CA2059602A1 - Pour-on formulation for the administration of anthelmintics - Google Patents
Pour-on formulation for the administration of anthelminticsInfo
- Publication number
- CA2059602A1 CA2059602A1 CA002059602A CA2059602A CA2059602A1 CA 2059602 A1 CA2059602 A1 CA 2059602A1 CA 002059602 A CA002059602 A CA 002059602A CA 2059602 A CA2059602 A CA 2059602A CA 2059602 A1 CA2059602 A1 CA 2059602A1
- Authority
- CA
- Canada
- Prior art keywords
- weight
- fenbendazole
- pour
- agent
- formulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000004540 pour-on Substances 0.000 title claims abstract description 37
- 230000000507 anthelmentic effect Effects 0.000 title claims abstract description 11
- 239000000203 mixture Substances 0.000 title abstract description 42
- 238000009472 formulation Methods 0.000 title abstract description 38
- 229940124339 anthelmintic agent Drugs 0.000 title abstract description 4
- 239000000921 anthelmintic agent Substances 0.000 title abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 239000004480 active ingredient Substances 0.000 claims abstract description 20
- 239000006185 dispersion Substances 0.000 claims abstract description 12
- 244000144972 livestock Species 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000010419 fine particle Substances 0.000 claims abstract description 9
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 244000000013 helminth Species 0.000 claims abstract description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims abstract 2
- 229960005473 fenbendazole Drugs 0.000 claims description 58
- HDDSHPAODJUKPD-UHFFFAOYSA-N fenbendazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1SC1=CC=CC=C1 HDDSHPAODJUKPD-UHFFFAOYSA-N 0.000 claims description 58
- 239000002245 particle Substances 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 239000003995 emulsifying agent Substances 0.000 claims description 8
- 239000000080 wetting agent Substances 0.000 claims description 7
- 239000002518 antifoaming agent Substances 0.000 claims description 6
- 150000001556 benzimidazoles Chemical class 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000002270 dispersing agent Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 20
- 239000003921 oil Substances 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 5
- 241000244206 Nematoda Species 0.000 abstract description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 24
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 229960004546 thiabendazole Drugs 0.000 description 6
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 6
- 235000010296 thiabendazole Nutrition 0.000 description 6
- 239000004308 thiabendazole Substances 0.000 description 6
- 239000011324 bead Substances 0.000 description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 5
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- -1 phenylmercapto Chemical class 0.000 description 5
- 229920001296 polysiloxane Polymers 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HMCCXLBXIJMERM-UHFFFAOYSA-N Febantel Chemical compound C1=C(NC(NC(=O)OC)=NC(=O)OC)C(NC(=O)COC)=CC(SC=2C=CC=CC=2)=C1 HMCCXLBXIJMERM-UHFFFAOYSA-N 0.000 description 3
- YRWLZFXJFBZBEY-UHFFFAOYSA-N N-(6-butyl-1H-benzimidazol-2-yl)carbamic acid methyl ester Chemical compound CCCCC1=CC=C2N=C(NC(=O)OC)NC2=C1 YRWLZFXJFBZBEY-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229960005282 febantel Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000003801 milling Methods 0.000 description 3
- 229950007337 parbendazole Drugs 0.000 description 3
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 3
- 229920000151 polyglycol Polymers 0.000 description 3
- 239000010695 polyglycol Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- RAOCRURYZCVHMG-UHFFFAOYSA-N N-(6-propoxy-1H-benzimidazol-2-yl)carbamic acid methyl ester Chemical compound CCCOC1=CC=C2N=C(NC(=O)OC)NC2=C1 RAOCRURYZCVHMG-UHFFFAOYSA-N 0.000 description 2
- 229960002669 albendazole Drugs 0.000 description 2
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 2
- 125000002877 alkyl aryl group Chemical group 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- YDEXUEFDPVHGHE-GGMCWBHBSA-L disodium;(2r)-3-(2-hydroxy-3-methoxyphenyl)-2-[2-methoxy-4-(3-sulfonatopropyl)phenoxy]propane-1-sulfonate Chemical compound [Na+].[Na+].COC1=CC=CC(C[C@H](CS([O-])(=O)=O)OC=2C(=CC(CCCS([O-])(=O)=O)=CC=2)OC)=C1O YDEXUEFDPVHGHE-GGMCWBHBSA-L 0.000 description 2
- 238000009837 dry grinding Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229960003439 mebendazole Drugs 0.000 description 2
- OPXLLQIJSORQAM-UHFFFAOYSA-N mebendazole Chemical compound C=1C=C2NC(NC(=O)OC)=NC2=CC=1C(=O)C1=CC=CC=C1 OPXLLQIJSORQAM-UHFFFAOYSA-N 0.000 description 2
- 229960002762 oxibendazole Drugs 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- TVFWYUWNQVRQRG-UHFFFAOYSA-N 2,3,4-tris(2-phenylethenyl)phenol Chemical compound C=1C=CC=CC=1C=CC1=C(C=CC=2C=CC=CC=2)C(O)=CC=C1C=CC1=CC=CC=C1 TVFWYUWNQVRQRG-UHFFFAOYSA-N 0.000 description 1
- WCBVUETZRWGIJQ-UHFFFAOYSA-N 2-[[(methoxycarbonylamino)-(2-nitro-5-propylsulfanylanilino)methylidene]amino]ethanesulfonic acid Chemical compound CCCSC1=CC=C([N+]([O-])=O)C(NC(NC(=O)OC)=NCCS(O)(=O)=O)=C1 WCBVUETZRWGIJQ-UHFFFAOYSA-N 0.000 description 1
- XULHFMYCBKQGEE-UHFFFAOYSA-N 2-hexyl-1-Decanol Chemical compound CCCCCCCCC(CO)CCCCCC XULHFMYCBKQGEE-UHFFFAOYSA-N 0.000 description 1
- JYZLSYFPFQTNNO-UHFFFAOYSA-N 2-octyldecan-1-ol Chemical compound CCCCCCCCC(CO)CCCCCCCC JYZLSYFPFQTNNO-UHFFFAOYSA-N 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241001126267 Cooperia oncophora Species 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- XTJFFFGAUHQWII-UHFFFAOYSA-N Dibutyl adipate Chemical compound CCCCOC(=O)CCCCC(=O)OCCCC XTJFFFGAUHQWII-UHFFFAOYSA-N 0.000 description 1
- CMBYOWLFQAFZCP-UHFFFAOYSA-N Hexyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCCCCC CMBYOWLFQAFZCP-UHFFFAOYSA-N 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 229920001732 Lignosulfonate Polymers 0.000 description 1
- 241000699696 Meriones Species 0.000 description 1
- 241000699684 Meriones unguiculatus Species 0.000 description 1
- 241000243794 Ostertagia ostertagi Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241001307210 Pene Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000212342 Sium Species 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 241000243797 Trichostrongylus Species 0.000 description 1
- 241000122945 Trichostrongylus axei Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical class [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960003475 cambendazole Drugs 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 244000078703 ectoparasite Species 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 244000079386 endoparasite Species 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960004500 flubendazole Drugs 0.000 description 1
- CPEUVMUXAHMANV-UHFFFAOYSA-N flubendazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=C(F)C=C1 CPEUVMUXAHMANV-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 244000144980 herd Species 0.000 description 1
- 229940100463 hexyl laurate Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 229940089456 isopropyl stearate Drugs 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000006626 methoxycarbonylamino group Chemical group 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229950006716 netobimin Drugs 0.000 description 1
- 229920000847 nonoxynol Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BARWIPMJPCRCTP-UHFFFAOYSA-N oleic acid oleyl ester Natural products CCCCCCCCC=CCCCCCCCCOC(=O)CCCCCCCC=CCCCCCCCC BARWIPMJPCRCTP-UHFFFAOYSA-N 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BARWIPMJPCRCTP-CLFAGFIQSA-N oleyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC BARWIPMJPCRCTP-CLFAGFIQSA-N 0.000 description 1
- BEZZFPOZAYTVHN-UHFFFAOYSA-N oxfendazole Chemical compound C=1C=C2NC(NC(=O)OC)=NC2=CC=1S(=O)C1=CC=CC=C1 BEZZFPOZAYTVHN-UHFFFAOYSA-N 0.000 description 1
- 229960004454 oxfendazole Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- QZWHWHNCPFEXLL-UHFFFAOYSA-N propan-2-yl n-[2-(1,3-thiazol-4-yl)-3h-benzimidazol-5-yl]carbamate Chemical compound N1C2=CC(NC(=O)OC(C)C)=CC=C2N=C1C1=CSC=N1 QZWHWHNCPFEXLL-UHFFFAOYSA-N 0.000 description 1
- ZPWFUIUNWDIYCJ-UHFFFAOYSA-N propan-2-yl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(C)C ZPWFUIUNWDIYCJ-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical class [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YFNCATAIYKQPOO-UHFFFAOYSA-N thiophanate Chemical compound CCOC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OCC YFNCATAIYKQPOO-UHFFFAOYSA-N 0.000 description 1
- HLLICFJUWSZHRJ-UHFFFAOYSA-N tioxidazole Chemical compound CCCOC1=CC=C2N=C(NC(=O)OC)SC2=C1 HLLICFJUWSZHRJ-UHFFFAOYSA-N 0.000 description 1
- 229950004788 tioxidazole Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
- 125000002256 xylenyl group Chemical class C1(C(C=CC=C1)C)(C)* 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
- A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Dermatology (AREA)
- Zoology (AREA)
- Emergency Medicine (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Abstract of the disclosure A pour-on formulation for the administration of anthel-mintics Fine-particle dispersions of benzimidazole or benzothia-zole derivatives or probenzimidazoles with anthelmintic activity in water in which penetration-promoting oils are emulsified, or fine-particle dispersions of the said active ingredients in penetration-promoting oils as pour on formulation, a process for the preparation thereof and processes for controlling helminths in livestock.
The novel formulations have high activity against parasi-tizing nematodes and their stages in the digestive tract and in tissues.
The novel formulations have high activity against parasi-tizing nematodes and their stages in the digestive tract and in tissues.
Description
-- 2~6~2 ~OECHST ARTI~N&E5~LLSC~AFT HO~ 91~F 016 Dr. WS~Le Description A pour-on formulation for the administration o anthel-min~ics The present in~ention relates to pour-on formulations, to a process for the preparation thereof and to the use thereof for controlling helmin~h~ in live~tock.
A number of publications descrlbe the pour-on, also ~pot-on, proce~ for controlling ectoparasites in livestock:
Journ. Econ. Entomology, 53, (1960), pp. 814-817, ~P-A-045424, DE-A-3208334, EP-A-120286, EP A-311180. ~his entails the liquid preparation of an insecticidal/acari-cidal agent being administered by pouring on along the dorsal line from the withers to the tailhead of agricul-tural productive livestock, especially cattle. The nature of the formulations must be such that spreading achieves an action against the pests on the entire animal body.
Pour-on formulations ~hich are also active against ; endoparasites when admini~tered in the way described must transport ~ystemically active age~ts through the animal skin into the bloodstream. Preparations of thi6 type are known for levami~ole (EP-A-1376~7~ D~-A-3212735, DE-A-2614841) and for ivermectin (EP 89302680). Both compounds are readily ~oluble in water and solvents so that penetration of the animal skin can be achieved 2S relatively ea~ily.
A very important group of agents for controlling endoparasitic helminths are suitably substituted banzimidazole and benxothiazole derivativas, as well as the gxoup of so-called prohenzimidazoles (compounds which 30 can be metabolized to benzimidazole derivatives with anthelmintic activity), like the compound~ of the for-mulae I to III listed hereinafter:
- .
: ~ , ; :. . .
.
, ..
~9~0~
. - 2 -.
A number of publications descrlbe the pour-on, also ~pot-on, proce~ for controlling ectoparasites in livestock:
Journ. Econ. Entomology, 53, (1960), pp. 814-817, ~P-A-045424, DE-A-3208334, EP-A-120286, EP A-311180. ~his entails the liquid preparation of an insecticidal/acari-cidal agent being administered by pouring on along the dorsal line from the withers to the tailhead of agricul-tural productive livestock, especially cattle. The nature of the formulations must be such that spreading achieves an action against the pests on the entire animal body.
Pour-on formulations ~hich are also active against ; endoparasites when admini~tered in the way described must transport ~ystemically active age~ts through the animal skin into the bloodstream. Preparations of thi6 type are known for levami~ole (EP-A-1376~7~ D~-A-3212735, DE-A-2614841) and for ivermectin (EP 89302680). Both compounds are readily ~oluble in water and solvents so that penetration of the animal skin can be achieved 2S relatively ea~ily.
A very important group of agents for controlling endoparasitic helminths are suitably substituted banzimidazole and benxothiazole derivativas, as well as the gxoup of so-called prohenzimidazoles (compounds which 30 can be metabolized to benzimidazole derivatives with anthelmintic activity), like the compound~ of the for-mulae I to III listed hereinafter:
- .
: ~ , ; :. . .
.
, ..
~9~0~
. - 2 -.
2~, N
\~ R 1 ` ~ N
H
Ia) in which Rl i8 methoxycarbonylamino and R2 i~ n-propylmercap~o (albendazo]Le)~ phenylmercapto (fenbendazole), phenyl~ulfinyl (oxfendazole), benzoyl (mebendazole3, p-~luorobenzoyl (flu-bendazole), p-~luorophenylsulfonyloxy (luxa-bendazolej~cyclopropylcarbonyl(cyclobendazol~) t butyl (parbendazole), n-propoxy ~oxibendazole) ::10 ~ or ~ (carbendaæim); or Ib) in which iL~ 4-thiazolyl and 2 i~ :H (thiabendazole) or isopr~poxycarbonylamino (cambendazole).
: 15 ~ R~3 tII) :in~::which : : : : :
R3 is methoa~carbonylamino and R4 iB n-propo~y ( tioxidazole ~ .
~III) in which ~.
`" 2 0 ~ -- 3 R5 is -N-C(NHCOOCH3)2, R6 is -NHCOCH20CH3, R7 is phenylmercapto and R8 i~ H ~febantel); or Rs is N C ~ NHCH2CH2S3H
R5 is NO2, R7 is H and R8 iB n-propylmercapto : 5 (netobimin); or R5 and R8 are each -NXCSNH-COOC2H~, ~' and R8 are each H (thiophanate).
These agents are sparingly ~oluble substances so that it has not hitherto been possible to prepare pour-Qn for-: 10 mulations in suitable ~olvents. Thi~ is why it ha~
hitherto been necessary to carry out a treatment o~
~ helminth-infected livestock (for example cattle or sheep) . :
: by the so-called drench proces~ or orally with the ~id of ; a bolus.
The use of th pour-on process would be consi.derably more economic for the treatment of large herds be~ause it is, inter alia, considerabIy les~ time-consuming and labor intensive. It i~ not necessary to immobilizs the live-~:~ stock, ~here is less risk to the treating person from -~: 20 defensive movement of the livestock, and thare i~ less tres~0 especially for livestQck unused to being handled.
It has been found, surprisingly, that fine-parkicle dispersions (suspenslons) o~ the said benzimidazoles, banzothiazoles and prQbenzimidazoles with anthelmintic ~ 25 activity are able, when suitable pene~ration-promoting : oils are u~ed and admini~tration i~ by the pour on process, to enter the body by the tran~dermal route, whera they display a good effect against nematodas and their stages parasitizing the dige~tive tract and tissues. To do this, it is merely necessary, when the do~age is suitable, to apply a stxip of the ~ormulation to ~he back of the livestock.
~: .
.
- - . . i , .
- 2 ~ 2 ~he invention therefore relates ~o preparations which have anthelmintic activity and which contain a~ active ingredient at least one henzimida~ole, b~nzothiazole or probenzimidazole with anthelmintic activity in fine-particle dispersion in a penetration-promoting agent. It is also possible to use mixtures of the said active : ingredients.
The particles of active ingredient in the~e disper~ion~
should have a parti~le ~ize from 0.05 to about 30 ~m, pre~erably from 0.5 to lU ~m.
Penetration-promoting oils which can be employecl are triglycerides of saturat2d vegetable fatty acids, for :~ example Miglyol 812~, triglycercol dii~ostearate or esters ~: of long-chain acid6, ~uch a~, for ~xample, oleyl oleate, : 15 isopropyl myristate, i~opropyl palmitate, 2-ethylhex~l palmitate r i~ooctyl stearate, isopropyl stearate, hexyl laurate or di n-butyl adipate; a~ w811 a~ long-chain alcohol~ such ~, for example, hexylalcohol, octyl al-cohol, decyl alcohol, oleyl alcoho~, 2-oetyldodecanol, 2-hexyldecanol or 2~octyldecanol. All the penetration-promoting agent~ can be employed alone or mixed with one another. A particularly good penetration-promoting ef~ect is produced by long-chain alcohol~ and, among the~e, in particular the 2-alkyl-substituted alcohols~ ~he oil~ are employed in contents of 5-95~ by weight, preferably from 30 to 90% by w~ight. The fine-particle actlve ingredie~ts can al80 be dispersed in water in which penetration-promoting oils are emulsified, in which ca~e ~he water content of the~e di~persions can be up ~o 50% by weight, preferably up to 30% by weight.
The following can be used as emulsifiers and wetting agent~:
alkylaryl polyglycol ether a}eohols, for example ~rriton types, ~Sapogena T, Arkopal t~pes; ~atty alcohol poly-3S glycol ether3 such as, for example, Emulsogen M, A and :
, : :
~05961D2 MS12, ~Genapol X-080,o al~yl diglycol ether ~ul$ate N~
salts such as, for example, Genapol LRO; Na lauryl sul~ate, for example ~Texapon R12; ethoxylated CaBtOr oil types ~uch as, for e~ample, ~Emulsogen ~; C3 to C2~-alcohol propylene oxide block alko~ylate~ such a~, for example, Hoe S 3510 and HOE S 2436, xylenol ethoxylate with 4-5 EO, tri~tyrylph2nol polyglycol ether and tri-styrylphenol polyglycol ether pho~phates such asy for example, ~oe S 3474 and Hoe S 3775r alkylaryl~ulfonic acid calcium and sodium salt~ such as, for example, phenylsulfonate Ca(70), sorbitan fa~ty acid esters, for example Span 60 and 80, polyoxyethylene ~orbitan fatty acld esters, for example l~een 60 and 80 and polyoxyethy-lene stearates, for e~ample ~Nyrj 45, 4g and 51.
Dispersant~ w~ich csn be employed are, inter alia:
ligninsulfonates such as, for ex~mple, ~Vani~perse CB and polymerized arylalkylsulfonlc acid~ such as, for example, ~Darvan No. 3, magn sium and aluminum stearates, especially al~minum monostearate. The auxiliarie~ are employed in contents of 0.5 to 30%, preferably from 1 to 10%, by weight.
Silicone antifoam S~2 can be used, inter alia, as anti- :
foam agent.
~he content of active ingredient in the formulation can be 1 to 60% by weight, preferably 5 20~ by weight.
::
The invention also relates to a process for the prepara-tion of a pour-on formulation, which compri~e~ converting the fine-particle active ingredients into a suitable : administration form.
Various proces~2s can be used to prepare the pour-on ~ormulation~/ as follows:
1. The active ingredient from the clas~ of benzimida-zoles, benzothiazoles or probenzimidazoles is finely ground în water with the addition of wetting agents -~
. , , . ~ .
,: . ~ , , . . .. : :
- . .
-` 2~9~2 - 6 ~
and using a bead mill; the penetration~ promoting oil i8 mi~ed wi~h an emulsifier and emulslfied in the aqueous disper~ion of active ingredient. ~his results in a ~u~po-emulsion in which the active ingredient i8 suspended as fine particles in water and in which the penetration-promoting oil i8 emulsified.
2. The active ingredient i~ ground in a penetration-promoting oil with the addition o~ wetting agent~
and disper~ants and u~ing a bead mlll.
\~ R 1 ` ~ N
H
Ia) in which Rl i8 methoxycarbonylamino and R2 i~ n-propylmercap~o (albendazo]Le)~ phenylmercapto (fenbendazole), phenyl~ulfinyl (oxfendazole), benzoyl (mebendazole3, p-~luorobenzoyl (flu-bendazole), p-~luorophenylsulfonyloxy (luxa-bendazolej~cyclopropylcarbonyl(cyclobendazol~) t butyl (parbendazole), n-propoxy ~oxibendazole) ::10 ~ or ~ (carbendaæim); or Ib) in which iL~ 4-thiazolyl and 2 i~ :H (thiabendazole) or isopr~poxycarbonylamino (cambendazole).
: 15 ~ R~3 tII) :in~::which : : : : :
R3 is methoa~carbonylamino and R4 iB n-propo~y ( tioxidazole ~ .
~III) in which ~.
`" 2 0 ~ -- 3 R5 is -N-C(NHCOOCH3)2, R6 is -NHCOCH20CH3, R7 is phenylmercapto and R8 i~ H ~febantel); or Rs is N C ~ NHCH2CH2S3H
R5 is NO2, R7 is H and R8 iB n-propylmercapto : 5 (netobimin); or R5 and R8 are each -NXCSNH-COOC2H~, ~' and R8 are each H (thiophanate).
These agents are sparingly ~oluble substances so that it has not hitherto been possible to prepare pour-Qn for-: 10 mulations in suitable ~olvents. Thi~ is why it ha~
hitherto been necessary to carry out a treatment o~
~ helminth-infected livestock (for example cattle or sheep) . :
: by the so-called drench proces~ or orally with the ~id of ; a bolus.
The use of th pour-on process would be consi.derably more economic for the treatment of large herds be~ause it is, inter alia, considerabIy les~ time-consuming and labor intensive. It i~ not necessary to immobilizs the live-~:~ stock, ~here is less risk to the treating person from -~: 20 defensive movement of the livestock, and thare i~ less tres~0 especially for livestQck unused to being handled.
It has been found, surprisingly, that fine-parkicle dispersions (suspenslons) o~ the said benzimidazoles, banzothiazoles and prQbenzimidazoles with anthelmintic ~ 25 activity are able, when suitable pene~ration-promoting : oils are u~ed and admini~tration i~ by the pour on process, to enter the body by the tran~dermal route, whera they display a good effect against nematodas and their stages parasitizing the dige~tive tract and tissues. To do this, it is merely necessary, when the do~age is suitable, to apply a stxip of the ~ormulation to ~he back of the livestock.
~: .
.
- - . . i , .
- 2 ~ 2 ~he invention therefore relates ~o preparations which have anthelmintic activity and which contain a~ active ingredient at least one henzimida~ole, b~nzothiazole or probenzimidazole with anthelmintic activity in fine-particle dispersion in a penetration-promoting agent. It is also possible to use mixtures of the said active : ingredients.
The particles of active ingredient in the~e disper~ion~
should have a parti~le ~ize from 0.05 to about 30 ~m, pre~erably from 0.5 to lU ~m.
Penetration-promoting oils which can be employecl are triglycerides of saturat2d vegetable fatty acids, for :~ example Miglyol 812~, triglycercol dii~ostearate or esters ~: of long-chain acid6, ~uch a~, for ~xample, oleyl oleate, : 15 isopropyl myristate, i~opropyl palmitate, 2-ethylhex~l palmitate r i~ooctyl stearate, isopropyl stearate, hexyl laurate or di n-butyl adipate; a~ w811 a~ long-chain alcohol~ such ~, for example, hexylalcohol, octyl al-cohol, decyl alcohol, oleyl alcoho~, 2-oetyldodecanol, 2-hexyldecanol or 2~octyldecanol. All the penetration-promoting agent~ can be employed alone or mixed with one another. A particularly good penetration-promoting ef~ect is produced by long-chain alcohol~ and, among the~e, in particular the 2-alkyl-substituted alcohols~ ~he oil~ are employed in contents of 5-95~ by weight, preferably from 30 to 90% by w~ight. The fine-particle actlve ingredie~ts can al80 be dispersed in water in which penetration-promoting oils are emulsified, in which ca~e ~he water content of the~e di~persions can be up ~o 50% by weight, preferably up to 30% by weight.
The following can be used as emulsifiers and wetting agent~:
alkylaryl polyglycol ether a}eohols, for example ~rriton types, ~Sapogena T, Arkopal t~pes; ~atty alcohol poly-3S glycol ether3 such as, for example, Emulsogen M, A and :
, : :
~05961D2 MS12, ~Genapol X-080,o al~yl diglycol ether ~ul$ate N~
salts such as, for example, Genapol LRO; Na lauryl sul~ate, for example ~Texapon R12; ethoxylated CaBtOr oil types ~uch as, for e~ample, ~Emulsogen ~; C3 to C2~-alcohol propylene oxide block alko~ylate~ such a~, for example, Hoe S 3510 and HOE S 2436, xylenol ethoxylate with 4-5 EO, tri~tyrylph2nol polyglycol ether and tri-styrylphenol polyglycol ether pho~phates such asy for example, ~oe S 3474 and Hoe S 3775r alkylaryl~ulfonic acid calcium and sodium salt~ such as, for example, phenylsulfonate Ca(70), sorbitan fa~ty acid esters, for example Span 60 and 80, polyoxyethylene ~orbitan fatty acld esters, for example l~een 60 and 80 and polyoxyethy-lene stearates, for e~ample ~Nyrj 45, 4g and 51.
Dispersant~ w~ich csn be employed are, inter alia:
ligninsulfonates such as, for ex~mple, ~Vani~perse CB and polymerized arylalkylsulfonlc acid~ such as, for example, ~Darvan No. 3, magn sium and aluminum stearates, especially al~minum monostearate. The auxiliarie~ are employed in contents of 0.5 to 30%, preferably from 1 to 10%, by weight.
Silicone antifoam S~2 can be used, inter alia, as anti- :
foam agent.
~he content of active ingredient in the formulation can be 1 to 60% by weight, preferably 5 20~ by weight.
::
The invention also relates to a process for the prepara-tion of a pour-on formulation, which compri~e~ converting the fine-particle active ingredients into a suitable : administration form.
Various proces~2s can be used to prepare the pour-on ~ormulation~/ as follows:
1. The active ingredient from the clas~ of benzimida-zoles, benzothiazoles or probenzimidazoles is finely ground în water with the addition of wetting agents -~
. , , . ~ .
,: . ~ , , . . .. : :
- . .
-` 2~9~2 - 6 ~
and using a bead mill; the penetration~ promoting oil i8 mi~ed wi~h an emulsifier and emulslfied in the aqueous disper~ion of active ingredient. ~his results in a ~u~po-emulsion in which the active ingredient i8 suspended as fine particles in water and in which the penetration-promoting oil i8 emulsified.
2. The active ingredient i~ ground in a penetration-promoting oil with the addition o~ wetting agent~
and disper~ants and u~ing a bead mlll.
3. When the substance with anthelmintic activity has the particle finenes described, wheth~r by the u~e of suitab1e precipitation methods in the preparation or by u~e of dry milling, for example~ it can also be homogenized in water after addition of wetting agents and dispersants without wet millin~. Tha oil is then emalsi~ied in the aqueou~ di~persion as described under 1. An air ~et mill such as, for ; example, a spiral ~et mill can be used for the dry milling of the active ingredients.
4. When the active ingredient has sufficient particle : fineness as described under 3., it can also be , , dispersQd in the penetration-promoting oil without wet milling when suitable wetting agent~ and dis-: ~ 25 persants, and ~uitable mixing and stirring equip-ment, are used.
;
~he following descriptions of preparationæ carried out with ~enbendazole by way ~f example are intended to explain processes 1. to 4. without restricting the invention thereto.
; A PE 075 stirrer mill from Netzsch-~einmahltechnik GmbH
was used for ~et milling o~ ~he active ingredients.
An ~ltra ~urra~ apparatus from Janke and Kunkel was . . , . , ~ , , , , .
~- ,, , , ; : , ~
: : : . : . ~ ::
205~2 employed :Eor the homogenization with a high-speed stirrer .
Example 1 7 . 5% strength fenbendazole pour-on formulation S Fenbendazole is milled together with wetting agents and dispexsants and with an antifoam in a stirrex mill until 8596 of the particles are smaller than 1 ~m, milling for about 4 hours being necessary for this. Glass beads with a diameter of 2 mm are used, the amount of ~hem present being twice as high as that of the active ingredient ~enbendaæole:
1. fenbendazole dispersion 40.00% by weight fenbendazole, 99.8% pu:re A.004 by weight ~enapol X-080 7.00% by weight ~Vanisperse CB
.00~ by weight 0Darvan No. 3 1~00% by weight silicone antifoam SE2 46.00% by weight water A solution of the emulsifier~ in the oils is pre-: 20 pared by stirring and heating ~ently at 35-40Cs 2. emulsi:Eier ~olution 9.3896 by weight phenylsulfonate Ca~70) 4 . 37~ by weight Hoe S 3510 6 . 25~ by weight Hoe S 3474-2 40.00~ by weight 2-octyldodecanol 21.25% by weight ~Miglyol 812 18.75% by weight of enbendazole dispersio~ ~1.) are added to the stirred emulsifier solution. ~he result ls a su~po-emulsion which can easily be poured, is stable on storage and can be used as pour-on .
2 ~
preparation.
Example 2 - 10~ strength fenbendazole pour-on formul~tion The ~ollowing mixture is ground in a ~tirrer mill using glass beads (diameter 2 mm~ until 80~ o the particles are smaller than 1 ~m:
1. fenbendazole di~persion 35.00% by weight fenbenda ole, techn. 99.8% p~re 4.00~ by weight Genapol X-080 7.00% by weight banisperse CB
2.00% by weight Darvan Mo. 3 1.00% by weighk ~Silicone antifoam SE2 51.00% by weight water ~ Then a solution of the emulsifiers in the oils i8 pre-: 15 pared by ~tirring and heating at 35-40~C:
2. emulsifier solution .38% by weight phenylsulfonate Ca (70 :4.37% by weight Hoe S 3510 6.25% by weight Hoa S 3474-2 30.00% by weight 2-octyldodecanol : 21.40~ by wei~ht ~iglyol 812 28.6~ by weighk of the aqueou3 fenbendazole di~per ~ion (1.) iB added 810wly to this emul~ifier 901u-tion wikh stirring. ~his re~ults in a fenbendazole pour-on formulation which can easily be poured and is stable on ~torage.
Example 3 10% ~trength fenbendazole pour-on ormulation '~
A formulation of khe following compo~ition i8 prepared as : : - ...................... .
:: :; . . :
-" 2~96~
_ 9 _ described in Example~ 1 and 2:
10.02~ by weight fenbenda~ol~, 99.8~ pure - 1.00~ by weight ~Genapol X-080 1.75% by weight ~Vanisperse C~
0.50% by weight ~Darvan No. 3 0.25~ by weight silicone antifoam SE2 11.48% by w~ight water 9.37~ by weight phenylsulfonate Ca (70) 6.25% by weight Hoe S 3474-2 4.38% by weight Hoe S 3510 35.00~ by wei~ht 2-octyldodecanol 20.00% by ~eight ~Miglyol 812 The formulation can easily he poured and is ~table on : s~orage with respect to homogeneity and stabili~.y of active in~redient.
; Example 4 ::
A fenbenda~ole dispersion is milled in a bead mill for 4 hours as described in Examples 1 and 2 until 82% of the particles are ~maller than 1 ~m-: 20 1. fenbendazole di~persion 40.00% by weight fenbendaæole, techn. ~9.8% pure 4.00% by weight Genapol LRO pa~te 56.00% by weight water Then a solution of the emulsi~iers in the mixture of 2-octyldodecanol and MiglyoI 812~ i8 prepared by stirrin~
and heating at 35-40Cs 2. emulsifiex solution 9.38% by weight phenylsulfonate Ca (70) 4.37% by weight Hoe S 3510 6.25% by weight Hoe S 3474-2 2 ~
~ 10 -35.00% by weight 2-octyldodecanol ~0.00~ by w~ight qMiglyol 812 25O00~ by weigh~ of the described fenbendazole dispersion (l.) are 810wly ad~ed to the emulsifier solution with stirring. This re~ults in a fenben-dazole pour-on formulation which can be adminis~ered satis~actorily.
Example 5 Firstly a 40% ~krength fenbendazole di~persion in water is prepared. Milling tLme 4 hour6, particle si~e reached:
80% < l ~m.
1. fenbendaæole dispersion 40.00% by weight fenbendazole, techn. 9~.8~ pure 4.00% by weight ~enapol LRO paste 56.00~ by weight water 25.0% by weight of the fenbendazole dispersion (1.~
is added to 70.0% by weight of 2 octyldodecanol with stirring; subsequently 5% o$ water are al~o added, ; likewise with stirring.
The result is a 10% strength fenbendazole pour-on formulation which has good pourahility and has very good storage stability.
.
Example 6 The preparation method is as described in Example 5 but the fenbendazole dispersion is only homogenized and not milled 80 that the active ingredient fenbendazole i~ u ed in the particle size as produced:in the preparation~ 50%
o~ the particles ~ 6 ~m.
10% strength fenbendazole pour-on formulation 10.00% by weight fenbendazole, 99.98% pure 1.00% by weight ~Texapon X12 . , . - .
- ~ , . .
- . .: .
. . . . ~ . . .
.
2 ~ 0 2 19.00~ by weight water 70.00% by weight 2-octyldodecanol The formulation is stable on storage and can be administered satisfactorily.
~xample 7 Preparation method as described for E~ample 5. Fenben-dazole particle finene~s 80~ m.
10% strength fenbendazole pour-on formulation :, ~
: 10.00% by weight fenbendazole, 99.98% pure ~:
1.0~% by weig~t ~Te~apon R12 24.00~ by weight water 25,Q0% by weight ~Miglyol 812 40.00% by weight 2-octyldodecanol ~' .
: The result is a pour-on formulation which i~ stable on storage and can be administered sati6factorily.
: Example 8 Preparation method as described for ~xample 5. ~enben-dazole particle finenes~ 50~ ~ 6 ~im.
.:
~; 10% strength fenb~ndazole pour-on formulation : 20 10.00~ by wei~ht fenbendazole, 99.98~ pure 1.00% by weight ~Texapon X12 : 24.00% by weight water 25.00% by weight ~Mlglyol 812 40.00% by weight 2-octyldodecanol The o.rmulation has good storage stability and can be poured satisfactorily.
' ,' ~ .
2 ~
Example 9 Preparation method as descxibed in Example 4. Particle fineness 82% < 1 ~m.
10% strength fenbendazole pour~on formulation 10.00% by wei~ht fenbendazole, 99.98% pure l.Q0~ by weight ~Genapol LRO
39.00% by weight water 15.00% by weight Emulsogen A
35.00% by weight 2-octyldodecanol The result is a pour-on formulation which has good storage stability and good pourabili~y.
Example 10 Preparation method as described for Example 4, but ~Span 60 is dissolved in 2-octyldodecanol at 80-90C. Fenben-dazole particle fineness 82% < 1 ~m.
10% strangth fenbendazole pour-on for~ulation 10.00~ by weight fenbendazole, 99.98~ pure 0.89~ by weigh~ 0Texapon ~12 Zl.33% by weight water 1.00% by weight Span 60 66.78% by weight 2-octyldodecanol The formulation is stable on storag2 and can be administered sat.isfactorily.
Example 11 Fixstly, ~Span ~0 i8 dissolved in 2-octyldodecanol at 80-90C with stirring. Afker cooling to about 50~C, fenbendazole is added; particle ~ize: 5Q% of particles c 6 ~m.
10% ~tr~ngth fenbendazole pour-on formulation .
, - , ~ . .
:
:~ :
2~9~
10.00% by weight fenbenda201e, 99.98~ pure 10.00% ~y weight 0Span 60 80.00% by weight 2-octyldodecanol `
~he mixtuxe i5 homogenized with a high-~peed Ultra Turrax ~ stirrer.
Example 12 For preparation, see Example 11; fenbendazole particle siæe: 50% of particles < 6 ~m.
7.5~ strength fenbendazole pour-on formulation 7.50% by weigh~ feDbendazole, 99.98% pure 10.00~ by weight ~Span 60 82.50% by weight 2-octyldodecanol The mixture is homogenized with a high-~peed Ultxa Turrax stirrer.
.
.: 15 Example 13 Preparation method as described in Exampie 4 and 10.
Fenbendazole pa~ticle ~ize 50% < 5 ~m.
10% strength fenbendazole pour-on formulation 10.00% by weight fenbendazole, 99.98% pure 1.00~ by weigh~ qTexapon ~12 24.00% by weight water 1.00% by weight ~Span 60 64.00% by weight 2~octyldodecanol .
A formulation which can be administered satl~ac-torily is obtained.
Example 14 Alumin~m mono~tearate ia dissolved in 2-octyldodecanol at `
140~150C and kept at this temperature for 30 :minutes .. ~
- 14 - 2~ 2 with stirring. ~fter cooling to About 50C, fenb~ndazole is added and homoganized with a high speed ~ltra-Turra~
stirrer.
Fenbendazvle particle siæe: 50% of particleB ~ 6 ~m.
10% strength fenbendazole pour-on fo.rmulation 10.00~ by weight fenbendazole, ~9.98% pure 1.00% by weight aluminum monosteara~e 89.00~ by weight 2-oc~yldodecano].
A suspension which can easily be poured is obtained.
Example 15 Aluminum monostearate is dissolved in 2-octyldodecanol at 1~0-150C and kept at this temperature for 30 minukes with ætirring. After cooling to about 100C, ~Span 60 is added and, at 50 fenbendazole, both likewise with stirring. Homogenization is ~ubse~uently ¢arried out wlth a high-speed Ultra-~urrax stirrer.
Fenbendazole particle size. 50% o~ particle~ < 6 ~m.
i 10% ~kFength fenbendazole pour-on formulation 10.00% by weight fenbendazole, 99.98~ pure 1.00~ by weight ~Span 60 2.50%:by wei~ht aluminum monostearate :~ 86.50~ by weight 2-octyldodecano1 A formula~ion with good s~orage stability and good pourability i8 obtained.
Example 16 Preparation method as described for Example 15 Fenbendazole paxticle ~ize: 50~ of particles < 6 ~m.
20% strength fenbendazole pour-on formulation 20.00~ by weight fenbendazole~ 99.98% pure .. . .. ..
: : , ~ . . . - - .
. . .
20~9~2 l.00~ by weight ~Span 60 1.50~ by weight aluminum monostearate 77.50% by weight 2-octyldodecanol Example 17 S Preparation method as described or ExEmple 15.
Fenbendazole particle ~ize: 50~ of particles ~ 6 ~m.
11.37~ strength fenb~ndazole pour-on formulation 11.37~ by weight fenbendazole, 99.98~ pure - 100 g/l 1.14% by weight ~Span 60 2.85% by weigh~ aluminum mono~tearate 84.64% by weight 2-octyldodecanol Example 18 8.53~ stxength fenbendazole pour-on formulation 8.53~ by weight fenbendazole, 99.98% pure - 75 g/l 1.14% by weight ~Span ~0 ~, 2.85% by weight aluminum monostearate 87.48% by weight 2-octyldodecanol .
Example 19 ~ ' 5.75% strength fenbendazole pour-on formulation ':
5.75~ by weight fenbendazole, 99.98~ pure - 50 gJl ~:
1.15~ by weight 5pan 60 2.88~ by weight aluminum monosteara~e 90.22% by weight 2-octyldodecanol The products prepared in Examples 16 to 19 have ~ood ~5 storage stability with regard to pha~e separation and con~tancy of ac~ive ingredient content. ~hey can easily be poured and can thsrefore be administered :
as pour-on formulation~ satisfactorily.
, .
. .
2~6~2 Example 20 11.37% strength fenbendazole pour-on formulation 11.37% by weight fenbendazole, 99.98% pure g~l S 2.30% by weight Spa~ 60 1.70% by weight aluminum monostearate 84.62~ by weight 2-octyldodecanol ::
The process i8 as described i~ Example 15. The fenbendazole used is previously milled in a spiral jet mill until 50% of the particle~ have a particle ; size ~ 2.8 ~m.
:~ ~xamples 21-26 ~.
For preparation method, ~ee Example 11 lO.OOg by weight anthelmintic agent ~see Tab. I) I0.00% by weight ~Span 60 80.00% by wei~ht 2-octyldodecanol .
A 5~ strength formulation o~ thiabendazole was prepared:
: 5.0~% by weight thiabendazole 10.00% by wei~ht Qspan 60 85.00~ by weight 2-octyldo~ecanol . ~ , -20S~2 Table I
xample Anthelmin~ic agQnt Formula __.
S 21 O~ibendazole Ia . _ _ _ _ ,_ _ 22 Parbendazole Ia _ ___ _ _ 23 Albendazole a 24 Mebendazole Ia .
Thiabendazole Ib __ _ _ r _ _ _ ;
26 Febantel III
Biological activity The investigations were carried out on cattle which had been arti~icially infected wi~h the economically impor-tant gastrointestinal nematodes of r~minants - Ostertagia ostertagi, Trichostrongylus axei, Trlchostrongylus colubriformis and Cooperia oncophora. The activity was measured by dissection with determination of the worm burden compared with untreated control animal~. The ~5 treatment by pouring on the formulations along the dorsal line of the livestock usually takes place 14 days after infec~ion; at this time the nematodes are still immature and particularly difficult to influence by anthelmintics.
~ he investigations were carried out in accordance with the guidelines of the WAA~P (World Assoaiation for the Advancement of ~eterinary Parasitology; Powers, R.~ et al., Vet. Parasitvl. ~1982) lO, 265-284).
Individual investigations and results are compiled in the following Table II.
.. . .
. ~ , ~ , , .- ~ :
. : - . -. : ~ . - . : : -: :
18 2~5~602 Table I I
~cti~ity oiE feD~endazole in various eour-oDL prsparations against innnature stages of 5~astrointestinal n~matodes of ~attle ___ __ __ ~ hÆ~ ~ 1~ D ~e R~mil~ rq~ c~3e P~l~ d t~[l h~n, ~ ~n~ 0~1s exa~e ~. n~ a~s --`T--~ __ O~p~ I T~a~ C~peru .. __ _ ~ ~_ :olcbdlo=~c oncophora 1 3.75 4 g9 98 lOO 100 7.50 4 72 94 1~0 94 I .
l I
2 3.75 4 ~ 9~ 98 .S~ 4 86 92 94 93 3 3~75 4 98 99 100 g9 l 7.50 4 ~9 lOO 100 100 I as~ ~xm h~l aE I
l t~ csr~:iL gr~> (~) 3922 48~ 132 27 __ === _== _~ r=31: ~= ==_ !
4 7.~0 3 _ _ 100 99,1 750 3 78 g8 100 100 6 7.50 3 91 80 IOD 100 7 7.50 3 36 ~9 99 8 7,50 3 60 20 ~8 100 9 7.50 ~ 99 100 100 100 ¦ ~F ~m~n ~ 2610 26D 1067 1957 I ~ c~ g~p (rF3) I
, ___ __ __ __ _= _ _.==
7.50 7 99 99 Iloo 99 l ~1 7.5~:) 7 91 99 ~9 99 .-a~ ~I h~ 6S73 649 479 2279 ~e ~a C~lp tlE=7) I_c__ _ _== _ _ _ -!
11 ~.0 7 82 92 100 99 7.S 7 70 g3 ~9 98 13 5.0 7 66 B6 100 9t .5 7 91 99 D9 199 ~4 5.0 7 68 97 99 99 7.5 7 84 98 g9 99 S.O 7 > B0 :~ 90 ~ 98 > 98 7,5 7 > ~0 ~ 95 :~ Dl~ > 98 ,a~ ~ h~l aE 5763 1190 ~SI~g 3t67 a~L 9L~p (IF7) __ _~
::
`
19 2~ 2 An indicati~e test was carried out ~o establish the activity of pour-on formulations of fenbendazole, oxiben--dazole, parbendazole, albendazole, mebendazole, thiaben-dazole and febantel (preparation examples 20-25~ on Trichostrongylus oolubriformis in rodents: ~irds (Meriones unguiculatus).
The dosage was in ~ach ca~e 0~2 ml per animal, and 0.4 ml with thiabendazole and additionally 0.1 and O.OS ml with fenbendazole; this volume was dripped onto the ~haven area of the back of the neck of the jirds. ~he possi-bility of intake of active ingredient by licking was prevented l:y khe location of the admini6tration site and the housing of the animals ~ingly.
The re~ult~ ar= li~ted in l!able III.
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;
~he following descriptions of preparationæ carried out with ~enbendazole by way ~f example are intended to explain processes 1. to 4. without restricting the invention thereto.
; A PE 075 stirrer mill from Netzsch-~einmahltechnik GmbH
was used for ~et milling o~ ~he active ingredients.
An ~ltra ~urra~ apparatus from Janke and Kunkel was . . , . , ~ , , , , .
~- ,, , , ; : , ~
: : : . : . ~ ::
205~2 employed :Eor the homogenization with a high-speed stirrer .
Example 1 7 . 5% strength fenbendazole pour-on formulation S Fenbendazole is milled together with wetting agents and dispexsants and with an antifoam in a stirrex mill until 8596 of the particles are smaller than 1 ~m, milling for about 4 hours being necessary for this. Glass beads with a diameter of 2 mm are used, the amount of ~hem present being twice as high as that of the active ingredient ~enbendaæole:
1. fenbendazole dispersion 40.00% by weight fenbendazole, 99.8% pu:re A.004 by weight ~enapol X-080 7.00% by weight ~Vanisperse CB
.00~ by weight 0Darvan No. 3 1~00% by weight silicone antifoam SE2 46.00% by weight water A solution of the emulsifier~ in the oils is pre-: 20 pared by stirring and heating ~ently at 35-40Cs 2. emulsi:Eier ~olution 9.3896 by weight phenylsulfonate Ca~70) 4 . 37~ by weight Hoe S 3510 6 . 25~ by weight Hoe S 3474-2 40.00~ by weight 2-octyldodecanol 21.25% by weight ~Miglyol 812 18.75% by weight of enbendazole dispersio~ ~1.) are added to the stirred emulsifier solution. ~he result ls a su~po-emulsion which can easily be poured, is stable on storage and can be used as pour-on .
2 ~
preparation.
Example 2 - 10~ strength fenbendazole pour-on formul~tion The ~ollowing mixture is ground in a ~tirrer mill using glass beads (diameter 2 mm~ until 80~ o the particles are smaller than 1 ~m:
1. fenbendazole di~persion 35.00% by weight fenbenda ole, techn. 99.8% p~re 4.00~ by weight Genapol X-080 7.00% by weight banisperse CB
2.00% by weight Darvan Mo. 3 1.00% by weighk ~Silicone antifoam SE2 51.00% by weight water ~ Then a solution of the emulsifiers in the oils i8 pre-: 15 pared by ~tirring and heating at 35-40~C:
2. emulsifier solution .38% by weight phenylsulfonate Ca (70 :4.37% by weight Hoe S 3510 6.25% by weight Hoa S 3474-2 30.00% by weight 2-octyldodecanol : 21.40~ by wei~ht ~iglyol 812 28.6~ by weighk of the aqueou3 fenbendazole di~per ~ion (1.) iB added 810wly to this emul~ifier 901u-tion wikh stirring. ~his re~ults in a fenbendazole pour-on formulation which can easily be poured and is stable on ~torage.
Example 3 10% ~trength fenbendazole pour-on ormulation '~
A formulation of khe following compo~ition i8 prepared as : : - ...................... .
:: :; . . :
-" 2~96~
_ 9 _ described in Example~ 1 and 2:
10.02~ by weight fenbenda~ol~, 99.8~ pure - 1.00~ by weight ~Genapol X-080 1.75% by weight ~Vanisperse C~
0.50% by weight ~Darvan No. 3 0.25~ by weight silicone antifoam SE2 11.48% by w~ight water 9.37~ by weight phenylsulfonate Ca (70) 6.25% by weight Hoe S 3474-2 4.38% by weight Hoe S 3510 35.00~ by wei~ht 2-octyldodecanol 20.00% by ~eight ~Miglyol 812 The formulation can easily he poured and is ~table on : s~orage with respect to homogeneity and stabili~.y of active in~redient.
; Example 4 ::
A fenbenda~ole dispersion is milled in a bead mill for 4 hours as described in Examples 1 and 2 until 82% of the particles are ~maller than 1 ~m-: 20 1. fenbendazole di~persion 40.00% by weight fenbendaæole, techn. ~9.8% pure 4.00% by weight Genapol LRO pa~te 56.00% by weight water Then a solution of the emulsi~iers in the mixture of 2-octyldodecanol and MiglyoI 812~ i8 prepared by stirrin~
and heating at 35-40Cs 2. emulsifiex solution 9.38% by weight phenylsulfonate Ca (70) 4.37% by weight Hoe S 3510 6.25% by weight Hoe S 3474-2 2 ~
~ 10 -35.00% by weight 2-octyldodecanol ~0.00~ by w~ight qMiglyol 812 25O00~ by weigh~ of the described fenbendazole dispersion (l.) are 810wly ad~ed to the emulsifier solution with stirring. This re~ults in a fenben-dazole pour-on formulation which can be adminis~ered satis~actorily.
Example 5 Firstly a 40% ~krength fenbendazole di~persion in water is prepared. Milling tLme 4 hour6, particle si~e reached:
80% < l ~m.
1. fenbendaæole dispersion 40.00% by weight fenbendazole, techn. 9~.8~ pure 4.00% by weight ~enapol LRO paste 56.00~ by weight water 25.0% by weight of the fenbendazole dispersion (1.~
is added to 70.0% by weight of 2 octyldodecanol with stirring; subsequently 5% o$ water are al~o added, ; likewise with stirring.
The result is a 10% strength fenbendazole pour-on formulation which has good pourahility and has very good storage stability.
.
Example 6 The preparation method is as described in Example 5 but the fenbendazole dispersion is only homogenized and not milled 80 that the active ingredient fenbendazole i~ u ed in the particle size as produced:in the preparation~ 50%
o~ the particles ~ 6 ~m.
10% strength fenbendazole pour-on formulation 10.00% by weight fenbendazole, 99.98% pure 1.00% by weight ~Texapon X12 . , . - .
- ~ , . .
- . .: .
. . . . ~ . . .
.
2 ~ 0 2 19.00~ by weight water 70.00% by weight 2-octyldodecanol The formulation is stable on storage and can be administered satisfactorily.
~xample 7 Preparation method as described for E~ample 5. Fenben-dazole particle finene~s 80~ m.
10% strength fenbendazole pour-on formulation :, ~
: 10.00% by weight fenbendazole, 99.98% pure ~:
1.0~% by weig~t ~Te~apon R12 24.00~ by weight water 25,Q0% by weight ~Miglyol 812 40.00% by weight 2-octyldodecanol ~' .
: The result is a pour-on formulation which i~ stable on storage and can be administered sati6factorily.
: Example 8 Preparation method as described for ~xample 5. ~enben-dazole particle finenes~ 50~ ~ 6 ~im.
.:
~; 10% strength fenb~ndazole pour-on formulation : 20 10.00~ by wei~ht fenbendazole, 99.98~ pure 1.00% by weight ~Texapon X12 : 24.00% by weight water 25.00% by weight ~Mlglyol 812 40.00% by weight 2-octyldodecanol The o.rmulation has good storage stability and can be poured satisfactorily.
' ,' ~ .
2 ~
Example 9 Preparation method as descxibed in Example 4. Particle fineness 82% < 1 ~m.
10% strength fenbendazole pour~on formulation 10.00% by wei~ht fenbendazole, 99.98% pure l.Q0~ by weight ~Genapol LRO
39.00% by weight water 15.00% by weight Emulsogen A
35.00% by weight 2-octyldodecanol The result is a pour-on formulation which has good storage stability and good pourabili~y.
Example 10 Preparation method as described for Example 4, but ~Span 60 is dissolved in 2-octyldodecanol at 80-90C. Fenben-dazole particle fineness 82% < 1 ~m.
10% strangth fenbendazole pour-on for~ulation 10.00~ by weight fenbendazole, 99.98~ pure 0.89~ by weigh~ 0Texapon ~12 Zl.33% by weight water 1.00% by weight Span 60 66.78% by weight 2-octyldodecanol The formulation is stable on storag2 and can be administered sat.isfactorily.
Example 11 Fixstly, ~Span ~0 i8 dissolved in 2-octyldodecanol at 80-90C with stirring. Afker cooling to about 50~C, fenbendazole is added; particle ~ize: 5Q% of particles c 6 ~m.
10% ~tr~ngth fenbendazole pour-on formulation .
, - , ~ . .
:
:~ :
2~9~
10.00% by weight fenbenda201e, 99.98~ pure 10.00% ~y weight 0Span 60 80.00% by weight 2-octyldodecanol `
~he mixtuxe i5 homogenized with a high-~peed Ultra Turrax ~ stirrer.
Example 12 For preparation, see Example 11; fenbendazole particle siæe: 50% of particles < 6 ~m.
7.5~ strength fenbendazole pour-on formulation 7.50% by weigh~ feDbendazole, 99.98% pure 10.00~ by weight ~Span 60 82.50% by weight 2-octyldodecanol The mixture is homogenized with a high-~peed Ultxa Turrax stirrer.
.
.: 15 Example 13 Preparation method as described in Exampie 4 and 10.
Fenbendazole pa~ticle ~ize 50% < 5 ~m.
10% strength fenbendazole pour-on formulation 10.00% by weight fenbendazole, 99.98% pure 1.00~ by weigh~ qTexapon ~12 24.00% by weight water 1.00% by weight ~Span 60 64.00% by weight 2~octyldodecanol .
A formulation which can be administered satl~ac-torily is obtained.
Example 14 Alumin~m mono~tearate ia dissolved in 2-octyldodecanol at `
140~150C and kept at this temperature for 30 :minutes .. ~
- 14 - 2~ 2 with stirring. ~fter cooling to About 50C, fenb~ndazole is added and homoganized with a high speed ~ltra-Turra~
stirrer.
Fenbendazvle particle siæe: 50% of particleB ~ 6 ~m.
10% strength fenbendazole pour-on fo.rmulation 10.00~ by weight fenbendazole, ~9.98% pure 1.00% by weight aluminum monosteara~e 89.00~ by weight 2-oc~yldodecano].
A suspension which can easily be poured is obtained.
Example 15 Aluminum monostearate is dissolved in 2-octyldodecanol at 1~0-150C and kept at this temperature for 30 minukes with ætirring. After cooling to about 100C, ~Span 60 is added and, at 50 fenbendazole, both likewise with stirring. Homogenization is ~ubse~uently ¢arried out wlth a high-speed Ultra-~urrax stirrer.
Fenbendazole particle size. 50% o~ particle~ < 6 ~m.
i 10% ~kFength fenbendazole pour-on formulation 10.00% by weight fenbendazole, 99.98~ pure 1.00~ by weight ~Span 60 2.50%:by wei~ht aluminum monostearate :~ 86.50~ by weight 2-octyldodecano1 A formula~ion with good s~orage stability and good pourability i8 obtained.
Example 16 Preparation method as described for Example 15 Fenbendazole paxticle ~ize: 50~ of particles < 6 ~m.
20% strength fenbendazole pour-on formulation 20.00~ by weight fenbendazole~ 99.98% pure .. . .. ..
: : , ~ . . . - - .
. . .
20~9~2 l.00~ by weight ~Span 60 1.50~ by weight aluminum monostearate 77.50% by weight 2-octyldodecanol Example 17 S Preparation method as described or ExEmple 15.
Fenbendazole particle ~ize: 50~ of particles ~ 6 ~m.
11.37~ strength fenb~ndazole pour-on formulation 11.37~ by weight fenbendazole, 99.98~ pure - 100 g/l 1.14% by weight ~Span 60 2.85% by weigh~ aluminum mono~tearate 84.64% by weight 2-octyldodecanol Example 18 8.53~ stxength fenbendazole pour-on formulation 8.53~ by weight fenbendazole, 99.98% pure - 75 g/l 1.14% by weight ~Span ~0 ~, 2.85% by weight aluminum monostearate 87.48% by weight 2-octyldodecanol .
Example 19 ~ ' 5.75% strength fenbendazole pour-on formulation ':
5.75~ by weight fenbendazole, 99.98~ pure - 50 gJl ~:
1.15~ by weight 5pan 60 2.88~ by weight aluminum monosteara~e 90.22% by weight 2-octyldodecanol The products prepared in Examples 16 to 19 have ~ood ~5 storage stability with regard to pha~e separation and con~tancy of ac~ive ingredient content. ~hey can easily be poured and can thsrefore be administered :
as pour-on formulation~ satisfactorily.
, .
. .
2~6~2 Example 20 11.37% strength fenbendazole pour-on formulation 11.37% by weight fenbendazole, 99.98% pure g~l S 2.30% by weight Spa~ 60 1.70% by weight aluminum monostearate 84.62~ by weight 2-octyldodecanol ::
The process i8 as described i~ Example 15. The fenbendazole used is previously milled in a spiral jet mill until 50% of the particle~ have a particle ; size ~ 2.8 ~m.
:~ ~xamples 21-26 ~.
For preparation method, ~ee Example 11 lO.OOg by weight anthelmintic agent ~see Tab. I) I0.00% by weight ~Span 60 80.00% by wei~ht 2-octyldodecanol .
A 5~ strength formulation o~ thiabendazole was prepared:
: 5.0~% by weight thiabendazole 10.00% by wei~ht Qspan 60 85.00~ by weight 2-octyldo~ecanol . ~ , -20S~2 Table I
xample Anthelmin~ic agQnt Formula __.
S 21 O~ibendazole Ia . _ _ _ _ ,_ _ 22 Parbendazole Ia _ ___ _ _ 23 Albendazole a 24 Mebendazole Ia .
Thiabendazole Ib __ _ _ r _ _ _ ;
26 Febantel III
Biological activity The investigations were carried out on cattle which had been arti~icially infected wi~h the economically impor-tant gastrointestinal nematodes of r~minants - Ostertagia ostertagi, Trichostrongylus axei, Trlchostrongylus colubriformis and Cooperia oncophora. The activity was measured by dissection with determination of the worm burden compared with untreated control animal~. The ~5 treatment by pouring on the formulations along the dorsal line of the livestock usually takes place 14 days after infec~ion; at this time the nematodes are still immature and particularly difficult to influence by anthelmintics.
~ he investigations were carried out in accordance with the guidelines of the WAA~P (World Assoaiation for the Advancement of ~eterinary Parasitology; Powers, R.~ et al., Vet. Parasitvl. ~1982) lO, 265-284).
Individual investigations and results are compiled in the following Table II.
.. . .
. ~ , ~ , , .- ~ :
. : - . -. : ~ . - . : : -: :
18 2~5~602 Table I I
~cti~ity oiE feD~endazole in various eour-oDL prsparations against innnature stages of 5~astrointestinal n~matodes of ~attle ___ __ __ ~ hÆ~ ~ 1~ D ~e R~mil~ rq~ c~3e P~l~ d t~[l h~n, ~ ~n~ 0~1s exa~e ~. n~ a~s --`T--~ __ O~p~ I T~a~ C~peru .. __ _ ~ ~_ :olcbdlo=~c oncophora 1 3.75 4 g9 98 lOO 100 7.50 4 72 94 1~0 94 I .
l I
2 3.75 4 ~ 9~ 98 .S~ 4 86 92 94 93 3 3~75 4 98 99 100 g9 l 7.50 4 ~9 lOO 100 100 I as~ ~xm h~l aE I
l t~ csr~:iL gr~> (~) 3922 48~ 132 27 __ === _== _~ r=31: ~= ==_ !
4 7.~0 3 _ _ 100 99,1 750 3 78 g8 100 100 6 7.50 3 91 80 IOD 100 7 7.50 3 36 ~9 99 8 7,50 3 60 20 ~8 100 9 7.50 ~ 99 100 100 100 ¦ ~F ~m~n ~ 2610 26D 1067 1957 I ~ c~ g~p (rF3) I
, ___ __ __ __ _= _ _.==
7.50 7 99 99 Iloo 99 l ~1 7.5~:) 7 91 99 ~9 99 .-a~ ~I h~ 6S73 649 479 2279 ~e ~a C~lp tlE=7) I_c__ _ _== _ _ _ -!
11 ~.0 7 82 92 100 99 7.S 7 70 g3 ~9 98 13 5.0 7 66 B6 100 9t .5 7 91 99 D9 199 ~4 5.0 7 68 97 99 99 7.5 7 84 98 g9 99 S.O 7 > B0 :~ 90 ~ 98 > 98 7,5 7 > ~0 ~ 95 :~ Dl~ > 98 ,a~ ~ h~l aE 5763 1190 ~SI~g 3t67 a~L 9L~p (IF7) __ _~
::
`
19 2~ 2 An indicati~e test was carried out ~o establish the activity of pour-on formulations of fenbendazole, oxiben--dazole, parbendazole, albendazole, mebendazole, thiaben-dazole and febantel (preparation examples 20-25~ on Trichostrongylus oolubriformis in rodents: ~irds (Meriones unguiculatus).
The dosage was in ~ach ca~e 0~2 ml per animal, and 0.4 ml with thiabendazole and additionally 0.1 and O.OS ml with fenbendazole; this volume was dripped onto the ~haven area of the back of the neck of the jirds. ~he possi-bility of intake of active ingredient by licking was prevented l:y khe location of the admini6tration site and the housing of the animals ~ingly.
The re~ult~ ar= li~ted in l!able III.
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,............ ~ . . . . ~ . .
Claims (10)
1. A preparation which has anthelmintic activity and contains as active ingredient at least one ben-zimidazole, benzothiazole or probenzimidazole with anthelmintic activity in fine-particle dispersion in a penetration-promoting agent.
2. An agent as claimed in claim 1, in which the par-ticles of active ingredient in the dispersion have a particle size of 0.05-30 µm.
3. An agent as claimed in claim 1 or 2, in which the content of active ingredient is 1-60% by weight, preferably 5-20% by weight.
4. An agent as claimed in any of claims 1 to 3, in which are employed a penetration-promoting oil as penetration-promoting agent in a content of 5-95% by weight, together with auxiliaries such as emul-sifiers, wetting agents and/or dispersants in contents of 0.5-30% by weight and antifoam agents in contents of 3-60% by weight.
5. An agent as claimed in any of claims 1 to 4, con-taining the active ingredient fenbendazole.
6. An agent as claimed in any of claims 1 to 5 for transdermal use for the control of helminths in livestock.
7. A process for the preparation of an agent as claimed in any of claims 1 to 6, which comprises converting the fine-particle active ingredient into a suitable administration form.
8. Derivatives of benzimidazoles, benzothiazoles or probenzimidazoles in fine-particle form for trans-dermal use for the control of helminths in livestock.
9. A pour-on process for controlling helminths in livestock, which comprises transdermal use of an agent as claimed in any of claims 1 to 6.
10. The use of an agent as claimed in any of claims 1 to 5 or of a compound as claimed in claim 8 for the transdermal treatment of livestock.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4101540.1 | 1991-01-19 | ||
DE4101540 | 1991-01-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2059602A1 true CA2059602A1 (en) | 1992-07-20 |
Family
ID=6423341
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002059602A Abandoned CA2059602A1 (en) | 1991-01-19 | 1992-01-17 | Pour-on formulation for the administration of anthelmintics |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP0496316A1 (en) |
JP (1) | JPH04312504A (en) |
AU (1) | AU658598B2 (en) |
BG (1) | BG95755A (en) |
BR (1) | BR9200163A (en) |
CA (1) | CA2059602A1 (en) |
CS (1) | CS14992A3 (en) |
FI (1) | FI920190A (en) |
HU (1) | HU208623B (en) |
IE (1) | IE920150A1 (en) |
MX (1) | MX9200225A (en) |
NO (1) | NO920234L (en) |
PL (1) | PL293227A1 (en) |
TR (1) | TR27833A (en) |
UY (1) | UY23355A1 (en) |
YU (1) | YU2792A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6955818B1 (en) | 1999-12-02 | 2005-10-18 | Eli Lilly And Company | Pour-on formulations |
US7772194B2 (en) | 2001-09-17 | 2010-08-10 | Eli Lilly And Company | Pesticidal formulations |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX9207344A (en) * | 1991-12-16 | 1993-07-01 | Alza Corp | IMPROVED FORMULATIONS THAT HAVE HYDROPHOBIC IMPROVERS OF TRANSDERMIC PENETRATION AND METHOD TO PROVIDE IT. |
US5629019A (en) * | 1992-02-27 | 1997-05-13 | Alza Corporation | Formulations with hydrophobic permeation enhancers |
NZ260018A (en) * | 1994-03-03 | 1995-10-26 | Bomac Lab Ltd | Benzimidazole compositions and anthelmintic compositions |
FR2755824B1 (en) * | 1996-11-19 | 1999-01-08 | Virbac Sa | GALENIC FORMULATION OF BENZIMIDAZOLES FOR TOPICAL USE, PREPARATION METHOD AND USES THEREOF |
CR6243A (en) * | 1999-09-20 | 2008-04-16 | Syngenta Participations Ag | PESTICIDED FORMULATIONS CONTAINING ALCOXYLATED POLYARYLPHENOLPHOSPHATOESTER TENSOACTIVE AND ALCOXYLATED LIGNOSULPHONATE TENSOACTIVE |
WO2001095723A1 (en) * | 2000-06-15 | 2001-12-20 | Ssl International Plc | Parasiticidal composition |
US11160867B2 (en) * | 2017-05-11 | 2021-11-02 | Auburn University | Anti-protozoal compounds and uses thereof |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA751024B (en) * | 1974-03-11 | 1976-01-28 | Lilly Co Eli | Control of animal parasites with benzimidazoles |
US4018932A (en) * | 1975-11-03 | 1977-04-19 | American Cyanamid Company | Anthelmintic pour-on formulations for topical use on domestic and farm animals |
DE3029426A1 (en) * | 1980-08-02 | 1982-03-11 | Bayer Ag, 5090 Leverkusen | AGAINST EFFECTIVE POUR-ON FORMULATIONS |
DE3045913A1 (en) * | 1980-12-05 | 1982-07-08 | Bayer Ag, 5090 Leverkusen | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE |
US4607050A (en) * | 1981-10-19 | 1986-08-19 | Wellcome Australia Limited | Method of controlling insects and parasites with an aqueous localized pour-on formulation |
MA19678A1 (en) * | 1982-01-13 | 1983-10-01 | Ciba Geigy Ag | ANTI-HELMINTIC AGENTS. |
GB8304927D0 (en) * | 1983-02-22 | 1983-03-23 | Wellcome Found | Pesticidal formulations |
IE58016B1 (en) * | 1983-08-12 | 1993-06-16 | Ici Australia Ltd | Pour-on formulation for the control of parasites |
DE3411627A1 (en) * | 1984-03-29 | 1985-10-03 | Bayer Ag, 5090 Leverkusen | STABILIZED ANTHELMINTIC FORMULATIONS |
-
1992
- 1992-01-13 BG BG095755A patent/BG95755A/en unknown
- 1992-01-13 YU YU2792A patent/YU2792A/en unknown
- 1992-01-16 UY UY23355A patent/UY23355A1/en unknown
- 1992-01-16 FI FI920190A patent/FI920190A/en unknown
- 1992-01-17 CS CS92149A patent/CS14992A3/en unknown
- 1992-01-17 AU AU10277/92A patent/AU658598B2/en not_active Ceased
- 1992-01-17 BR BR929200163A patent/BR9200163A/en not_active Application Discontinuation
- 1992-01-17 NO NO92920234A patent/NO920234L/en unknown
- 1992-01-17 HU HU9200171A patent/HU208623B/en not_active IP Right Cessation
- 1992-01-17 PL PL29322792A patent/PL293227A1/en unknown
- 1992-01-17 TR TR00058/92A patent/TR27833A/en unknown
- 1992-01-17 CA CA002059602A patent/CA2059602A1/en not_active Abandoned
- 1992-01-17 JP JP4006570A patent/JPH04312504A/en active Pending
- 1992-01-17 MX MX9200225A patent/MX9200225A/en unknown
- 1992-01-17 IE IE015092A patent/IE920150A1/en unknown
- 1992-01-18 EP EP92100818A patent/EP0496316A1/en not_active Withdrawn
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6955818B1 (en) | 1999-12-02 | 2005-10-18 | Eli Lilly And Company | Pour-on formulations |
US7772194B2 (en) | 2001-09-17 | 2010-08-10 | Eli Lilly And Company | Pesticidal formulations |
US8048861B2 (en) | 2001-09-17 | 2011-11-01 | Eli Lilly And Company | Pesticidal formulations |
Also Published As
Publication number | Publication date |
---|---|
BR9200163A (en) | 1992-10-06 |
PL293227A1 (en) | 1992-11-16 |
BG95755A (en) | 1993-12-24 |
MX9200225A (en) | 1992-07-01 |
AU658598B2 (en) | 1995-04-27 |
HUT62453A (en) | 1993-05-28 |
CS14992A3 (en) | 1992-11-18 |
IE920150A1 (en) | 1992-07-29 |
YU2792A (en) | 1995-01-31 |
EP0496316A1 (en) | 1992-07-29 |
NO920234D0 (en) | 1992-01-17 |
HU9200171D0 (en) | 1992-05-28 |
TR27833A (en) | 1995-08-31 |
NO920234L (en) | 1992-07-20 |
JPH04312504A (en) | 1992-11-04 |
HU208623B (en) | 1993-12-28 |
UY23355A1 (en) | 1992-01-23 |
AU1027792A (en) | 1992-08-06 |
FI920190A (en) | 1992-07-20 |
FI920190A0 (en) | 1992-01-16 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |