CN101466373B

CN101466373B - A suspension comprising benzimidazole carbamate and a polysorbate

Info

Publication number: CN101466373B
Application number: CN2007800221002A
Authority: CN
Inventors: E·B·D·德斯查姆普斯; C·施米特; M·阿尔兰
Original assignee: Intervet International BV
Current assignee: Intervet International BV
Priority date: 2006-06-14
Filing date: 2007-06-13
Publication date: 2012-11-21
Anticipated expiration: 2027-06-13
Also published as: ES2440485T3; CL2007001713A1; RU2445089C2; BRPI0712734B1; UA93403C2; CN101466373A; BRPI0712734A2; RU2009100919A; MY153292A; DK2037914T3; TW200815001A

Abstract

This invention is directed to a pharmaceutical composition for drinking water administration comprising benzimidazole carbamate particles having an effective average particle size of less than 450 nm and a Tween-type surfactant; a method for making the composition; use of the composition to make a medicament for controlling parasites; and use of said composition for the manufacture of a medicament or protecting an animal from a parasitic infection. The invention also provides a method for protecting an animal from a parasitic infection.

Description

The suspension that comprises benzimidazole carbamate and polysorbate

Invention field

The present invention relates generally to use the pharmaceutical composition that comprises benzimidazole carbamate of drinking-water administration; The method for preparing this pharmaceutical composition, said composition be used for controlling in preparation parazoon medicament application and use said composition to prevent that animal from the method for parasitic infection taking place.

Background of invention

Benzimidazole is developed at first and is plant fungicide, and is developed subsequently and is beasts and human vermifuge (for example deworming agent).Have the active benzimidazole of anthelmintic family and comprise thibendole class and benzimidazole carbamate class.Benzimidazole shows especially the broad spectrum of activity to helminthism worm (for example ascarid or cestode).

Have the active well-known benzimidazole of anthelmintic and for example be thiabendazole; Cambendazole; With the benzimidazole carbamate class, such as parbendazole, mebendazole, flubendazole; Fenbendazole, oxfendazole, oxibendazole; Albendazole, but auspicious parbendazole (ricobendazole) and luxabendazole, all the substituent group on the benzimidazole parent nucleus is different for they.

Also researched and developed the guanidines prodrug that is converted to the anthelmintic benzimidazole through metabolic way.For example febantel is that precursor medicine and the netobimin that changes into fenbendazole produces albendazole.

The benzimidazole carbamate class generally is insoluble in water.With regard to some useful application of these chemical compounds, the poorly water-soluble of benzimidazole is a major obstacle.

Fenbendazole (FBZ) comprises the benzimidazole carbamate of the anthelmintic veterinary drug in poultry, pig and the cattle for as numerous species.Fenbendazole is used to control nematicide, such as the Ascaridia in poultry and the pig (Ascaridia sp.), and Heterakis (Heterakis sp.) and Hepaticola (Capillaria sp.).

Be insoluble in the medicament of water up to now in a large number, like the benzimidazole carbamate class pig that concentrate to raise and poultry administration be limited to as topdressing and be applied on the feedstuff oral administration or sneak into feedstuff.Yet the feedstuff of this type pastille need prepare separately on the farm or with feed mill, and existence and the not risk of the feedstuff cross-contamination of pastille all the time.On the other hand, topdressing need be paid additional effort.

Therefore, preferably be administered for to concentrating the domesticated animal deworming, because be easy to usually simultaneously to a large amount of animals administers through drinking-water system.

Many pigs and poultry farms have equipped necessary device and have come through the drinking-water system administration.The drinking-water system of this type on the farm is jar, pipe, coil, the complication system of fence water fountain and nipple.Average stable system can comprise hundreds of meters pipe with many coils and hundreds of single cup and/or nipples.Water in the drinking-water system in pig or poultry room defer to through the pipe and the streamlined principle of coil and advance to experience so-called influence flow velocity " shearing force ".In the complicated tubing of this type, exist the medicine of certain degree to separate or settled risk, yes when relating to the situation of water-fast chemical compound.

Medicine is through the general main quality of compositions and the palatability of medicine of depending on of effectiveness of drinking-water system.This based composition should provide the maximum use degree of active component; Reactive compound is at drinking-water system; Administration pump, MIN separation and sedimentation in the nipple cup etc., reactive compound is very accurate administration and uniform distribution and the reactive compound stability of guaranteeing in drinking-water.

Up at present, still there is not the veterinary drug that is insoluble in water that solution can be applicable to satisfy these requirements, like this farm-animals route of administration of benzimidazole carbamate class.

Disclosed moisture fenbendazole suspension in the International Patent Application WO 95/13065 with Tween-class surfactant and antiseptic.In this aqueous suspension, if store the certain hour time limit, fenbendazole keeps suspendible and does not have cohesion or granularity change generation so.This granularity is about 1 micron.Yet this fenbendazole aqueous suspension is not suitable for through the drinking-water system administration, because it is applied to aforesaid big pig or poultry room.If it is diluted to the drinking-water concentration of 60ppm fenbendazole, it shows sedimentation after the time limit at certain hour so.These precipitums can not make fenbendazole uniform distribution and risk of exist blocking the drinking-water system equipment of the nipple of for example drinking water in drinking-water system.

Suspension-the emulsion composition of the administration that is used to drink water has been discussed in the International Patent Application WO 01/17504.Yet these compositionss do not satisfy the requirement of administration in relating to equally distributed drinking-water system.

Discussed in the International Patent Application WO 00/50009 water unstable or water-fast chemical compound be encapsulated in and be used to the administration of drinking water in the liposome.

The Antithelmintic compositions that is used for oral administration has been discussed in the International Patent Application WO 95/16447; It comprises the micronized particle of rafoxanide and fenbendazole; Granule in these granules more than 98% has and is lower than 20 microns particle mean size, but said composition can't administration in drinking-water system.

The method of the industrially scalable of the aqueous suspension that does not use any particle size reduction technology preparation oxfendazole has been discussed among the UK patent application GB 2307871.

Summary of the invention

The present invention relates generally to can be expediently stable, the effective Aquo-composition of benzimidazole carbamate class through the drinking-water system administration.

Therefore, a part of the present invention provides the pharmaceutical composition that uses drinking-water administration benzimidazole carbamate class.Said composition is characterised in that it comprises the aqueous suspension that contains benzimidazole carbamate granule and Tween-class surfactant with the effective particle mean size that is lower than about 450nm.

A part of the present invention provides above-mentioned composition to be used for controlling the application of the medicament of parazoon in preparation, carries out through giving this medicament through animal drinking-water.

A part of the present invention provides preparation to use the method for the pharmaceutical composition of drinking-water administration.This method comprises:

I. make the benzimidazole carbamate Dispersion of Particles in the pharmaceutically useful carrier that contains Tween-class surfactant; And

Ii. through mechanical system the particulate granularity of benzimidazole carbamate is brought down below effective particle mean size of about 450nm.

A part of the present invention provides the method that prevents animal generation parasitic infection.This method comprises through animal drinking-water and gives above-mentioned composition to animal.This prevention method comprises one or more in prevention parasitic infection and/or its symptom, reduces its risk, delays its outbreak, reduces its diffusion, improvement, inhibition and/or eradicates them.

Other interests of applicant of the present invention are obvious when those skilled in the art read this description.

The accompanying drawing summary

Fig. 1 representes not carry out the particle size distribution of fenbendazole (FBZ) suspension after wet grinding (bullion) and the wet grinding.

Use the clarification dynamics of the 60ppm FBZ pastille drinking-water of FBZ suspension preparation after the wet grinding that Fig. 2 representes to measure in 24 hours at the cell middle part with

.

Fig. 3 representes the particle size distribution of thick suspension of FBZ (not wet grinding) and FBZ suspension (slight and intensity wet grinding).

Fig. 4 representes the clarification dynamics of the 60ppmFBZ pastille drinking-water that the thick suspension of use FBZ (not wet grinding) of 24 hours mensuration and FBZ suspension (slight and intensity wet grinding) prepare at the cell middle part with

.

Fig. 5 representes the particle size distribution of

and FBZ suspension.

Figure 6 shows a

24 hours in the determination of the central pool measured using

prepared 85.6ppm fluorobenzene up azole-containing syrup and use of FBZ suspensions prepared 60ppm? FBZ medicated drinking water clarification dynamics.

The 60ppm FBZ that the FBZ suspension diluent by containing the different surfaces activating agent that Fig. 7 representes to measure in 24 hours at cell middle part with

is processed contains the physical stability of liquid medicine.

The 60ppm FBZ that the FBZ suspension diluent by the polysorbate80 that contains variable concentrations that Fig. 8 representes to measure in 24 hours at cell middle part with

is processed contains the physical stability of liquid medicine.

Fig. 9 represented to use thick suspension of FBZ and FBZ 0.2g/ml suspension to disperse the FBZ concentration in the liquid medicine that contains of back preparation at 3 hours; From medicinal cupping and in the end sampling of 25m pipe.

Figure 10 representes the particle size distribution according to the flubendazole suspension of embodiment 2 preparations.

Figure 11 representes with

the 60ppm FluBZ pastille water clarification dynamics of the use FluBZ 0.2g/ml suspension preparation of 24 hours mensuration in the middle part of cell.

Detailed description of the preferred embodiments

This detailed description of the preferred embodiments only is used for making others skilled in the art to know the present invention of applicant; Its principle and practical application thereof; Make others skilled in the art to adopt and use the present invention, because they are suitable for the requirement of application-specific most with its various ways.This detailed description and specific embodiment thereof are specified and only are used for illustration, represent the preferred embodiments of the invention simultaneously.Therefore, the present invention is not limited to the preferred embodiment described in this description and can advances various modification.

The present inventor has been verified to the present invention includes the compositions that contains the aqueous suspension with the benzimidazole carbamate granule that is lower than the effective particle mean size of about 450nm and Tween-class surfactant and is fully stable and can be evenly distributed in the system so that effectively effectively give the benzimidazole carbamate chemical compound through drinking-water system.

Through this new compositions, can benzimidazole carbamate be delivered to target animals through the drinking-water system of selecting, through in center water tank or independent storage tank, said composition being mixed with water and dilute with water carries out.

Selectively, using dosage tuner or administration pump system or quantifier drug-supplying system inject high or low pressure ring road system so that drinking-water distributes continuously with compositions.

The administration pump system depends on the pump of the concentrate of measured quantity being sent oral siphon with the typical dilution factor of 1-5%.In the administration pump system; Can use electronics administration pump system; Such as KONTI-DOS from Buerkert; Or mechanical administration pump; Such as waterpower administration pump, the dispenser in proportion of

water-driven.The kind of field apparatus also relates to water system self: have cecum or the closed loop system and the water fountain that is suitable for target animals of the different length of different tube materials (for example PVC, iron plating), such as bell formula water fountain, nipple.

In one embodiment, effective particle mean size of benzimidazole carbamate is lower than about 450nm or is lower than 400nm, in another embodiment, is lower than about 350nm or is lower than about 300nm.In another embodiment, effective particle mean size of benzimidazole carbamate is lower than about 250nm, in another embodiment, is lower than about 200nm.

In one embodiment, effective particle mean size of benzimidazole carbamate is at about 50nm-450nm, in another embodiment, and at about 100nm-400nm, in another embodiment, at about 150-350nm or about 180nm-300nm.In another embodiment, effective particle mean size of benzimidazole carbamate is at about 190nm-220nm, in another embodiment, and at about 200nm.

Selectively, can benzimidazole carbamate be mixed with the injectable product that is used for the animal parenterai administration.

Granularity used herein means as according to the well-known regular particle size determination techniques of those skilled in the art, such as laser light scattering, and sedimentation field flow fractionated, the number average particle size of photon correlation spectroscopy method or the centrifugal mensuration of disc type.

Can use Malvern Mastersizer2000 or Horiba LA-910 Laser Scattering Particle Size Distribution Analyzer to carry out granulometry with Hydro 2000G cell.

Effective particle mean size ＂ that so-called ＂ is lower than about 450nm means through above-mentioned technical measurement the time, and at least 90% granule has the average particle size (D (0.90) that is lower than about 450nm.

Tween-class surfactant (the polysorbate esters, the sorbitan ester class is gathered (Oxy-1; 2 second, two bases) derivant; Tweens) be complicated esters and ester-ethers hexitan (hexitrol anhydrides)) the water-soluble nonionic type surfactant formed, described esters and ester-ethers through on the hydroxyl that polyoxyethylene chain is added to sorbitol derived from hexa-atomic alcohols, alkylene oxide and fatty acid; And described hexitan (hexitol one acid anhydride (hexitans) and hexides (hexides)) is derived from sorbitol and use fatty acid commonly used then; Such as lauric acid, Palmic acid, stearic acid and oleic acid partial esterification.

In one embodiment, Tween-class surfactant is selected from Tween 20, and Tween 40; Among Tween 60 or the Tween 80 one or more; In pharmaceuticals industry, be also referred to as polysorbate20, polysorbate40, polysorbate60 and polysorbate80.Polysorbate20 (polyoxy ethylization sorbitan laurate) is a laurate, and polysorbate60 (polyoxy ethylization sorbitan stearate) is the mixture of stearate and cetylate; And polysorbate80 (polyoxy ethylization dehydrating sorbitol monooleate) is an oleate.

This type Tween class surfactant be purchased and/or can be through technology preparation well known in the art.

In one embodiment; Tween-class surfactant is for having the polyoxyethylene sorbitan monoleate (polysorbate80 of chemical name polyoxyethylene (20) dehydrating sorbitol monooleate; Tween 80), for example available from ICI Specialty Chemicals.

The amount of Tween-class surfactant in compositions is about about 50% weight of 0.1-.In certain embodiments, Tween-class surfactant concentrations is in about 20% weight of about 5%-, about 15% weight of about 7.5%-or about 10% weight.

Compositions of the present invention comprises one or more benzimidazole carbamate classes.Well-known benzimidazole carbamate class does, parbendazole (for example) for example referring to U.S. Pat 3,480,642, and mebendazole is (for example, referring to U.S. Pat 3; 657,267), flubendazole (for example) referring to U.S. Pat 3,657,267, fenbendazole is (for example; Referring to U.S. Pat 3,954,791), oxfendazole is (for example, referring to U.S. Pat 3,929; 821), oxibendazole (for example) referring to U.S. Pat 3,574,845, albendazole is (for example; Referring to U.S. Pat 3,915,986), auspicious department parbendazole (albendazole oxysulfide) is (for example, referring to U.S. Pat 3,915; 986) and luxabendazole (for example, referring to U.S. Pat 4,639,463), they all are that substituent group on the benzimidazole parent nucleus is different or be prodrug, like febantel and netobimin.

In one embodiment, benzimidazole carbamate is fenbendazole (for example, referring to U.S. Pat 3,954,791).In another embodiment, benzimidazole carbamate is flubendazole (for example, referring to U.S. Pat 3,657,267).

The general amount of benzimidazole carbamate in compositions is about about 50% weight of 5-.In certain embodiments, the concentration that exists of benzimidazole carbamate is about about 40% weight of 10%-, about 25% weight of about 15%-about 30% or about 17.5%-or about 20% weight.

In certain embodiments, compositions comprises pharmaceutically useful carrier.This carrier can for, aqueous carrier for example, preferred (pure) water.Yet, can use other liquid medium embodiment of the present invention, wherein the benzimidazole carbamate indissoluble with can disperse aqueous salt solution for example.

The optional combination thing can also comprise defoamer, such as, for example, Simethicone emulsion 30% USP, enuatrol, sodium caprylate or its mixture.The concentration that exists of defoamer is enough to prevent that foam forms when the dilute with water present composition.In the present invention, the concentration that exists of Simethicone emulsion can be in about 0.2% weight-Yue 1% weight.In certain embodiments, the concentration that exists of Simethicone emulsion is about 0.5% weight.

The optional combination thing can also comprise antiseptic.Antiseptic be well known in the art and can for, benzylalcohol for example, nipabutyl sodium salt, Sodium Methyl Hydroxybenzoate salt, Sodium Propyl Hydroxybenzoate salt and composition thereof.General amount is about about 3% weight of 0.01%-.In certain embodiments, the concentration that exists of benzylalcohol is about about 2.5% weight of 1.5%-or about 2% weight.

One aspect of the present invention is that compositions of the present invention is used for controlling the application of the medicament of parazoon in preparation, carries out through giving this medicament through animal drinking-water to animal.

The invention provides and prevent that animal from the method for parasitic infection taking place, wherein this method comprises through animal drinking-water and gives compositions of the present invention to animal.

In one embodiment, compositions of the present invention can be used to use the benzimidazole carbamate chemical compound, and for example fenbendazole is through drinking-water system treatment animal, especially livestock animal (for example cattle, poultry and pig).Said composition (finished product) can be used for quantifier or dispenser so that the drinking-water of preparation as pastille as known in the art.

Dispenser is used the finished product of 1oz for example and is further made water generally obtain having the pastille drinking-water of benzimidazole carbamate according to about 1:128 dilution proportion, and for example fenbendazole concentration is about the about 150ppm of 10-.

In certain embodiments, benzimidazole carbamate, for example the concentration of fenbendazole in pastille drinking-water is about the about 120ppm of 40-, and this depends on effective dose, the weight of animals, animal water consumption and treatment time limit.

In one embodiment, spissated premix compositions directly is diluted to the concentration of the about 150ppm of about 10ppm-.In certain embodiments, spissated premix compositions directly is diluted to the benzimidazole carbamate of the about 120ppm of about 40-, for example fenbendazole concentration, and the administration (for example being used for poultry) that directly is used to drink water.

An embodiment that is used for concrete benzimidazole carbamate fenbendazole; Calculating concentration so as the scope that fenbendazole targeting consumption/wait to treat poultry body weight (BW) is provided in the about 5mg fenbendazole/kg body weight of about 1mg-/sky; In the drinking-water of the volume of treating the poultry normal consumption, the treatment time limit is 2-24 hour.Targeting dosage is according to the parasitic infection kind decision of being treated and for well known in the art.For to other kind administration, distinguish calculating concentration.

Pastille drinking-water is used for the about 24 hours treatment time limits of the about 2-of poultry treatment usually preferred about 8 hours treatment time limits, were carried out 1-6 days continuously.For to other kind administration, calculate the treatment time limit respectively.

In order to treat pig, the dilution finished product to obtaining desired concn so that obtain containing effective dose benzimidazole carbamate class, such as, the drinking-water of fenbendazole for example, thereby the anthelmintic in the control pig.Effective dose depends on the infection of the parasite species of being treated and is well known in the art.

Selectively, can pass through non-intestinal, for example through intravenous, intramuscular or subcutaneous injection give compositions of the present invention to animal.

Provide in another aspect of the present invention to prevent that animal from the method for parasitic infection taking place, wherein this method comprises through parenteral route and gives compositions of the present invention to animal.

Through can the selection approach carrying out non-intestinal treatment also is possible.Blood plasma and tissue level that the parenterai administration approach is particularly useful for benzimidazole carbamate are important situation, because for whole body works, must make benzimidazole be absorbed into blood flow.To be benzimidazole for example have anti-that some cestode belongs to the for example application in the whole body parasitic infection of the larval phase of Echinococcus multicularis (Echinococcus multicularis) and Echinococcus granulosus (Echinococcusgranulosis) to a kind of this type instance.

Generally speaking, compositions of the present invention can or be prevented all kinds animals administer of parasitic infection to the needs treatment, such as pig, and cattle, horse, goat, sheep, cat, Canis familiaris L., poultry and fish.

The method for preparing the present composition is provided in another aspect of the present invention.

This method comprises the benzimidazole carbamate Dispersion of Particles in comprising pharmaceutically suitable carrier and Tween-class surfactant mixtures, and the particulate granularity of benzimidazole carbamate is brought down below effective particle mean size of about 450nm through mechanical system.

In one embodiment; The particulate effective particle mean size of benzimidazole carbamate is brought down below about 400nm or about 350nm or about 300nm, in another embodiment, is brought down below about 250nm; In another embodiment, be brought down below about 200nm.

In one embodiment, the particulate effective particle mean size of benzimidazole carbamate is reduced to the granularity of about 50nm-450nm, in another embodiment, about 100nm-400nm, in another embodiment, about 150-350nm or about 180nm-300nm.In another embodiment, the particulate effective particle mean size of benzimidazole carbamate is reduced to about 190nm-220nm, in another embodiment, about 200nm.

Provide the effective ways of the mechanical force of effective particle mean size that the granularity that makes benzimidazole carbamate is brought down below about 450nm to comprise ball milling; Medium milling and homogenize are for example used (Microfluidics Corp.).

In one embodiment, provide medium milling to carry out mechanical particle size reduction.

Ball milling is for using abrasive media, medicine, the low-yield polishing of stabilizing agent and liquid.Material is put into the grinding container with optimum speed rotation, make medium cascade and reduce drug particle size through bump.Used medium must have high density, is provided by gravity and abrasive media quality because be used for the energy of particle size reduction.

Medium milling is the high energy milling method.With medicine, stabilizing agent and liquid are put into reservoir and are being contained the indoor recirculation of medium and rotating handle/impeller.The rotating handle agitated medium makes medicine contact impact and shearing force, reduces drug particle size thus.Preferable medium is ground, because the expectation effect is provided, promptly to reduce required milling time shorter relatively for desired particle size.In a concrete embodiment, use available from WAB the Dyno Mill Type KDL A of Basel or Dyno MillMulti Lab.

Selectable grinder is available from Hosokawa Alpine, Agitated Lab Ball Mill 90 AHM of Augsburg or available from the DCP HighPerformance Media Mill Megavantis ACS of Draiswerke Inc. or from DCPSuperflow or the Advantis perl grinder of B ü hler.

In order to grind, the apparent viscosity of selecting premix is to guarantee the optimum balance between effective grain breakage and the erosion medium resistance.

The abrasive media (pearl) that is used for particle size reduction step (wet grinding) can be selected from rigid media, preferred sphere or particle form.

In one embodiment, abrasive media has the average-size that is lower than about 1mm.In another embodiment, abrasive media has the average-size of 0.5-0.7mm.In another embodiment, abrasive media has the average-size that is lower than 0.5mm.In another embodiment, abrasive media has the average-size of 0.25-0.3mm.

Do not think that the material chosen that is used for abrasive media is crucial.Known zirconium oxide, such as using yttrium, magnesium oxide, 95% or 93% ZrO that Zirconium orthosilicate. is stable and glass grinding media provide thinks as far as pharmaceutical compositions it is the granule of acceptable level of pollution.Yet, estimate other medium, such as rustless steel, titanium and aluminium oxide are useful.Preferred medium has greater than about 3g/cm ³Density.

Wearing time can extensively change and depend primarily on the concrete mechanical system and the processing conditions of selection.With regard to ball milling, possibly reach the process time more than 5 days or 5 days.

On the other hand; Used high shear media mill the process time (1 minute-several hours holdup times) that is less than 1 day, and for example MILL KDL A or

MILLMulti Lab or Agitated Lab Ball Mill 90 AHM or DCP High PerformanceMedia Mill Megavantis ACS provide required effect.

Wearing time is confirmed according to the particle size distribution specification; It depends on many parameters, such as used grinding technique, and Method type (batch process or the continuity method of recycled product is provided), batch sizes, the size of pearl, the quantity of pearl, the rotary speed of rotor and product flow velocity.

Must under the temperature of not obvious degraded drug substance, reduce particulate size.If desired, can use conventional cooling device cooling process equipment.This method is carried out under as far as process of lapping safety and effective environmental temperature and tonnage condition expediently.For example, the environment tonnage is with ball mill, and abrasion grinder and oscillating mill are the typical case.Reach 20psi (1.4kg/cm approximately ₂) tonnage be typical to medium milling.

Through like U.S. Pat 5; 510; Homogenize described in 118 reduces granularity can alternatively be used as the method for using

, thereby produces the granule that is lower than 450nm.

In order to reduce granularity, can benzimidazole carbamate be joined in its insoluble basically liquid dispersion medium and forms and concentrate premix.The disperse medium that is preferred for reducing granularity is moisture.

The concentration of benzimidazole carbamate in premix can change between the about 0.6g/ml of about 0.05-(about 60% (w/v) of promptly about 5-).In certain embodiments, the concentration of benzimidazole carbamate in premix can change between about 0.50g/ml of about 0.15-or the about 0.4g/ml of about 0.2-.

Can directly use premix to make it stand mechanical system so that the benzimidazole carbamate particle mean size in the dispersion liquid is brought down below about 450nm.Preferably, directly uses ball milling premix when being used to wear and tear.

Selectively; Can use suitable stirring; For example Cowles type blender in liquid medium, till observing homodisperse liquid, wherein no longer includes visible big aggregation of bore hole and further dilution with benzimidazole carbamate and surfactant-dispersed.Preferably, the recirculation medium grinder make premix carry out this type beforehand research mill dispersion steps when being used to wear and tear.

In one embodiment; Through using following three preparation processes to prepare benzimidazole carbamate compositions of the present invention: preparation premixing suspension (for example 0.4g/mlFBZ); Through with this premixing suspension wet grinding to the particle size reduction granularity that is lower than 450nm and use this premixing suspension of pharmaceutically useful aqueous carrier dilution to obtain end-product (0.2g/mlFBZ), it is for directly adding the pharmaceutical composition in the drinking-water to.Can in premix, add defoamer maybe can select it is joined in the aqueous carrier so that the preparation end-product.

With pharmaceutically useful carrier the concentration of premixing diluted chemical compound to benzimidazole carbamate in end-product is about about 50% weight of 5-.In certain embodiments, this concentration is about about 30% weight of 10%-, about 15%-about 25% or about 20% weight.

The invention provides preparation and use the method for the pharmaceutical composition of drinking-water administration, wherein said composition comprises: the benzimidazole carbamate granule with the effective particle mean size that is lower than about 450nm; Tween-class surfactant; With pharmaceutically useful carrier, prepare through the following step:

A. with the benzimidazole carbamate Dispersion of Particles in the liquid dispersion medium that contains Tween-class surfactant; And

B. mechanically the granularity of benzimidazole carbamate is brought down below effective particle mean size of about 450nm.

In one embodiment, carry out mechanical particle size reduction through medium milling.

In one embodiment, use pharmaceutically useful carrier further dilution through above-mentioned steps a) and b) pharmaceutical composition of acquisition forms the end-product that directly adds in the drinking-water.

This method comprises the following steps:

A) disperse the benzimidazole carbamate granule to comprising in pharmaceutically suitable carrier and the Tween-class surfactant mixtures;

B) mechanically the particulate granularity of benzimidazole carbamate is brought down below effective particle mean size of about 450nm and forms the enriched product mixture;

C) pharmaceutically useful carrier is joined in the enriched product and form cut back; And

D) end-product is added in the drinking-water.

Embodiment

It is illustrative that the following example is merely, and limits the remainder of this description never in any form.

Embodiment 1 fenbendazole preparation of compositions of the present invention

Use following three preparation processes to prepare 0.2g/ml fenbendazole (FBZ) drinking-water suspension: dilution premixing suspension and obtain end-product (0.2g/ml FBZ) a) preparation premixing suspension (0.4g/ml FBZ), b) this premixing suspension and c of wet grinding).

The prescription of end-product (0.2g/ml FBZ suspension)

Material	Amount
		Fenbendazole	20.0g
Polysorbate80	10.0g
		Benzylalcohol	2.0g
Simethicone emulsion	0.5g
		Water	Add to 100ml

A. the preparation of premixing suspension

Use magnetic stirrer in part water, to mix the Simethicone emulsion and the polysorbate80 of aequum.In order to obtain homogeneous mixture, with its appropriate heating (being lower than 60 ℃).Obtain white and uniform premixing suspension at the water of fenbendazole that adds down aequum than strong mixing (Ultra-Turrax) and residual volume then.Be lower than 60 ℃ in order in adding the fenbendazole process, to keep the product temperature, the beaker that will hold product remains in the cooling bath.

The prescription of premixing suspension

Material	Amount
		Fenbendazole	40g
Polysorbate80	20g
		Simethicone emulsion 30% USP	1g
Pure water	Add to 100ml

B. wet grinding

At first, give the 0.6L vessel filling 450mL 0.25-0.3mm bead (supplier VWR) of

MILL KDL A and be added on the 270mL premixing suspension for preparing in the steps A then.The rotating speed that uses polyurethanes dish and 4200rpm was with premixing suspension wet grinding 45 minutes.

In the wet grinding process, the product stable maintenance is being lower than 50 ℃ because of using double-deck coolant jacket to carry out the heat transfer.

Before the Malvern Mastersizer2000 that use has a Hydro 2000G cell grinds with afterwards according to the granularity of following method mensuration fenbendazole suspension: (agitator speed 500rpm under agitation; Pump speed: 1000rpm), measure the background of the dispersant (water) that comprises in the dispersal unit.Add FBZ suspension sample then, fuzzy up to 10-16%.Use 100% is ultrasonic with this dispersion liquid stirring 2 minutes before measuring particle size distribution.

C. for obtaining the dilution of 0.2g/ml FBZ suspension

The volume of the premixing suspension of mensuration wet grinding and the water of the aequum that adding contains 4% benzylalcohol obtain 0.2g/ml fenbendazole (FBZ) drinking-water suspension so that dilute the premixing suspension.Gained 0.2g/ml fenbendazole (FBZ) drinking-water suspension is used for preparing the water of drinking-water system pastille.

Embodiment 2 flubendazole preparation of compositions of the present invention

Use following three preparation processes to prepare 0.2g/ml flubendazole (FluBZ) drinking-water suspension: the premixing suspension that grinds of dilution and obtain end-product (0.2g/mlFluBZ) a) preparation premixing suspension (0.4g/ml FluBZ), b) this premixing suspension and c of wet grinding).

The prescription of end-product (0.2g/ml FluBZ suspension)

Material	Amount	Supplier
			Flubendazole	20.0g	Transchem
Polysorbate80	10.0g	Merck
			Benzylalcohol	2.0g	Fluka
Simethicone emulsion	0.5g	Dow?Corning
			Pure water	Add to 100ml	-

A. the preparation of premixing suspension

Use magnetic stirrer in part water, to mix the Simethicone emulsion and the polysorbate80 of aequum.In order to obtain homogeneous mixture, with its appropriate heating (being lower than 60 ℃).Obtain white and uniform premixing suspension at the water of flubendazole that adds down aequum than strong mixing (Ultra-Turrax) and residual volume then.Be lower than 60 ℃ in order in adding the flubendazole process, to keep the product temperature, the beaker that will hold product remains in the cooling bath.

The prescription of premixing suspension

Material	Amount
		Flubendazole	40g
Polysorbate80	20g
		Simethicone emulsion 30% USP	1g
Pure water	Add to 100ml

B. wet grinding

At first, give the 0.6L vessel filling 450mL 0.25-0.3mm bead (supplier VWR) of

Before the Malvern Mastersizer2000 that use has a Hydro 2000G cell grinds with afterwards according to the granularity of following method mensuration flubendazole suspension: (agitator speed 500rpm under agitation; Pump speed: 1000rpm), measure the background of the dispersant (water) that comprises in the dispersal unit.Add FBZ suspension sample then, fuzzy up to 10-16%.Use 100% is ultrasonic with this dispersion liquid stirring 2 minutes before measuring particle size distribution.

C. for obtaining the dilution of 0.2g/ml FluBZ suspension

The volume of the premixing suspension of mensuration wet grinding and the water of the aequum that adding contains 4% benzylalcohol obtain 0.2g/ml flubendazole (FBZ) drinking-water suspension so that dilute the premixing suspension.Gained 0.2g/ml flubendazole (FBZ) drinking-water suspension is used for preparing the water of drinking-water system pastille.

The granularity that contains the present composition of FluBZ

Particle size distribution

	50% granular size	90% particulate size
			FluBZ
0, the 2g/ml suspension	≤130nm	320nm

Figure 10 illustrates the particle size distribution according to the flubendazole suspension of embodiment 2 preparations.

Figure 11 is illustrated in the clarification dynamics of the 60ppm FluBZ pastille drinking-water of 24 hours the use FluBZ suspension preparation in cell middle part and (measures through macroscopical optical scanner;

is (by Formulaction; France provides), described in WO 01/17504).

The result. through containing that liquid medicine uses

at 24 hours and measure in the process no tangible physical instability (clarity far below 1%, no sedimentation) according to the flubendazole suspension preparation of embodiment 2 preparations to using.

Embodiment 3 is through the alternative wet grinding-continuation method of recirculation premixing suspension

At first, give the 0.6L vessel filling 450mL 0.25-0.3mm bead (supplier B.Braun Biotech International) of MILL KDL A and be added on the 270mL premixing suspension for preparing in the steps A of

embodiment

1 or 2 then.

Grinding container is connected so that close suspension for continuously the grinder feed pre-mixer with pump; Flow velocity is set in about 1.3L/h.The premixing suspension with its complete form (500mL) through grinder, make it separate the 0.1mm gap with abrasive media and drain into new container after accomplish a wet grinding circulation.6 that will have polyurethanes dish and 4200rpm rotating speed are ground cycle applications in the suspension premix.

In the wet grinding process, the product temperature maintenance is being lower than 50 ℃ because of using double-deck coolant jacket to carry out the heat transfer.

Before the Malvern Mastersizer2000 that use has a Hydro 2000G cell grinds with afterwards according to the granularity of following method mensuration fenbendazole suspension: (agitator speed 500rpm under agitation; Pump speed: 1000rpm), measure the background of the dispersant (water) that comprises in the dispersal unit.Add FBZ suspension sample then, fuzzy up to 10-16%.Use 100% is ultrasonic with this dispersion liquid stirring 2 minutes before measuring particle size distribution.Described in the step C of

embodiment

1 or 2, dilute the premixing suspension of wet grinding then.

Embodiment 4 is through the alternative wet grinding-continuation method of recirculation premixing suspension

At first, give the stable zirconium oxide bead (supplier M ü hlmeier) of the 0.6L vessel filling 360mL0.25-0.3mm yttrium of

MILL MULTI LAB and being connected with pump then so that the premixing suspension for preparing in the steps A of

embodiment

1 or 2 to the grinder charging continuously.

Flow velocity is set in about 37L/h.It is a closed circulation: uninterrupted pumping premixing suspension (2L) from feed containers, make its separate through grinder, with abrasive media the 0.1mm gap from and drain into feed containers.Agitator is installed so that keep the uniformity of premixing suspension to feed containers.Use -Accelerators and 10m/s rotating speed that the suspension premix is carried out grinding in 55 minutes.In the wet grinding process, the product temperature maintenance is being lower than 50 ℃ because of using double-deck coolant jacket to carry out the heat transfer.

embodiment

1 or 2, dilute the premixing suspension of wet grinding then.

Embodiment 5 present compositions and according to the granularity contrast of the compositions of WO 95/13065 preparation

Compositions like the said preparation of embodiment 1 steps A WO 95/13065.Do not use wet grinding (compositions of WO 95/13065) and after wet grinding (according to the present composition of embodiment 1 steps A-B preparation) use Malvern Master separator GMAL 01 with Hydro 2000G cell, measure granularity according to the Frauenhofer method.Wet grinding causes the particulate granularity of fenbendazole to be brought down below the effective size of grain of 200nm.

Do not carry out the particle size distribution after wet grinding and the wet grinding

	D(0.50)	D(0.90)
			The thick suspension of FBZ	≤2440nm	≤32640nm
FBZ 0.2g/ml suspension	≤120nm	≤200nm

Fig. 1 illustrates the particle size distribution of not using after wet grinding and the wet grinding.

Fig. 2 representes that the clarification dynamics of the 60ppm FBZ pastille drinking-water of 24 hours the use FBZ suspension preparation in cell middle part is (through macroscopical optical scanner mensuration;

is (by Formulaction; France provides), described in WO 01/17504).

equipment has detected any change in the disperse system (for example clarification, sedimentation etc.) based on multiple light scattering.It is by moving along flat cylindrical pond, scanning the vertical scanning macroscopic analysis appearance of the playback head composition of whole sample height simultaneously.Playback head self is made up of pulse near-infrared light source and two synchronizing indicators: the transmission-type detector picks up the light through the product transmission, and backscatter detector receives the backscattered light of product.Playback head whenever just obtains a transmission and backscattered data at a distance from 40 μ m to the 80mm limit for height.The characteristic present who obtains the uniformity of product, granule density and particle mean size.The result is expressed as as the backscatter of high (in the mm) function of sample or the percentage ratio of transillumination.Use programmable frequency to repeat to obtain characterizing product stability then along obtaining of product or instable product fingerprint overlapping, no matter they are identical or inequality.

The result. through no tangible physical instability sign (not having clarification, no sedimentation) was measured in the liquid medicine use

that contains of using the fenbendazole suspension preparation for preparing according to embodiment 1 in the process at 24 hours.

The physical stability contrast of the compositions of embodiment 6 present compositions and WO 95/13065 preparation

Preparation compositions of the present invention is called " the FBZ suspensions of more wet grindings " described in embodiment 1.Preparation fenbendazole suspension (being called " the thick suspension of FBZ ") described in WO 95/13065.According to preparing compositions with identical preparation process described in the embodiment 1; But use softer wet grinding condition: use 490ml 0.5mm bead to grind 1L premixing suspension; Use polyurethanes and 3200rpm rotating speed only to carry out 3 and grind circulation, this is called " the FBZ suspension of appropriate wet grinding ".These wet grinding conditions can obtain the middle particle size distribution of comparing with " the FBZ suspensions of more wet grindings " and the thick suspension of FBZ.

The thick suspension of FBZ (not carrying out wet grinding) and

The particle size distribution of FBZ suspension (appropriateness and more wet grinding)

	D(0.50)	D(0.90)
			The thick suspension of FBZ (according to WO 95/13065)	≤2430nm	≤24710nm
The more wet grindings of FBZ 0.2g/ml suspension appropriateness wet grinding	≤350nm≤120nm	?≤1030nm≤200nm?

Fig. 3 illustrates these particle size distribution.

The dilute with water preparation obtains 60ppm fenbendazole concentration, for example contains liquid medicine and is used for the poultry treatment.Must contain the physical stability of liquid medicine by means of macroscopical optical scanner described in embodiment 5

institute.

evaluation result illustration is in Fig. 4, and their expressions are to the clarification dynamics of detection in 24 hours in the middle of each comfortable cell of three kinds of preparations.

The result. through

use is measured no physics unstability sign according to the liquid medicine that contains of the fenbendazole suspension preparation of embodiment 1 preparation in 24 hours analyze, and use the liquid medicine that contains of the thick suspension preparation of fenbendazole for preparing according to WO 95/13065 significantly clarification to occur.This clarification is equivalent to form detectable settled layer in about 6.5 hours in research beginning back.The suspension of appropriateness wet grinding shows the intermediate stable characteristic.Its clarification level is complementary with the detection of leaving standstill settled layer after 14 hours.

Embodiment 7 compositionss of the present invention be purchased suspendible-Emulsion product

Janssen-Cilag, Beerse Belgium) the physical stability contrast

Dilute with water is purchased suspendible-Emulsion product

and obtains 85.6ppm flubendazole concentration, for example contains liquid medicine and is used for the poultry treatment.With its particle size distribution be summarised in the following table and embodiment 1 described in the present composition (FBZ suspension) be shown among Fig. 5 as reference.

FBZ 0.2g/ml suspension with

Particle size distribution contrast

By means of

according to embodiment 2 in the physical stability that contains liquid medicine of identical analysis explanation

used in research preparation.

evaluation result illustration is at Fig. 6, and their expressions detect 24 hours clarification dynamics to the liquid medicine that contains that uses

formulation preparation at the cell middle part.

The result. use

pastille waterishlogging to give birth to obviously clarification, the liquid medicine that contains of the fenbendazole suspension preparation for preparing according to embodiment 1 is carried out assay determination in 24 hours and do not have physics unstability sign and pass through

.

Embodiment 8: the fenbendazole suspension that uses the preparation of different surfaces activating agent

Use the FBZ of preparation described in following component such as the embodiment 1 suspension.

Contain the physical stability evaluation of liquid medicine

Just water is diluted to the FBZ suspension of suspending agent-containing 60ppm and uses Turbiscan to measure the different physical stabilities (transmission and back-scattered light) that contain liquid medicine at room temperature 24 hours before analysis.Compare the premixing suspension that the following difference preparation of use contains poloxamer 188 with method described in the embodiment 1.With fusing poloxamer 188 before Simethicone emulsion mixes and add fenbendazole then, this mixture under agitation becomes sticky, and makes it be not easy to through grinder.

Particle size distribution

Before wet grinding with the particle size distribution of measuring different suspensions afterwards and be reported in the following table.

All polysorbate ester compositions all present meticulous and narrow particle size distribution after wet grinding.

Contain the physical stability evaluation of liquid medicine

Just water is diluted to 60ppm and use

according to being determined under the room temperature the different physical stabilities (transmission and back-scattered light) that contain liquid medicine in 24 hours with embodiment 3 identical analysis explanations with the FBZ suspension of suspending agent-containing before analysis.The evaluation result illustration of

in Fig. 7, their expressions use is contained different suspending agents FBZ 0.2g/ml suspension preparation contain liquid medicine at cell middle part 24 hours detected clarification dynamicss.

The result. by the FBZ suspension diluent preparation that contains poloxamer 188 to contain liquid medicine unstable physically.This is confirmed through the settled layer that detects with 0.77 μ m/min growth, and contain different polysorbate esters other contain liquid medicine and do not detect settled layer.

The liquid medicine that contains of the polysorbate esters of use test demonstrates 24 hours and is lower than 10% acceptable transmission variation value.

Embodiment 9 uses the fenbendazole suspension of the polysorbate80 preparation of variable concentrations

Described in embodiment 1, use following component to prepare the FBZ suspension.

Particle size distribution

Before wet grinding with the particle size distribution of measuring different FBZ suspensions afterwards and be reported in the following table.

All FBZ suspensions all present meticulous and narrow particle size distribution after wet grinding.

Contain the physical stability evaluation of liquid medicine

Just water is diluted to the FBZ suspension of suspending agent-containing 60ppm and uses Turbiscan to measure the different physical stabilities (transmission and back-scattered light) that contain liquid medicine at room temperature 24 hours before analysis.The physical stability that contains liquid medicine by means of

according to the analyses explanation research identical with embodiment 5.

The evaluation result illustration of

in Fig. 8, their expressions use is contained variable concentrations polysorbate80 suspension preparation contain liquid medicine at cell middle part 24 hours detected clarification dynamicss.

The result: the liquid medicine that contains to the polysorbate80 that contains variable concentrations does not detect settled layer.Figure confirms this good physical stability according to the transmission variation: maximum variation value is equivalent to 1% after acceptable 24 hours.

The wet grinding of embodiment 10 fenbendazoles 20% and 40% suspension

Preparation compositions of the present invention is called " FBZ 0.2g/ml suspension " described in embodiment 3.

Preparation fenbendazole suspension (being called " the thick suspension of FBZ ") and following wet grinding described in WO 95/13065.

At first give the stable zirconium oxide bead (supplier M ü hlmeier) of the 0.6L vessel filling 360mL 0.3mm yttrium of MILL MULTI LAB and is connected with pump then so that continuously to the thick suspension of grinder charging FBZ.Flow velocity is set in about 112L/h.It is a closed circulation: uninterrupted pumping premixing suspension (2L) from feed containers makes it through grinder, through separating with abrasive media and drain into feed containers in the 0.1mm gap.It is even so that keep the premixing suspension to feed containers agitator to be installed.Use -Accelerators and 10m/s rotating speed that the suspension premix is carried out grinding in 55 minutes.

In the wet grinding process, the product temperature maintenance is being lower than 50 ℃ because of using double-deck coolant jacket.

Described in embodiment 3, measure the particle size distribution of fenbendazole suspension. FBZ 0.2 The particle size distribution of the thick suspension of FBZ of g/ml suspension and wet grinding relatively

	D(0.50)	D(0.90)
			The thick suspension of the FBZ of wet grinding	≤130nm	≤300nm
FBZ 0.2g/ml suspension	≤130nm	≤290nm

The result. grind the end-product " the thick suspension of FBZ " or the grinding that contain 20% w/v FBZ and treat that dilution has produced the particle size distribution that is equal to the premixing suspension that contains 40% FBZ that obtains end-product " FBZ 0.2g/ml suspension ".

Embodiment 11 uses the duct test of fenbendazole suspension

Preparation compositions of the present invention described in embodiment 2 is called " FBZ 0.2g/ml suspension " (use and carry out grinding steps from the stable zirconium oxide bead of the 420mL 0.3mm yttrium of M ü hlheimer, use the 1L/h flow velocity to carry out two circulations).

The particle size distribution that FBZ 0.2g/ml suspension is compared with the thick suspension of FBZ

	D(0.50)	D(0.90)
			The thick suspension of FBZ	≤1910nm	≤13180nm
FBZ 0.2g/ml suspension	≤130nm	≤270nm

Preparation fenbendazole suspension (being called " the thick suspension of FBZ ") described in WO 95/13065.Described in embodiment 3, measure the particle size distribution of fenbendazole suspension.

Test the stability that contains liquid medicine and the uniformity of two kinds of preparation of compositions of use in 3-hour time limit through the distribution of simulation pastille water under the condition at the scene.Use is carried out these researchs from the drinking water of the water supply of locality.

Preparation contains liquid medicine with drinking-water to use compositions in the medicinal cupping of aequum, so that obtain the fenbendazole of 60ppm concentration, for example contains liquid medicine and is used for the poultry treatment.Jar is connected through the pot bottom outlet with the 25-m transparent pipeline.Flow velocity is set in about 3.5L/h.In assigning process in medicinal cupping (from the teeth outwards) and 25-m pipe end regularly to the pastille water sampling.

The fenbendazole content of analytic sample.In allotment period, do not stir containing liquid medicine.In addition, any precipitum through forming in visual inspection medicinal cupping and the pipeline.Illustration is in Fig. 9 as a result, and their expressions are from two kinds of FBZ concentration variation values that contain liquid medicine of medicinal cupping and pipe end sampling.

The result does not all detect precipitum in medicinal cupping and pipeline in two kinds of researchs; Yet, contain in the medicinal cupping of liquid medicine comprising the thick suspension of FBZ, when off-test, contain liquid medicine and seem denseer in the medicinal cupping bottom.Confirmed this unstability according to following analysis result, what described analysis result promptly used the thick suspension preparation of FBZ contains liquid medicine and all even stable pastille water that uses FBZ 0.2g/ml suspension preparation than significantly descending in the FBZ of allotment period concentration.

Embodiment 12 field trial pig and poultry

Preparation compositions of the present invention is called " FBZ 0.2g/ml suspension " described in embodiment 1.Carry out two kinds of field studys so that estimate uniformity and the stability that contains FBZ 0.2g/ml suspension in the liquid medicine when using under the condition at the scene.

Use medicinal cupping; The long closed circulation water system (being made up of PVC and stainless steel pipes) of about 60m carries out a kind of research in the pig of growth, and uses electronics administration pump (from the KONTI-DOS of Buerkert) and the long water system cecum (being made up of galvanized iron and plastic conduit) of about 220m in the turkey of growth, to carry out another kind research.

General Study operates in every kind of research identical: use on the farm drinking-water of the available 7.2-8.2pH of having value scope and 7.3-13.7 ° of dH total hardness to prepare and contain liquid medicine.Based on the single dose of 5mg FBZ/kg body weight, the water loss preparation of estimating in the weight of animals and 3 hours (medicinal cupping) and 8 hours (administration pump) is in the concentration of FBZ in water of the umber (ppm) in 1,000,000.

Whenever in the administration process, getting the sample that contains liquid medicine from the bottom of jar with top with at nipple and the water fountain be scheduled to along water system at a distance from 30-60 minute.Whole administration interim not to jar in inclusions stir.

The precipitum of any kind of that active component or any excipient form in inspection jar and nipple or the water fountain.

Stop about 24 hours of back in administration, extract water sample again so that estimate the residual FBZ content of possibility.Use the FBZ content of all water samples of HPLC method analysis of checking subsequently.

The result. all analysis results (actual FBZ concentration) are all consistent with nominal (calculating) concentration.Obtained conforming FBZ concentration in the jar neutralization along water pipe at 2 or 8 hours in the administration process.Take from the bottom of jar and sample zero difference aspect FBZ concentration on top.

In jar, do not observe particles settling or floating.Sedimentation does not take place or block nipple.Stop the back water sample of getting in 24 hours in administration and do not show any FBZ residue of measuring (being lower than the detectability of about 0.4ppm), show that new FBZ suspension can not form any residue in drinking-water system.To be summarised in the following table from the result of these field studys.

Mean F BZ concentration according to the field study report

Be that from the conclusion of these field studys FBZ 0.2g/ml suspension is evenly distributed in containing in the liquid medicine in the representational water system of pig and poultry farms of selection; And in the administration process, can guarantee accurate administration, because in the predetermined administration time limit, produced conforming FBZ concentration.

********

Word ＂ in this patent (comprising claim) comprises ＂, and ＂ comprises ＂ and " contains ＂ and be interpreted as and comprise, but non-exclusive.Specify this explanation identical with these words provide these words in united states patent law explanation.

All lists of references of quoting from this patent are introduced this patent as a reference.

Above-mentioned detailed description of the preferred embodiments only is appointed as and is made those skilled in the art be familiar with the present invention, and its principle and practical application thereof make those skilled in the art to adopt and use the present invention with many forms, because they are suitable for concrete application requirements.Therefore, the present invention is not limited to above-mentioned embodiment and can carries out various modification.

Claims

1. use drinking-water to give the pharmaceutical composition of benzimidazole carbamate, it is characterized in that said composition comprises aqueous suspension, this suspension comprises:

The benzimidazole carbamate granule that has amount that effective particle mean size is lower than 450nm and be 5-50% weight is the Tween-class surfactant of 0.1-50% weight with amount.

2. the described compositions of claim 1, wherein the particulate effective particle mean size of benzimidazole carbamate is lower than 300nm.

3. claim 1 or 2 described compositionss, wherein said Tween-class surfactant is a polysorbate80.

4. claim 1 or 2 described compositionss, the amount of wherein said Tween-class surfactant is a 5-20% weight.

5. claim 1 or 2 described compositionss, wherein benzimidazole carbamate is a fenbendazole.

6. claim 1 or 2 described compositionss, wherein the amount of benzimidazole carbamate is a 10-40% weight.

7. any described compositions of claim 1-6 is controlled the application in the parasitic medicament in this animal in preparation through administration that animal via is drunk water.

8. the method for the pharmaceutical composition of drinking-water administration is used in preparation, and wherein this method comprises:

Is in the Tween-class surfactant mixtures of 0.1-50% weight with the benzimidazole carbamate Dispersion of Particles of measuring to 5-50% weight in comprising pharmaceutically useful carrier and measuring; And

Make the particulate granularity of benzimidazole carbamate be brought down below effective particle mean size of 450nm through mechanical system.

9. the described method of claim 8, wherein this method further comprises:

With the benzimidazole carbamate Dispersion of Particles in comprising pharmaceutically useful carrier and Tween-class surfactant mixtures;

Make the particulate granularity of benzimidazole carbamate be brought down below effective particle mean size of 450nm through mechanical system so that form the enriched product mixture;

In this enriched product, add pharmaceutically useful carrier and form the cut back form; And

End-product is joined in the drinking-water.

10. claim 8 or 9 described methods are wherein carried out mechanical particle size reduction through medium milling.

11. any described preparation of compositions is used to prevent that animal from the purposes of the medicine of parasitic infection taking place among the claim 1-6, wherein this medicine gives animal through drinking water.