CA2059602A1

CA2059602A1 - Pour-on formulation for the administration of anthelmintics

Info

Publication number: CA2059602A1
Application number: CA002059602A
Authority: CA
Inventors: Hans Roechling; Dieter Duewel; Karlheinrich Schmid
Original assignee: Individual
Current assignee: Hoechst AG
Priority date: 1991-01-19
Filing date: 1992-01-17
Publication date: 1992-07-20
Also published as: BR9200163A; PL293227A1; BG95755A; MX9200225A; AU658598B2; HUT62453A; CS14992A3; IE920150A1; YU2792A; EP0496316A1; NO920234D0; HU9200171D0; TR27833A; NO920234L; JPH04312504A; HU208623B; UY23355A1; AU1027792A; FI920190A; FI920190A0

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.

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:

- .

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.
, ..

~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.
~: .
.

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- 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 . . , . , ~ , , , , .

~- ,, , , ; : , ~
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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.

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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

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.