cooperia spp. (Cooperia ?ling date of 16 Dec. 2005, both of which are incorporated oncophora), Nemalordirus spp. (example: Oesaphagoslo herein by this reference in their entireties. mum venulosum), Slrongyloides spp. (example: Slrongy loidespapillosus), Bunoslomum spp. (ex: Bunoslomum trigo BACKGROUND OF THE INVENTION nocephalum), Chaberlia spp (ex: Chaberlia ovina), Trichuris spp. (ex: Trichuris ovis) and Dictyocaulus spp. (ex: Dictyo The association of different classes of substances present caulus?laria and Diclyocaulus viviparous) with the action of ing antihelminthic actions aims to combat an increasing resis disophenol or nitroxinil against trematodes, for example, tance of parasites to most of the drugs used. The resistance of 20 Fasciola hepatic and gigantic Fasciola, and some nematodes, parasites to different classes of antihelminthic drugs has been for example, Haemonchus contorlus, Bunoslomum spp. reported since early use of these drugs. The resistance for Oesaphagoslomum spp., Para?laria bovicola. Considering benZimidazole is all over the world. Studies have been that levamisole presents a low action against Oslerlagia para reported, mainly related to three main species of bovine’s sites and a good action against Cooperia class, and avermec parasites: Oslerlagia, Trichoslrongylus, Cooperia. Although 25 tins and milbemycin has a good inverse action, which means parasites resistance to levamisole is well known, it is much low action against Cooperia and good action against Osler more restrict than to benZimidazoles. Resistance and crossed Zagia, a combination of actions of levamisole salt of 2,6 resistance reports have been reported, mainly to Cooperia diiodo-4-nitrophenol and levamisole salt of 4-hydroxy-3 species. iodo-5-nitrobenzonitrile with avermectins and milbemycins, The strategy to combat this resistance has been trying to 30 aiming a wide spectrum formulation against parasites, avoid the indiscriminate use of antihelminthic drugs, to alter besides a synergism of actions among actives. In such case, nate drugs during treatment and to use potential number of this association maybe indicated as a parasiticide in the treat parasites which survive the treatment. The association of ment of nematodes, cestodes, and trematodes in bovines, active principles aiming a synergetic function among them is swine, caprines, equines, ovines, canines and felines. a well known strategy, mainly in the treatment of pathogenic 35 Associations of avermectins and levamisole have already agents with bacteria, protozoans, fungus, and parasites. A real been described before, in patent WO 00061068 and in patent synergism occurs when the association of two or more phar application WO 2004/009080 Al. The greatest discovery in maceutical actives is higher than all individual actions the study is the use of salts of levamisole, which besides together. levamisole action they present fascioliscide action, when The aim of this invention is to describe the use of organic 40 associated with avermectins. Other associations with fasci salts of levamisole associated to avermectins and/or milbe oliscide compounds were proposed in documents W0 mycins in the combat to helminthiasis. 95/ 058 l 2 and GB 2386067A, both describing the association Levamisole (L-2,3,5,6-tetrahydro-6-phenil-imidazo-[2,l of avermectins and milbemycins with closantel. b]thiazole), it is an antiparasitary widely used for intestinal control of nematodes and respiratory worms in some animals. 45 BRIEF SUMMARY OF THE INVENTION Due to its basic characteristic, it forms salts with organic and inorganic acids, depending on pka of this acid. This invention is a veterinarian pharmaceutical formula Antiparasitaries such as disophenol (2,6-dilodo-4-nitro tion which presents fascioliscide action and a potent action phenol) and nitroxinil (4-hydroxy-3-iodo-5-nitrobenzoni against nematodes, cestodes, trematodes. This invention also trile), which are used to control trematodes and some nema 50 is a new veterinarian pharmaceutical product presenting the todes, produce a salt with levamisole under some conditions association of organic salts of levamisole with avermectins due to its acid characteristic of phenol group of these mol and milbemycins. This invention also is an association of ecules. The description, obtainment, and use of levamisole levamisole salt of 2,6-diiodo-4-nitrophenol with avermectins salt of 4-hydroxy-3-iodo-5-nitrobenzonitrile were described and milbemycins for antiparasitary agent. in the patent GB 2150024 A. Levamisole salt of 2,6-diiodo 55 This invention presents new veterinarian products from the 4-nitrophenol and levamisole salt of 4-hydroxy-3-iodo-5-ni association of avermectins and milbemycins with other anti trobenzonitrile from now on will be referred only as levami parasitary agents, such as organic salts of levamisole. sole organic salts, when suitable. Levamisole organic salts used in this invention are of Averrnectins, a compound which belongs to macrocyclic levamisole salt of 4-hydroxy-3-iodo-5-nitrobenzonitrile and lactones, are powerful antiparasitary agents which are used to 60 levamisole salt of 2,6-diiodo-4-nitrophenol. combat parasites in mammals. They are secondary metabolic Avermectins and milbemycins used in this invention are produced by Slreplomyces avemililis, obtained through a fer abamectin, ivermectin, doramectin, eprinomectin, selamec menting process. Some avermectins are obtained in a semi tin, moxidectin, milbemycin and milbemycin oxime. synthetic composition as ivermectin, which is obtained The used do sage will depend on the helminthes ’ nature, the through abamectin hydrogenization. A series of compounds 65 animal which will be treated and administration route. denominated avermectins are abamectin, doramectin, epri Levamisole salt of 4-hydroxy-3-iodo-5-nitrobenzonitrile can nomectin, ivermectin and selamectin. range from 1 to 50 mg per kilogram of body weight, prefer US 8,227,427 B2 3 4 ably from 5 to 15 mg per kilogram of body weight, consider 2,6-diiodo-4-nitrophenol in dosages ranging from 20-80% in ing that dosage of 7.2 mg/kg of body weight brings satisfac weight of the levamisole salt of 2,6-diiodo-4-nitrophenol. tory results in the control of parasites. Levamisole salt of 4. The veterinarian composition according to claim 1, 2,6-diiodo-4-nitrophenol can range from 1 to 50 mg per kilo wherein the composition further comprises levamisole salt of gram of body weight, considering that a dosage of 8.9 mg/kg 4-hydroxy-3 -iodo-5-nitrobenzonitrile. of body weight generally brings satisfactory results in the 5. The veterinarian composition according to claim 1, com control of parasites. Avermectins and milbemycins dosages prising the levamisole salt of 2,6-diiodo-4-nitrophenol in dos range from 5 to 500 pg of the active per kilogram of weight, ages ranging from 1 to 50 mg per kg of body weight. preferably from 50 to 350 pg of the active per kilogram of 6. The veterinarian composition according to claim 5, com body weight, considering that a dosage of 200 pg/kg of body prising the levamisole salt of 2,6-diiodo-4-nitrophenol in dos weight generally has satisfactory results in the control of ages ranging from 5 to 15 mg per kg of body weight. parasites. 7. The veterinarian composition according to claim 4, com The pharmaceutical formulations, according to this inven prising the levamisole salt of 4-hydroxy-3-iodo-5-nitroben tion, can be used to administrate the associations of levami zonitrile in dosages ranging from 1 to 50 mg per kg of body sole organic salts with milbemycins and/or avermectins in weight. order to kill internal parasites, such as, nematodes, cestodes, 8. The veterinarian composition according to claim 4, com trematodes and fasciola, parasites in animals such as bovines, prising the levamisole salt of 4-hydroxy-3-iodo-5-nitroben swines, caprines, felines, canines, equines; according to the zonitrile in dosages ranging from 5 to 15 mg per kg of body dosages and purposes presented in this study speci?cally for weight. these associations. 20 9. The veterinarian composition according to claim 4, com The associations are rather done among levamisole organic prising the levamisole salt of 4-hydroxy-3-iodo-5-nitroben salt and avermectins or milbemycins. For example, the asso zonitrile in dosages of 8.9 mg per kg of body weight. ciation of levamisole salt of 4-hydroxy-3-iodo-5-nitroben 10. The veterinarian composition according to claim 1, zonitrile with abamectin in a parentheral veterinarian formu wherein the avermectins and/or milbemycins are in dosages lation. These can be free associations with the use of one or 25 ranging from 5 to 500 pg of active per kilogram of body more levamisole organic salts and one or more avermectins or weight. milbemycins, or the mix of them. 11. The veterinarian composition according to claim 1, What is claimed is: wherein the avermectins and/or milbemycins are in dosages 1. A veterinarian composition comprising an organic salt of ranging from 5 to 350 pg of active per kilogram of body levamisole having the formula 2,6-diiodo-4-nitrophenol in 30 weight. combination with avermectins, milbemycins, or combina 12. The veterinarian composition according to claim 1, tions thereof, wherein the composition has fasciolicide activ wherein the avermectins and/or milbemycins are in dosages ity. of 200 pg of active per kilogram of body weight. 2. The veterinarian composition according to claim 1, 13. The veterinarian composition according to claim 4, wherein said avermectins and milbemycins are selected from 35 wherein the levamisole salt of 4-hydroxy-3-iodo-5-nitroben the group consisting of abamectin, ivermectin, doramectin, zonitrile is present in dosages ranging from 20-80% by eprinomectin, selamectin, moxidectin, milbemycin, milbe weight of the levamisole salt of 4-hydroxy-3 -iodo-5-ni mycin oxime, and mixtures thereof. trobenzonitrile. 3. The veterinarian composition according to claim 1, wherein the composition comprises the levamisole salt of UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. I 8,227,427 B2 Page 1 ofl APPLICATION NO. : 12/097683 DATED : July 24, 2012 INVENTOR(S) : Dolivar Coraucci Neto, Nelson Henriques Fernandes Filho and Ricardo da Silva Sercheli

It is certified that error appears in the above-identi?ed patent and that said Letters Patent is hereby corrected as shown below:

Title Page,

On the Bibliographic page, paragraph (75) Inventors, “Dolivar Coraooi Neto” should be changed to --Dolivar Coraucci Neto--.

Signed and Sealed this Eighteenth Day of September, 2012

David J. Kappos Director 0fthe United States Patent and Trademark O?ice