CS14992A3 - Pour-on formulation for anthelmintics application - Google Patents

Description

dJ1g> F. OTci VŠETEČKAsížvskét $ 3804 PRAHA 1, Žitná 25 -1-

f i and c,

i - <m eóur-on formulation for application or heict

FIELD OF THE INVENTION The present invention relates to pour-on formulations, to a process for their manufacture and to their use for controlling helminths / parasitic worms in animals.

BACKGROUND OF THE INVENTION A number of publications describe a pour-on method, also called "Spoton" or an infusion method, for controlling ectoparasites in animals: Jour. Econ. Entomology, 53 (1960), pp. 814-817, EP-A-045424, DE-A-3208334, EP-A-120286, EP-A-31H80. In this case, the liquid preparation of the insecticidal and acaricidal active ingredient is applied along the dorsal line from the nape to the root of the tail of the livestock, in particular cattle.

Emulation must be adjusted so that the effects of pests are achieved by spraying the entire body of the animal.

Pour-on formulations, which are effective against endoparasites in the described method, must deliver the systemically active active ingredient through the skin of the animal into the bloodstream. Such formulations are known with levargine sol (EP-A-137 627: DE-A-2614841) and with Ivermectin (EP 89302680). Both compounds are well dissolved in water or solvents so that penetration through the skin of the animal can be easily accomplished.

A very important group for the control of endoparasitic helminths are suitably substituted benzimidazole and benzothiazole derivatives, as well as a group of so-called probenzimidazoles / compounds which can be metabolized to form enthelminally acting benzimidazole derivatives, such as the compounds of formulas I to III below:

Ia / where r! is methoxycarbonylamino and R2 is n-propylmercapto (albendazole), phenyl mercapto (phenebendazole), phenylsulfinyl (oxfendazole), benzoyl (mebendazole), p-fluorobenzoyl (flubendazole), p-fluorophenylsulfonyloxy (luxabendazole), cyclopropylcarbonyl (cyclobendazole), n-butyl / parbendazole (n-propoxy) oxi-bendazole (or H) carbendazim (s), or

Ib (wherein R 1 is 4-thiazolyl) and R 2 is H / thiabendazole (or isopropoxycarbonyl-Bosphenyl) cambendazole;

R 11 is methoxycarbonylamino, and R 4 is n-propoxy / thioxidazole (-3) (111),

R- wherein R 5 is -R = C / NHCOOCH 3/2, R 8 -RHCOCH 2 OCH 3, R 7 is phenylmercapto, and R 8 is / fenbenz; or R- -N = C;

NHCH2CE2SO3H KHCOOCH2.7-8 R is NC > 2, R = H and R = n-propylmercapto (non-tobirmin); or R 1 and R 8 are now -NHCSRH-COOC 9 H 11, R 7 and R 8 are H (thiophenyl). These active substances are sparingly soluble so that it has not been possible to produce pour-on formulations in suitable solvents. Thus, until now, the treatment of helminth-infected animals (e.g., bovine or ovine) had to be carried out by the so-called method of administering active ingredient-containing beverages or by using animal / animal / oral / oral formulations.

For the treatment of larger herds, the use of a pour-insignificantly more economical method would be considerably more time-consuming and labor-intensive. The animals do not need to be fixed, endangered by the defensive movements of the animals, and the animal's stress, especially the untamed animals, is thwarted. Surprisingly, it has been found that the dispersions / suspensions of said anthelmintically effective benzimidazoles, benzthiazoles and probenzimidazoles with finely divided particles can, when using penetration-promoting oils, be applied to the organotransformer when applied in a transdermally applied manner. where they develop a good effect in the digestive tract and tissues against parasitic nematodes and their stages. Here, with appropriate dosing, it is only necessary to apply a strip of animal to the back of the animal.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to anthelmintically active compositions which contain as active ingredient at least one anthelmintically active benzimidazole, beuzole or propenidazole in a finely dispersed dispersion in a foam-promoting composition. Mixtures of the active ingredients may also be used. The active agent particles in these dispersions should have a grain size of 0.05 to about 30 µm, preferably 0.5 to 10 µm.

As penetration-promoting oils, tri-glycerides of saturated plant carboxylic acids, such as Miglyol 812, triglycerol diisostearate or long chain esters such as oleyl oleate, isopropyl myristate, isopropyl palmitate, 2-ethylhexyl palmitate, iso-octyl stearate, isopropyl stearate, hexyl acid ester, may be used. lauric or di-n-butyl adipate; in addition, long chain alcohols such as hexyl alcohol, octyl alcohol, decyl alcohol, oleyl alcohol, 2-octyldodecanol, 2-hexyldecanol, or 2-octyldecanol. All penetration enhancers may be used alone or in admixture with each other. In particular, long-chain alcohols and, in particular, 2-alkyl-substituted alconoxy alcohols, are used in an amount of from 5 to 95% by weight, preferably from 30 to 90% by weight, in particular a good penetration-promoting effect. The finely divided active substances can also be dispersed in water, emulsified in soft foam-promoting oils, wherein the water content of the dispersion can be up to 50 wt.%, Preferably up to 30 wt.

As emulsifiers and wetting agents, alkylaryl polyglycol ether alcohols such as Triton-type can be used,

R

Sapogenat-T-types, Arkopal-types; polyglycol ethers of higher R aliphatic alcohols such as jimulsogen M, A and MS12,

E

Genapol X-080; Na-salts of alkyldiglycol ether sulfates such as ^ Genapol 1R0; Na-lauryl sulphate, for example, TexapoZn X12; ethoxylated types of castor oil such as EmulogenE1; C1-C20 -alcoholpropylene oxide block oxalkylates such as Hoe S 3510 and HOE S 2436, xylenol oxethylate with 4-5 EO, tristyrylphenylpolyglycol ether and tristyrylphenol polyglycoletherphosphates, such as HOE S 3474 and Hoe S 3775, calcium sodium salts of alkylaryl sulfonic acid such as phenyl sulfonate Esters of sorbitan higher aliphatic acids, for example Span 60 and 80, esters of polyoxyethylene sorbitan higher aliphatic acids, for example Tween 60 and 80, and polyoxyethylene stearates, for example, 45,49 and 51.

Dispersing agents include, but are not limited to, lignin sulfonates such as CBs and polymerized arylalkyldulfonic acids, such as Darvan # 3, magnesium stearates, and aluminum stearates, especially aluminum monostearate. Excipients are used in a weight of $ 0.5 to 30%, preferably 1 to 10%.

The antifoam agents used include, but are not limited to, the antifoam agent SE2.

The proportion of active ingredient in the formulation may be 1 to 60% by weight, preferably 5 to 20% by weight.

The invention also relates to a process for the preparation of a pour-on formulation, wherein the active ingredients are converted into a suitable form for administration by gentle dispersion. -6-

A variety of methods can be used to make pour-on formulations: 1. The active ingredient of the class of benzimidazoles, benzthiazoles or pro-benzimidazoles is finely ground in water with the addition of wetting agents and a bead mill; the penetration-promoting oil is mixed with the emulsifier and emulsified in the aqueous dispersion of the active ingredient. This gives a suspension emulsion in which the active ingredient is finely dispersed suspended in water and has a penetration promoting emulsion therein. 2. The active ingredient is ground with the addition of wetting and dispersing agents and using a bead mill in a penetration-promoting oil. 3. When the anthelmintic agent is present in the particulate fineness described above, even as a result of the use of suitable precipitation methods in the manufacture or the use of dry milling, it can be homogenized without wetting even after the addition of wetting agents and dispersing agents. grinding in water. The oil is then emulsified as described under 1. in an aqueous dispersion.

For dry-milling, a jet air mill, such as a spiral jet mill, may be used. 4. If the active ingredient is present in sufficient fineness as described below, it may also be wet-ground without the use of suitable wetting agents and Further dispersing the dispersing agents as well as the suitable mixing or mixing devices in the penetration-promoting oil. Further, for example, the exemplification procedures carried out with fenbendazole explain the methods described under 1 to 4 without limiting the invention thereto.

For wet grinding the PE 075 Netzsch-Peinmahltechnik GmbH mixer mill was used. -7-

Ultra p was used for homogenization with high speed stirrer

Turrax instrument Janke and Kunkel. Example 1 7.5 $ fenbendazole pour-on formulation

The penbendazole is ground in a mixer mill together with the wetting agents and dispersants as well as with an antifoam agent up to 85% of particles less than 1 µm, 4 hours of grinding are needed. Glass beads of 2 mm diameter are used, the amount of which is twice the active ingredient used. phenbendazole. 1. Phenbendazole dispersion 40.00 $ w / w fenbendazole, 99, ^ Genapol X-080

^ Vanisperse CBR 4.00 $ mass. Darvan Nr. 31.00 $ wt. of silicone defoamer SE246.00 $ wt. water

With stirring and gentle heating to 35 to 40%, the emulsifier solution in oils:

The emulsion solution C was 9.3% by weight. C-phenylsulfonate / 70 / 4.37 wt. Hoe S 35106.25 $ mass. Hoe S 3474-2 40.00 $ Mass. 2-octyldecanol 21.25 $ wt. Miglyol 812 18.75 $ wt. The phenbendazole dispersion (1) was added to the emulsifier solution with stirring. A suspension emulsion is formed which can be poured well and is stable to storage, and which can be used as a pour-on formulation. Example 2 10 $ fenbendazole pour-on formulation

Using glass beads (2 mm / s), the following mixture is ground in the agitator mill to yield up to 80% particles finer than 1 µm: 1. fenbendazole dispersion 35.00% w / w. fenbendazole, techn. 99.8 $ EGenapol X-080 4.00 $ mass. R. Bath Sperm CBDarvan Nr. 3 • n * 1.00 wt. silicone antifoaming agent SE251.00 $ wt. water

Subsequently, a solution of emulsifiers in oils is prepared with stirring and heating at 35 to 40 ° C: 2. Emulsifier solution 9.38% by mass. 30 »00 $ mass.

C-Phenylsulfonate (70) Hoe S 3510H 2 O 3474-2 2-octyldodecanol γ-Miglyol 812 28.6% by weight is slowly added to this emulsifier solution with stirring. aqueous dispersions of fenbendazole (1). It obtains a phenbendazole pour-on formulation that can be recharged and is stable to storage. Example 3 10 $ fenbendatol pour-on formulation

As described in Examples 1 and 2, the following formulation was prepared: 10.02 wt. fenbendazole, 99.8 $ 1.00 wt. EGenapol X-080 -9- 1.75 0.50 0.25 11.48

fy mass ^ Vanisperse CB mass, ^ Darvan Ur. 3 ph. of silicone antifoam SB2fy. water 9.37% by weight of 6.25% by weight of 4.38% by weight of 35.00% by weight of 20.00% by weight of mass

Ca-phenylsulfonate / 70 / Eoe S 3474-2Hoe S 35102-octyldodecanol ^ Miglyol 812

The formulation can be poured well and is stable to storage with respect to the homogeneity and stability of the active ingredient. Example 4

As described in Examples 1 and 2, the phenbendazole dispersion is milled for 4 hours in a bead mill, up to 82 micron particles finer than 1 micron. fenbendazole, those. 99.8 $ 4.00 phy. Genapol 1R0 pastes 56.00 wt. water

B. The solution of the emulsifiers in a mixture of 2-octyldecanol and Myglyol 812 is prepared by stirring with heating and heating at 35 to 40 ° C. 35.00 wt.

% C-phenylsulfonate (70) Hoe S 3510H 2 O with 3474-22-octyldodecanol; The described phenbendazole dispersion (1) is slowly added to the emulsifier solution while stirring. A -10-dbb pour-on formulation is obtained. Example 5

First, a 40 $ dispersion of fenbendazole in water is produced. Grinding time of 4 hours, achieved particle size: 80 $ 4l µm. 1. Phenebendazole dispersion of 40.00% by weight, phenbendazole, t-techs, 99.8 $ p 4.00% by weight. Genapol LRO - pastes 56.00 $ mass water 25.00 $ mass. The phenbendazole dispersion (1) is added to 70.00% by weight with stirring. 2-octyldodecanol; then mixing also adds $ 5 of water. It obtains 10 $ fenbendazole pour-on formulation which is poured well and stored very well. Example 6

The production method is the same as that described in Example 5, but the dispersion of fenbendazole is only homogenized and does not melt, so that the active ingredient fenbendazole is used with the grain size that is produced during manufacture: 50 µm 4.6 µm particles. 10 $ fenbendazole pour-on formulation 10.00 $ wt. fenbendazole, 99. 93 $ 1.00 wt. ^ Texapon K12 $ 19.00 Mass. water 70.00 $ wt. 2-octyldodecanol

The formulation is storage stable and is well applicable. Example 7

The production method is the same as in Example 5 · Fineness of fenbendazole 80 $ Z-1 µm. 10 $ fenbendazole pour-on formulation -II1.0 wt. of fenbendazole, 99.980 1.0. ^ Texapon K1224.00 f. water 25.00% by weight. iglyol 81240.00% by weight. 2-octyldodecanol is obtained by storage of a stable, well-applied formulation. Example 8

Production methods as described in Example 6. Fineness of fenbendazole particles 50 [mu] [mu] m. 100 fenbendazole pour-on formulation 10.00 ph. phenbendazole, 99.980 Έ5 1.00 0 wt. Texapon 1224.00 0 wt. water 25.00% RMiglyol 81240.00% by weight. 2-octyldodecanol

The formulation is well-stored and well poured. Example 9

The production method is the same as that described in Example 4. The fineness of the particles is 82 µm. 100 fenbendazole pour-on formulation 10.00 phy. 39.00% by weight. 15.00 0 wt. phenbendazole, 99,980 ^ Genapol 1R0vod

A2-octyldodecanol Emulsogen A pour-on formulation is obtained which is stable to storage and can be poured well. Example 10 -12-

The production method is the same as that described in Example 4, but dissolving Span 60 in octadodecanol at 80-90 ° C. Fineness of fenbendazole particles 82% 4 l / un. 10 fenbendazole pour-on formulation 10.00 $ mass 0.89 $ mass, 21.33 $ mass 1.00 $ wt. 66,78 $ weight of storage, 9,9 8 $ storage-stable Texapon K12 water Span 60 2-octyldodecanol can be applied well. Example 11

First, Span 60 is dissolved in 2-octyldodecanol under stirring at 80-9 ° C. After cooling to about 50 ° C, fenbendszole is added; particle size 50 µm particle 4 µm. 10 $ fenbendasol pour-on formulation 10.00 $ wt. fenbendazole, 99.98 $ 10.00 $ wt. ^ Span 60 80.00 $ wt. The 2-octyldodecanol mixture was homogenized with a high speed Ultra Turrax mixer. Example 12 Production See Example 11; grain size of fenbendazole: 50 µm particles 46 µm. 7.5 $ phenbendazole pour-on formulation 7.50 $ wt. fenbendazole, 99.98 $ 10.00 $ wt. ^ Span 60 82.50 $ mass. 2-octyldodecanol

from R Z

The mixture is homogenized with a high speed Ultra Turrax mixer. Example 13

The production method is the same as that described in Examples 4 and 10. The grain size of fenbendazole 50 is ≥6 µm. 10 $ fenbendazole pour-on formulation 10.00 $ wt. 1.00 $ mass. 1.00 $ wt.64.00 $ wt. fenbendazole, 99.98 $ ^ Texapon K 2 O 5 ^ Span 60 2-Ctyldodecanol A well-applicable formulation is obtained. Example 14

The aluminum monostearate is dissolved in 140 DEG-150 DEG C. in 2-octyldodecanol and maintained under stirring for 30 minutes. After cooling to about 50 ° C, fenbendazole is added and homogenized with a high speed UltraTTurrax mixer.

Grain size: 50 $ particles · <6 µm. 10 $ fenbendazole pour-on formulation 10.00 $ wt. phenbendazole, 99.98 $ 1.00% by weight. aluminum monostearate 89.00 $ 2-octyldodecanol A suspension is obtained which can be poured well. Example 15

The aluminum monostearate is dissolved in 140 DEG-150 DEG C. in 2-octyldodecanol and kept under stirring at this temperature for 30 minutes. After cooling to about 100 ° C, Span 60 and fenbendazole are added at 50 ° C; they are also added under agitation. Then they are homogenized with a high-speed Ultra-Turrax mixer.

Grain size of fenbendazole: 50 µm particles 46 µm. -14- $ 10 fenbendazole pour-on formulation 10.00 $ wt. of fenbendazole, 99.58 $ 1.00 wt. ^ Span 60 2.50 $ mass. aluminum monostearate 86.50 wt. 2-octyldodecanol A formulation is obtained which is very stable upon storage and can be poured. Example 16

The production method is the same as that described in Example 15.

Grain size of fenbendazole: 50 µl particles 6 6 µm. 20 $ fenbendazole pour-on formulation 20.00 $ wt. phenbendazole, 99.98 $ 1.00% by weight. ^ Span 60 1.50 $ mass. aluminum monostearate, 50 wt. 2-octyldodecanol

The production method is the same as that described in Example 15.

Grain size of fenbendazole: 50 µl particles from 6 µm. 11,37 $ fenbendazole pour-on formulation 11,35 $ wt. phenbendazole, 99.98 $ 100 g / l 1.14 $ wt. ^ Span 60 2.85 $ wt. aluminum monostearate84.64 $ wt. 2-octyldodecanol Example 18 8.53 $ fenbendazole pour-on formulation

87.48 $ wt. 2-octyldodecanol -15- Example 19 5,75 $ fenbendazole pour-on formulation 5,75 mass, fenbendazole, 99,98 $ = "5θ g / 1 I, 15 mass% RSpan 60 2,88 mass% aluminum monostearate90 22% by weight of 2-octyldodecanol

The preparations of Production Examples 16 to 19 are well-stable to storage in relation to phase separation and constant drug content. They can be poured well and are therefore useful as pour-on formulations. Example 20 II, 37 $ phenbendazole pour-on formulation 11.37 wt.%, Fenbendazole, 99.98 $ = * 100 g / l 2.50 wt. Sleep 60 ^ 1.70 $ Mass aluminum monostearate 84.62 $ wt. 2-octylododecanol The process is carried out as described in Example 15. The fenbendazole used is pre-milled in a spiral jet mill for up to 50% of particles having a particle size of 2.8 µm. Examples 21-26

For the production method, see Example 11, 10.00 $. anthelmintic active agents / see Tab. 1 / 10.00 $ wt. ^ Span 60 80.00 $ wt. Of 2-octyldodecanol A 5 $ formulation was made with thiabendazole: 5.00% by weight. thiabendazole10.00 $ wt. ^ Span 6085.00 $ wt. 2-octyldodecanol -16-

Table 1

example anthelmintic active ingredient of formula 21 oxibendazole I and 22 parbendazole I and 23 albendazole I and 24 mebandazole I and 25 thiabendazole I b 26 febantel III

Biological activity

Investigations were conducted on bovine animals that had been infected with artificially / artificially important gastrointestinal ruminant nematodes - Ostertagia estertagi, Trichostrongylus axei, Trichostrongylus colubriformis and Cooperia oncophora. The efficacy was determined by the worm counting section compared to untreated control animals. Treatment by pouring the formulation along the dorsal line was performed most frequently 14 days after infection; At this point in time, nematodes are still immature and especially hard-to-control ant-helminths.

Investigations were conducted in accordance with the Guidelines derWAAVP / World Association for the Advancement of Veterinary Medicine; Powers, K.G. et al. Vet. Barasitol. (1982 / 10,265-284). The following Table II lists some investigations and results. -17-

Table II Effectiveness of fenbendazole in various pour-on formulations Antibody stages of nematodes in bovine animals not formulated dose of bitches number average percentage reduction example no. bendazole animals worms compared to conglomerate / kg body trolls Ostertagia trichostron- coopers weight ostertagi gylus ria axei colcocarbriorora formis 1 3,75 4 99 98 100 100 7,50 4 72 94 100 94 2 3.75 4 98 99 98 100 7.50 4 86 92 94 93 3 3.75 4 98 99 100 99 7.50 4 99 100 100 100 average, worm control group n = 9 3922 480 132 274 4 7.50 3 - 100 99,8 5 7,50 3 78 88 100 100 6 7,50 3 91 80 100 100 7 7,50 3 36 99 99 8 7,50 3 62 20 98 100 9 7,50 3 99 100 100 100 .worms control group / n = 3/2610 260 1067 1937 10 7.50 7 99 99 100 99 11 7.50 7 98 99 99 99 average, worm control group / n = 7 / 65TČ3 649 479 2279 -18- cont Table IIformulation Example No. Fennium Bendazole Dosage mg / kg body weight Average percentage reduction of worm count compared to control

Ostertagia Irichostron- Coope · ostertagi gylus ria axei colco- bri- phora formis 11 5,0 7,5 7 7 82 70 92 93 100 99 99 98 13 5,0 7 66 86 100 98 7,5 7 91 99 99 99 14 5.0 7 68 97 99 99 7.5 7 84 98 99 99 15 5.0 7> 80> 90> 98> 98 7.5 7> 90> 95> 98> 98 averageworm group / n = 7/57 63 490 1589 3867 In an orientation experiment, the efficacy of pour-on formulations of phenbendazole, oxibendazole, parbendazole, albendazole, mebdenadazole, thiabendazole and febantel (Examples 20-25) against Trichonstrongylus clulubriformis in rodents / Jirds / Merionesunguiculates / was found. . The dosage was now 0.2 ml for the animal or 0.4 ml of uthiabendazole and for fenbendazole additionally 0.1 and 0.05 ml # this volume was dripped onto the sheared area of the back of sheep / Birds. No possibility to take the active substance by licking. -19-

The results are shown in Table II Table III Effectiveness of "pour-on" formulations against T. colubriformis in sheep / jirds / active ingredient adjuvanted. quantity quantity number effect effect trace / ml / mg / kg worms animal animal / / x / rene fenbendazole 11 10 0.2 about 300 0 11 100 fenbendazole 11 10 0.1 about 150 0 5 100 fenbendazole 11 10 $ 0.05 about 75 0 4 100 albendazole 23 ίο φ 0.2 about 300 0 5 100 febantel 26 10 0.2 about 300 0 5 100 mebendazole 24 10 $ 0.2 about 300 0 5 100 oxibendazole 21 10 $ 0, 2 about 300 0 5 100 parbendazole 22 10 # 0.2 about 300 0 5 100 thiabendazole 25 5 1 ° 0.4 about 300 0 5 100 control without treatment 67 9

Claims (10)

Λ »'; »· ^" RtíVŽETEČ * a ^ vv5'® "· -., _.- Γψ-Λ, ΚΛ 1, ΖΛη £ 25 ν * + -20 U Τ A Τ δ Ν I 0 V ELEMENTS c • c. (<> f- What is claimed is: 1. An anthelmintic composition comprising as active ingredient at least one anthelmintic-acting benzimidazole, benzothiazole or pro-benzimidazole in a finely divided dispersion in a penetration enhancer. The composition according to claim 2, wherein the particles of active substance in the dispersion have a grain size of 0.05 to 30 tons. Composition according to claim 1 or 2, wherein the active ingredients are from 1 to 60% by weight. , preferably 5 to 20 wt. Composition according to one of Claims 1 to 3, in which a penetration-promoting oil of from 5 to 95% by weight, together with auxiliaries, such as emulsifiers, wetting agents and / or dispersants, in an amount of 0.5 to 5% by weight is used as penetration enhancer. 30 and a defoamer of 3 to 60 phr. Composition according to one of Claims 1 to 4, containing the active substance fenbendazole. Composition according to one of Claims 1 to 5 for transdermal use in the control of helminths in animals. A process for the preparation of a composition according to one of claims 1 to 6, characterized in that the active ingredient is dispersed in fine particles in a suitable dosage form. 8. Derivatives of benzimidazoles, benzthiazoles or pro-benzimidazole dispersed form for transdermal use in the control of hemlmint in animals. 9. A pour-on method for controlling helminths in animals, wherein a device according to one of claims 1 to 6 is used transdermally. Use of a composition according to one of claims 1 to 5 or a compound according to claim 8 in the transdermal treatment of animals.