ES2440485T3 - A suspension comprising benzimidazole carbamate and a polysorbate - Google Patents

Abstract

A pharmaceutical composition for administration to drinking water of a benzimidazole carbamate characterized in that the composition comprises an aqueous suspension comprising: benzimidazole carbamate particles having an effective average particle size of less than about 450 nm, and a surfactant of the type Tween.

Description

A suspension comprising benzimidazole carbamate and a polysorbate

5 Field of the invention

The present invention generally relates to a pharmaceutical composition for administration in drinking water comprising a benzimidazole carbamate, a method of preparing the composition, the use of the composition to prepare a medicament for controlling a parasite in an animal, and a method to use the

10 composition to protect an animal from a parasitic infection.

Background of the invention

Benzimidazoles were originally developed as plant fungicides and subsequently as

15 anthelmintics for veterinary and human use (eg antiparasitic), The family of benzimidazoles with anthelmintic activity includes thiazolylbenzimidazoles and benzimidazole carbamates. Benzimidazoles show a broad spectrum of activity, especially against helminth parasites (for example, intestinal worms or tapeworms).

Well-known benzimidazoles with activity against helminths are for example thiabendazole; cambendazole; and benzimidazole carbamates, such as parbendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, ricobendazole and luxabendazole, all of which differ in the substituents of the parent benzimidazole core.

25 Phenylguanidine prodrugs have also been developed that are metabolically transformed into anthelmintic benzimidazoles. Febantel, for example, is a prodrug that is converted to fenbendazole, and netbimine results in albendazole.

Benzimidazole carbamates are generally poorly soluble in water. For some useful applications of the 30 compounds, the poor water solubility of benzimidazoles is a major obstacle.

Fenbendazole (FBZ) is a benzimidazole carbamate used as a veterinary anthelmintic in many species, including poultry, pigs and cattle. Fenbendazole is used to control nematodes such as Ascaridia sp., Heterakis sp., And Capillaria sp., In poultry and pigs.

35 The massive administration of water-soluble drugs analogous to benzimidazole carbamates to intensively raise pigs and poultry has so far been limited to oral administration as an additive to sprinkle on food or premix in food, Such medicated foods need, however, to be prepared separately on the farm or in a feed mill and there is always the risk of

40 cross contamination with unmedicated food. Sprinkling of the additive, on the other hand, requires additional labor.

Therefore, medication by a drinking water system is preferred for routine use in the deworming of intensively bred animals due to the ease of administration to numerous animals at

45 same time.

Many pig and poultry farms are already equipped with the necessary devices to administer medication through drinking water systems in complex bow systems for tank farms, pipes, coils, poultry drinkers and teats. A normal stable can contain hundreds of meters

50 pipes with many coils and hundreds of individual drinking fountains and / or teats. The water in the drinking water system in a pig or poultry house obeys the principles of laminar flow through the pipes and coils and is subject to the so-called "shear" forces that will affect the flow velocity. In said complex piping system there are considerable risks for the segregation or sedimentation of the medication, specifically when it refers to water insoluble compounds.

55 The effectiveness of the medication through the drinking water system depends in the last resort on the quality of the composition and the palatability of the medication. Said composition must provide maximum availability of the active substance, minimum segregation and sedimentation of the active compound in the beverage system, medication pumps, drinkers with teats, etc., a very precise dosage and distribution

60 homogeneous of the active compound in the drinking water and a guaranteed stability of the active compound.

Until now, no convenient solution has been available for this route of farm animal medication for veterinary drugs that are not very soluble in water, analogous to benzimidazole carbamates, which meets these requirements.

65 International Patent Application WO 95/13065 describes an aqueous suspension composition of fenbendazole with a Tween surfactant and a preservative. In this aqueous suspension, fenbendazole remains in suspension and without agglomeration or change in particle size if it has been stored for a period of time. The particle size is in the order of approximately 1 micron. This aqueous suspension

5 fenbendazole is not, however, suitable for administration through an irrigation system and is used in large pig or poultry houses as described above. It has sedimentation after a certain period of time if it is diluted to a concentration in the drinking water of 60 ppm of fenbendazole. These sediments do not allow a homogeneous distribution of fenbendazole in the irrigation system and pose the risk of blocking the equipment of the irrigation system, for example, of drinking teats.

10 International Patent Application WO 01/17504 describes a suspoemulsion composition for administration in drinking water. This composition, however, does not meet the requirements for administration in drinking water systems that refer to the homogeneous distribution.

The International Patent Application WO 00/50009 describes the encapsulation of labile compounds in water or insoluble in liposomes for administration in drinking water.

International Patent Application WO 95/16447 describes anthelmintic compositions comprising micronized particles of rafoxanide and fenbendazole having more than 98% of the particles an average particle size of less than 20 microns for oral administration, but not in oral systems. drinking water

UK Patent Application GB 2307871 describes an industrial scale method for formulating aqueous oxfendazole suspensions without employing any particle size reduction technique.

WO9516447, GB2307871 and EP0093497 disclose aqueous suspensions comprising benzimidazole derivatives without defining particle sizes.

Summary of the invention

The present invention generally relates to stable effective aqueous compositions of benzimidazole carbamates that can be conveniently administered through drinking water systems.

Thus, the present invention provides, in part, a pharmaceutical composition for the administration of benzimidazole carbamates in the drinking water. This composition is characterized in that it comprises an aqueous suspension comprising benzimidazole carbamate particles having an effective average particle size of less than about 450 nm, and a Tween type surfactant.

The present invention also provides, in part, a use of the above composition to prepare a medicament for controlling a parasite in an animal by administering the medicament through the drinking water of the animals.

The present invention also provides, in part, a method for preparing a pharmaceutical composition for administration in drinking water. The method comprises:

45 i. dispersing benzimidazole carbamate particles in a pharmaceutically acceptable carrier comprising a Tween surfactant, and

ii. mechanically reduce the particle size of the benzimidazole carbamate particles to an effective average particle size of less than about 450 nm.

The present invention also provides, in part, the use in the manufacture of a medicament for protecting an animal from parasitic infection. This use comprises administering the above composition to the animal through the animal's drinking water. This protection includes preventing, reducing risk, delaying the onset of, reducing dissemination, improving, reducing, and / or eradicating parasitic infection and / or one or more of the symptoms.

55 Additional benefits of the invention derived from the reading of this specification will be apparent to one skilled in the art.

Brief description of the figures

60 Figure 1 depicts the particle size distribution of the fenbendazole suspension (FBZ) both raw and after wet milling.

Figure 2 represents the clarification kinetics of 60 ppm of medicated FBZ in drinking water prepared with a suspension of FBZ after wet milling determined by TURBISCAN® in the intermediate part of the measuring cell for 24 hours.

Figure 3 depicts the particle size distribution of the raw FBZ suspension (without wet grinding) and FBZ suspensions (lightly ground and more wet ground)

Figure 4 represents the clarification kinetics of 60 ppm of medicated FBZ in drinking water prepared with a suspension of crude FBZ (without wet grinding) and suspensions of FBZ (lightly ground and more wet ground) determined by TURBISCAN® in the middle part of the measuring cell for 24 hours.

Figure 5 represents the particle size distribution of SOLUBENOL® and a suspension of FBZ.

Figure 6 depicts the clarification kinetics of 85.6 ppm of medicated water flubendazole prepared with SOLUBENOL® and 60 ppm of medicated water FBZ prepared with a suspension of FBZ, determined by TURBISCAN® in the middle part of the measuring cell for 24 hours

Figure 7 represents the physical stability of 60 ppm of medicated FBZ in medicated water in water characterized by

15 from the dilution of an FBZ suspension containing various surfactants determined by TURBISCAN® in the middle part of the measuring cell for 24 hours.

Figure 8 represents the physical stability of 60 ppm of medicated FBZ in medicated water in water characterized from the dilution of the FBZ suspension containing various concentrations of Polysorbate 80 determined by TURBISCAN® in the intermediate part of the measuring cell during 24 hours.

Figure 9 represents the concentration of FBZ in medicated waters prepared with a suspension of crude FBZ and 0.2 g / ml of a suspension of FBZ over a 3-hour distribution; Samples were taken from the medication reservoir and at the end of the 25 m pipe.

Figure 10 represents the particle size distribution of the fenbendazole suspension manufactured according to example 2.

Figure 11 depicts the clarification kinetics of 60 ppm of medicated FluBZ in prepared waters with 0.2 g / ml of a FluBZ suspension determined by TURBISCAN® in the middle part of the measuring cell for 24 hours.

Detailed description of the preferred embodiments

The present inventors have shown that the composition according to the invention, which comprises an aqueous suspension comprising benzimidazole carbamate particles having an effective average particle size of less than about 450 nm, and a Tween type surfactant is sufficiently stable and can be distributed homogeneously in the system to allow effective administration of benzimidazole carbamate compounds to animals through drinking water systems.

Through this new composition, benzimidazole carbamate can be administered to the target animal through a drinking water system of choice by mixing and diluting the composition with water in the central water tank or in the separate storage tank .

Alternatively, the composition is continuously injected into a high or low pressure ring system for the distribution of drinking water, using a dosing dispenser or a dosing pump system or a medication providing system.

Dosing pump systems are based on a pump that manages measured amounts of a concentrate in a water pipe at a typical 1-5% dilution. Including in dosing pump systems electronic dosing pump systems such as KONTI-DOS from Buerkert or mechanical dosing pump such as DOSATRON® water-fed dosing pump, DOSMATIC® water-powered proportional medications can be used . The variety of field facilities also refers to the water supply systems themselves; dead end or closed circuit systems in

55 different lengths with different materials for conduits (for example, PVC, galvanized iron) and drinking fountains that adapt to target animals such as bell drinkers, teats.

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

In one embodiment, the average effective particle size of the benzimidazole carbamate is between

About 50 nm and 450 nm, in another embodiment between about 100 nm and 400 nm, in another embodiment between about 150 and 350 nm, or between about 180 nm and 300 nm. In another embodiment, the average effective particle size of the benzimidazole carbamate is between about 190 nm and 220 nm, in another embodiment about 200 nm.

Alternatively, benzimidazole carbamate can be formulated as an injectable product for parenteral administration to animals.

As used herein, particle size refers to an average particle size in number as measured by conventional particle size measurement techniques, well known to those skilled in the art, such as laser dispersion, sedimentation of field flow fractionation, photon correlation spectroscopy, or disk centrifugation.

The particle size measurement can be carried out with a Malvern Mastersizer 2000 with the Hydro 200G measuring cell, or with a particle size distribution analyzer using Horiba LA-910 laser dispersion.

15 “An effective average particle size of less than approximately 450 nm” means that at least 90% of the particles have an average particle size by weight (D (0.90) of less than 450 nm when measured with the techniques mentioned above.

Tween surfactants (polysorbates, sorbitan esters, poly (oxy-1,2-ethanediyl) derivatives, Tweens) are water-soluble nonionic surface tension modifying agents comprised of complex esters and ester-ether esters derived from hexahydric alcohols , alkylene oxides and fatty acids by adding polyoxyethylene chains to sorbitol and hexitrol hydroxyl anhydrides (hexitans and hexides) derived from sorbitol and then partially esterifying with common fatty acids such as lauric, palmitic, stearic and oleic acids)

In one embodiment, the Tween surfactant is selected from one or more of Tween 20, Tween 40, Tween 60

or Tween 80, also known in the pharmaceutical industry as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80. Polysorbate 20 (polyoxyethylene sorbitan monolaurate), is a laurate ester. Polysorbate 60 (polyoxyethylene sorbitan monostearate) is a mixture of stearate and palmitate esters; and Polysorbate 80 (polyoxyethylene sorbitan monooleate) is an oleate ester.

Such Tween surfactants are commercially available and / or can be prepared by techniques known in the art.

In one embodiment, the Tween type surfactant is Polyoxyethylene sorbitan monoleate (polysorbate 80, Tween 80) which has the chemical name polyoxyethylene sorbitan monooleate (20), available, for example from ICI Specialty Chemicals.

The Tween surfactant is present in the composition of about 0.1 to about 50% by weight. In some embodiments, the concentration of the Tween surfactant is from about 5% to about 20% by weight, from about 7.5% to about 15% by weight, or about 10%.

The composition according to the invention comprises one or more benzimidazole carbamates. Well-known benzimidazole carbamates are for example parbendazole (see, for example, United States Patent No. 3.

480. 642), mebendazole (see, for example, United States Patent No. 3,657,667), flubendazole (see, for example, United States Patent No. 3,657,267), fenbendazole (see, for for example, United States Patent No. 3,954,791), oxfendazole (see, for example, United States Patent No. 3,929,821), oxibendazole (see, for example, United States Patent No. 3. 574. 845), albendazole (see, for example, U.S. Patent No. 3,915,998), ricobendazole (albendazole sulfoxide) (see, for example, U.S. Patent No. 3,915,998) and luxabendazole (see, for example, United States Patent No. 4,639,463, all of which differ in the substituents of the parent benzimidazole nucleus or prodrugs analogous to Febantel and Netbimine.

In one embodiment, the benzimidazole carbamate is fenbendazole (see, for example, U.S. Patent No. 3,954,791). In another embodiment the benzimidazole carbamate is flubendazole (see, for example, United States Patent No. 3,657,267).

Benzimidazole carbamate is generally present in the composition in an amount or about 5 to about 50% by weight. In some embodiments, benzimidazole carbamate is present at a concentration at a concentration of between about 10% to about 40% by weight, from about 15% to about 30%, or from about 17.5% to about 25% by weight

or about 20%.

In some embodiments, the composition comprises a pharmaceutically acceptable carrier. The vehicle can be, for example, an aqueous vehicle, preferably water (purified). However, the invention can be practiced with other liquid media in which benzimidazole carbamate is poorly soluble and dispersible, for example, aqueous salt solutions.

Optionally, the composition may also contain an antifoaming agent, such as, for example, emulsion

5 of 30% USP simethicone, sodium oleate, sodium caprylate or mixtures thereof. The antifoaming agent is present in a concentration sufficient to prevent foaming when the composition of the present invention is diluted with water. In the present invention, the simethicone emulsion may be present at a concentration of between about 0.2% by weight to about 1% by weight. In some embodiments, the simethicone emulsion is present at a concentration of approximately 0.5% by weight.

Optionally, the composition may also contain a preservative. The preservative is one known to those skilled in the art, and may be, for example, benzyl alcohol, sodium salt of butylparaben, sodium salt of methylparaben, sodium salt of propylparaben and mixtures thereof. It is generally present in an amount of between about 0.01% to about 3% by weight. In some embodiments, the benzyl alcohol is

15 present at a concentration of between about 1.5% to about 2.5% by weight, or about 2% by weight.

An aspect of the present invention is the use of the composition according to the invention in the manufacture of a medicament for controlling a parasite in an animal by administering the medicament to the animal by means of the water of

20 animal drink.

The present invention provides a method for protecting an animal from a parasitic infection, wherein the method comprises administering the composition according to the invention to the animal through the animal's drinking water.

In one embodiment, this composition can be used to treat animals, especially livestock animals (eg, cattle, poultry, pigs) with benzimidazole carbamate compounds, for example, fenbendazole, through drinking water systems. . The composition (finished product) can be used in a proportioner or medicator to prepare medicated drinking water as is known in the art.

30 The medicator uses, for example, 1 oz (2.8350 g) of the finished product and further dilutes it with water to approximately a 1: 128 ratio to obtain medicated drinking water having a concentration of benzimidazole carbamate, for example, fenbendazole between about 10 to about 150 ppm.

In some embodiments, benzimidazole carbamate, for example, the concentration of fenbendazole in medicated drinking water is about 40 to about 120 ppm, depending on the effective dose, the animal's body weight, the animal's water consumption. and the treatment period.

In one embodiment, the concentrated premix composition is diluted directly to a concentration of

40 between about 10 ppm to about 150 ppm. In some embodiments, the concentration of the concentrated premix is directly diluted to a concentration of between about 40 to about 120 ppm of the benzimidazole carbamate, for example, fenbendazole, and is used directly for the administration of drinking water (for example, for poultry).

In a specific embodiment for the specific benzimidazole carbamate, fenbendazole, the concentration is calculated to provide the target amount of fenbendazole per body weight (BW) of the poultry being treated in the range of about 1 mg to about 5 mg of fenbendazole per kilogram of body weight per day in the volume of drinking water normally consumed by poultry being treated in a period of 2 to 24 hours of treatment. The target dosage is dictated by the

50 infection of parasitic species that are being treated and is known in the art. For the administration of other species, the concentration is calculated respectively.

Medicated drinking water is used to treat poultry in treatment periods of between about 2 to about 24 hours, often preferably treatment periods of

55 approximately 8 hours in one to six consecutive days. For administration to other species, the treatment period is calculated respectively.

To treat pigs, the finished product is diluted to the desired concentration in order to obtain drinking water containing an effective amount of benzimidazole carbamates, such as, for example,

60 fenbendazole to control helminths in pigs. The effective amount is dependent on the infestation of parasite species that are being treated and is known in the art.

Alternatively, the composition according to the present invention can be administered parenterally to animals, for example, by intravenous, intramuscular or subcutaneous injection.

In another aspect, the present invention provides a method for protecting an animal from a parasitic infection, wherein the method comprises administering the composition according to the invention to the animal by parenteral route.

5 Parenteral treatment is also possible through alternative routes. The parenteral route of administration is especially useful in case the plasma and tissue levels of benzimidazole carbamate are important because, in order to act systemically, the benzimidazoles have to be captured in the bloodstream. One of the aforementioned examples is the use of benzimidazoles to combat systemic parasitic infections, for example, with the larval stage of certain cestodes, for example, Echinococcus multicularis and E.

10 granulosis

In general, the composition according to the present invention can be administered to all species of animals that need treatment or prevention of parasitic infections such as pigs, cattle, horses, cats, dogs, poultry and fish.

In another aspect of the invention, a method of preparing the composition according to the invention is provided.

The method comprises dispersing benzimidazole carbamate particles in a mixture comprising a

20 pharmaceutically acceptable carrier and a Tween surfactant and; mechanically reduce the particle size of the benzimidazole carbamate particles to an average particle size of less than about 450 nm.

In one embodiment, the average effective particle size of the benzimidazole carbamate particles is

25 reduces to less than about 400 nm, or about 350 nm or about 300 nm, in another embodiment to less than about 250 nm, in another embodiment to less than about 200 nm.

In one embodiment, the average effective particle size of the benzimidazole carbamate particles is reduced to a particle size between about 50 nm and 450 nm, in another embodiment between

About 100 nm and 400 nm, in another embodiment between about 150 and 350 nm, or between about 180 nm and 300 nm. In another embodiment, the average effective particle size of the benzimidazole carbamate particles is between about 190 nm and 220 nm, in another embodiment about 200 nm.

35 Effective methods of providing mechanical strength for reducing the particle size of the benzimidazole carbamate to an effective average particle size of less than about 450 nm include milling in a ball mill, milling in a mill with grinding media, and homogenization, for example with a MICROFLUIDIZER® (Microfluidics Corp.).

In one embodiment the mechanical reduction of the particle size is carried out by milling in a mill with grinding means.

The ball mill is a low energy grinding process that uses grinding media, drug, stabilizer and liquid. The materials are placed in a grinding vessel that is rotated at a speed

Optimal so that the media collide with each other and reduce the particle size of the drug by impact. The means used must have a high density since the energy for reducing the particle size is provided by gravity and the mass of the attrition means.

Grinding with grinding media is a high energy grinding process. The drug, the stabilizer and

The liquid is placed in a reservoir and recirculated in a chamber that contains the means and rotates the shaft / impeller. The rotating shaft agitates the means that subject the drug to impact and the shear forces, thereby reducing the particle size of the drug. A media mill is preferred due to the relatively shorter grinding time required to provide the expected result, that is, the desired reduction in particle size. In a specific embodiment, a Dyno Mill Type KDL A or Dyno Mill Multi Lab is used

55 available from WAB, Basel.

Alternative mills are Agitated Lab Ball Mill 90 AHM available from Hosokawa Alpine, Augsburg or DCP High Performance Media Mill Megavantis ACS, available from Draiswerke Inc. or DCP Superflow or Advantis Buhler pearl mills.

60 For milling, the apparent viscosity of the premix is selected to ensure an optimal balance between the effective fragmentation of the particles and the erosion of the media.

The crushing media (beads) for the step of particle size reduction (wet milling) can be selected from rigid media preferably in spherical or particulate form.

In one embodiment, the grinding media has an average size of less than about 1 mm. In another embodiment, the grinding media has an average size between 0.5 and 0.7 mm. In another embodiment, the grinding media has an average size of less than 0.5 mm. In another embodiment, the grinding media has an average size of 0.25 to 0.3 mm.

5 The selection of material for grinding media is not believed to be critical. It is known that zirconium oxide, such as 95% or 93% ZrO stabilized with yttrium, magnesium, zirconium silicate, and glass crushing media provide particles that have contamination levels that are believed to be acceptable for preparation. of pharmaceutical compositions. However, other means, such as stainless steel, titanium and alumina, are expected to be useful. Preferred media have a density greater than about 3 g / cm3.

The attrition time can vary widely and depends mainly on the specific mechanical means and the selected processing conditions. For ball mills, processing times of up to five days or longer may be required.

On the other hand, processing times of less than 1 day (residence times of one minute to a few hours) have provided the desired results using a high shear mill, similar, for example to DYNO® MILL KDL A or DYNO ® MILL Multi Lab or Agitated Lab Ball Mill 90 AHM or DCP High Performance Media Mill Megavantis ACS.

The attrition time is determined according to the specification of the particle size distribution; This depends on many parameters, such as the grinding technology used, the type of procedure (discontinuous procedure or continuous process recirculating the product), the size of the batch, the size of the pearl, the amount of pearls, the speed of rotation of the rotor and product flow.

25 Particle size should be reduced to a temperature that does not significantly degrade the drug substance. If desired, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out under ambient temperature conditions and at processing pressures that are safe and effective for the grinding process. For example, processing pressures at room temperature of ball mills, attrition mills and vibratory mills are typical. Typical processing pressures of up to about 20 psi (1.4 kg / cm2) of media grinding are typical.

Particle size reduction by homogenization as described in US Patent No. 5,510,118 can alternatively be used as a procedure using a MICROFLUIDIZER®

35 resulting in particles below 450 nm.

For the reduction of the particle size, benzimidazole carbamate can be added to a liquid dispersion medium in which it is essentially insoluble to form a concentrated premix. Preferably, the dispersion medium used for particle size reduction is aqueous.

The concentration of benzimidazole carbamate in the premix can range from about 0.05 to about 0.6 g / ml (ie, from about 5 to about 60% (w / v)). In some embodiments, the concentration of benzimidazole carbamate in the premix is from about 0.15 to about 0.50 g / ml, or from about 0.1 to about 0.4 g / ml.

The premix can be used directly by subjecting it to mechanical means to reduce the average particle size of the benzimidazole carbamate in the dispersion to less than about 450 nm. It is preferred that the premix be used directly when a ball mill is used for attrition.

Alternatively, the benzimidazole carbamate and the surfactant can be dispensed in the liquid medium using adequate agitation, for example, a Cowles-type mixer, until a homogeneous dispersion is observed in which there are no large agglomerates visible to the eye. simple sight and diluted additionally. It is preferred that the premix be subjected to said pre-melting dispersion stage when the recirculation media mill is used for attrition.

In one embodiment, a benzimidazole carbamate composition according to the present invention is prepared using the following three manufacturing steps: preparation of a premix suspension (for example, 0.4 g / ml of FBZ), size reduction of particle by wet milling of this premix suspension to a particle size of less than 450 nm and dilution of the premix suspension with a pharmaceutically acceptable aqueous vehicle to obtain the finished product (0.2 g / ml of FBZ) that It is the pharmaceutical composition that is added directly to the drinking water. The antifoam agent can be added to the premix or alternatively to the aqueous vehicle to prepare the finished product.

The premix compound is diluted with a pharmaceutically acceptable carrier to a concentration of

65 benzimidazole carbamate in the finished product between about 5 to about 50% by weight. In some embodiments, the concentration is from about 10% to about 30% by weight, from about 15% to about 25%, or about 20% by weight.

The present invention provides a process for preparing the pharmaceutical composition for administration in drinking water, wherein the composition comprises:

5 benzimidazole carbamate particles having an effective average particle size of less than about 450 nm, a Tween type surfactant; and a pharmaceutically acceptable vehicle, is prepared:

10 a. dispersing the benzimidazole carbamate particles in a liquid suspension medium comprising Tween type, and

b. mechanically reduce the particle size of the benzimidazole carbamate to an effective average particle size of less than about 450 nm.

In one embodiment, the mechanical reduction of the particle size is carried out by means of a media mill.

In one embodiment, the pharmaceutical composition obtained by steps a) and b) above is further diluted with a pharmaceutically acceptable carrier to form the finished product that is added directly to the drinking water.

20 The method comprises the following stages:

a) dispersing the benzimidazole carbamate particles in a mixture comprising a pharmaceutically acceptable carrier and a Tween type surfactant;

B) mechanically reduce the particle size of the benzimidazole carbamate particles to an effective average particle size of less than about 450 nm to form a mixture of concentrated product; c) adding a pharmaceutically acceptable carrier to the form of the concentrated product to form a diluted product, and

30 d) add the final product to the drinking water.

Examples

The following examples are merely illustrative, and do not limit the rest of this disclosure in any way. 35

Example 1 Manufacture of a fenbendazole composition according to the invention

The suspension of the drinking water was prepared with 0.2 g / ml of fenbendazole (FBZ) using the following three manufacturing steps: a) preparation of a premix suspension (0.4 g / ml of FBZ), b) grinding wet of this premix suspension, and c) dilution of the premix suspension to obtain the finished product (0.2 g / ml FBZ).

Formula of the finished product (0.2 g / ml of FBZ suspension)

Substance

 quantity

fenbendazole

 20.0 g

polysorbate 80

10.0 g

benzyl alcohol

2.0 g

simethicone emulsion

0.5 g

Water

 up to 100 ml

A. Manufacture of premix suspension

The required amounts of simethicone and polysorbate 80 emulsion were mixed with a magnetic stirrer in a portion of water. To obtain a homogeneous mixture, it was heated slightly (below 60 ° C). TO

Then, the required amount of fenbendazole and the volume of water lost were added with stronger agitation (Ultra-Turrax) to obtain a homogeneous white premix suspension. To maintain the product temperature below 60 ° C during the addition of fenbendazole, the flask containing the product was kept in a cooling bath.

55 Premix suspension formula

substance

 quantity

fenbendazole

 40 g

polysorbate 80

20 g

USP 30% simethicone emulsion

1 g

purified water

up to 100 ml

B. Wet grinding

5 First, the 0.6 liter container of the DYNO® MILL KDL A was loaded with 450 ml of 0.25-0.3 mm glass beads (VWR supplier), and then 270 ml of the premix suspension manufactured in stage A. The premix suspension was wet milled for 45 minutes with polyurethane discs and a rotor speed of 4200 rpm.

10 During the wet milling process, the product temperature was kept below 50 ° C due to heat transfer with the double cooling jacket.

The particle size of the fenbendazole suspension was determined before and after grinding with a

15 Malvern Mastersizer 2000 with the Hydro 2000G measuring cell according to the following method; With stirring (stirrer speed 500 rpm, pump speed: 1000 rpm), the bottom of the dispersant (water) contained in the dispersion unit was measured. A sample of the FBZ suspension was then added until a darkening of 10 to 16%. The dispersion was stirred for 2 minutes with 100% ultrasound before measuring the particle size distribution.

C. Dilution to obtain 0.2 g / ml of the FBZ suspension

The volume of the wet milled premix suspension was measured, and the required amount of water containing 4% benzyl alcohol was added to dilute the premix suspension to obtain a water suspension.

25 drink with 0.2 g / ml flubendazole (FBZ). The suspension of drinking water with 0.2 g / ml of flubendazole (FBZ) was used to prepare medicated water in the drinking water system.

Example 2 Manufacture of a fenbendazole composition according to the invention

The suspension of the drinking water was prepared with 0.2 g / ml of fenbendazole (FBZ) using the following three manufacturing steps: a) preparation of a premix suspension (0.4 g / ml of FBZ), b) wet milling of this premix suspension, and c) dilution of the premix suspension to obtain the finished product (0.2 g / ml of FBZ).

35 Finished product formula (0.2 g / ml FBZ suspension)

Substance

 quantity maker

fenbendazole

 20.0 g Transchem

polysorbate 80

10.0 g Merk

benzyl alcohol

2.0 g Fluka

simethicone emulsion

0.5 g Dow Corning

Water

 up to 100 ml -

A. Manufacture of premix suspension

The required amounts of simethicone and polysorbate 80 emulsion were mixed with a magnetic stirrer in a portion of water. To obtain a homogeneous mixture, it was heated slightly (below 60 ° C). Next, the required amount of fenbendazole and the volume of water lost were added with stronger agitation (Ultra-Turrax) to obtain a homogeneous white premix suspension. To maintain the product temperature below 60 ° C during the addition of fenbendazole, the flask containing the

45 product was kept in a cooling bath.

Premix suspension formula

substance

 quantity

fenbendazole

 40 g

polysorbate 80

20 g

USP 30% simethicone emulsion

1 g

purified water

up to 100 ml

B. Wet grinding

5 First, the 0.6 liter container of the DYNO® MILL KDL A was loaded with 450 ml of 0.25-0.3 mm glass beads (VWR supplier), and then 270 ml of the premix suspension manufactured in stage A. The premix suspension was wet milled for 45 minutes with polyurethane discs and a rotor speed of 4200 rpm.

10 During the wet milling process, the product temperature was kept below 50 ° C due to heat transfer with the double cooling jacket.

The particle size of the fenbendazole suspension was determined before and after grinding with a

15 Malvern Mastersizer 2000 with the Hydro 2000G measuring cell according to the following method; With stirring (stirrer speed 500 rpm, pump speed: 1000 rpm), the bottom of the dispersant (water) contained in the dispersion unit was measured. A sample of the FBZ suspension was then added until a darkening of 10 to 16%. The dispersion was stirred for 2 minutes with 100% ultrasound before measuring the particle size distribution.

C. Dilution to obtain 0.2 g / ml of the FBZ suspension

The volume of the wet milled premix suspension was measured, and the required amount of water containing 4% benzyl alcohol was added to dilute the premix suspension to obtain a water suspension.

25 drink with 0.2 g / ml flubendazole (FBZ). The suspension of drinking water with 0.2 g / ml of flubendazole (FBZ) was used to prepare medicated water in the drinking water system.

Particle size of a composition according to the invention containing FluBZ

30 Particle size distribution

50% particle size

90% particle size

0.2 g / ml suspension of FluBZ

: 130 nm : 320 nm

Figure 10 graphically depicts the particle size distribution of the flubendazole suspension manufactured according to example 2.

Figure 11 depicts the clarification kinetics of FluBz medicated drinking water made with the flubendazole suspension (determined by a macroscopic optical scanning device, TURBISCAN® (supplied by Formulaction, France), as described in WO 01/17504 in the center of the measuring cell for 24 hours.

40 Results. No significant physical instability is determined (clarification well below 1%, without sedimentation), measured with TURBISCAN® for medicated drinking water prepared with flubendazole suspension according to Example 2 during 24 hours.

45 Example 3 Alternative wet grinding procedure - Continuous procedure recirculating the premix suspension

First, the 0.6 l container of the DYNO® MILL KDL A was loaded with 450 ml of 0.25-0.3 mm glass beads (supplier B. Braun Biotech International), and then approximately 270 ml of a 50 premix suspension manufactured in step A of example 1 or 2.

The mill vessel was then connected to a pump in order to continuously feed the mill with the premix suspension; the flow rate was adjusted to around 1.3 l / h. A wet milling cycle was achieved when the entire premix suspension (500 ml) passed through the mill, was separated from the grinding media by a 0.1 mm gap and discharged into a new container. 6 grinding cycles with polyurethane discs and a rotor speed of 4200 rpm were applied to the suspension premix.

5 During the wet grinding process, the product temperature was kept below 50 ° C due to heat transfer with the double cooling jacket.

The particle size of the fenbendazole suspension was determined before and after grinding with a Malvern Mastersizer 2000 with the Hydro 2000G measuring cell according to the following method: with stirring (agitator speed 500 rpm, pump speed: 1000 rpm), the bottom of the dispersant (water) contained in the dispersing unit was measured. A sample of FBZ suspension was then added until a blackout of 10 to 16%. The dispersion was stirred for 2 minutes with 100% ultrasound before measuring the particle size distribution. Next, the wet milled premix suspension was diluted as described in step C of Example 1 or 2.

15 Example 4 Alternative wet grinding procedure - Continuous procedure recirculating the premix suspension.

First, the 0.6 L container of DYNO® MILL MULTI LAB was loaded with 360 ml of 0.25-0.3 mm zirconium oxide beads stabilized with yttrium (Mühlmeier supplier), and then connected to a pump in order to continuously feed the mill with the premix suspension manufactured in step A of Example 1 or 2.

The flow rate was adjusted to around 37 l / h. It was in a closed circuit: the premix suspension (2 l) was continuously pumped from the feed vessel, carried through the mill, separated from the grinding media

25 by means of a 0.1 mm gap and was discharged into the feeding vessel. The feed vessel was equipped with an agitator to maintain the homogeneous premix suspension. 55 minutes of grinding with DYNO®-Accelerators and a rotor speed of 10 m / s were applied to the premix suspension. During the wet milling process, the product temperature was kept below 50 ° C due to heat transfer with a double cooling jacket.

The particle size of the fenbendazole suspension was determined before and after grinding with a Malvern Mastersizer 2000 with the Hydro 2000 measuring cell according to the following method: with stirring (agitator speed 500 rpm, pump speed: 1000 rpm), the bottom of the dispersant (water) contained in the dispersing unit was measured. Next, a sample of an FBZ suspension was added to a

35 dimming from 10 to 16%. The dispersion was stirred for 2 minutes with 100% ultrasound before measuring the particle size distribution. Next, the wet milled premix suspension was diluted as described in step C of Example 1 or 2.

Example 5 Comparative particle size of a composition according to the invention and a composition manufactured in accordance with WO 95/13065

A composition was prepared according to WO 95/13065 as described in Step A of Example 1. The particle size without (composition according to WO 95/13065) was determined and after milling wet (composition according to the invention prepared according to the Stages

45 A-B of Example 1)) with a GMAL 01 dimensioner from Malvern Master with the Hydro 2000G measuring cell according to the Frauenhofer method. Wet milling resulted in a reduction in the particle size of the fenbendazole particles to an effective particle size of less than 200 nm.

Particle size distribution without and after wet grinding

D (0.50)

D (0.90)

Gross FBZ suspension

: 2440 nm : 32640 nm

0.2 g / ml suspension of FBZ

: 120 nm : 200 nm

Figure 1 graphically depicts the particle size distribution without and after wet milling.

Figure 2 depicts the kinetics of 60 ppm clarification of medicated FBZ in drinking water prepared with a suspension of FBZ (determined by a macroscopic optical scanning device, TURBISCAN ® (supplied by Formulaction, France) as described in WO 01/17504 in the middle part of the measuring cell for 24 hours.

The TURBISCAN® device detects any changes (for example, clarification, sedimentation, etc.) in scattered systems based on multiple light scattering. It is a macroscopic vertical scan analyzer that

It consists of a reading head that moves along a cylindrical cell with the flat bottom part, which at the same time sweeps the total height of the sample. The reading head itself consists of an almost pulsed infrared light source and two synchronous detectors. The transmission detector detects the light transmitted through the counter-dispersion product receives the counter-dispersed light by the product. The reading head acquires the transmission and the 5 counterdispersion data every 40 μm at a maximum height of 80 mm. The profile obtained characterizes the homogeneity of the product, the concentration of particles and the average diameter. The results are represented by the percentage of counterdispersed or transmitted light as a function of the sample height (in mm). Acquisition along the product is then repeated with a programmable frequency to obtain an overlay of the product's fingerprints that characterize the stability or instability of the product,

10 are both identical and not.

Results TURBISCAN® did not measure signs of physical instability (without clarification, without sedimentation) for medicated water prepared with fenbendazole suspension manufactured according to Example 1 for 24 hours.

Example 6 Comparison of the physical stability of a composition according to the invention and a composition manufactured in accordance with WO 95/13065

A composition according to the invention, called "more wet milled FBZ suspension" was manufactured as described in Example 1. A suspension of fenbendazole was manufactured as described in WO 95/13065 ( called "neutral FBZ suspension." A composition called "slightly wet milled FBZ suspension" was prepared according to the manufacturing steps as described in Example 1, but without milder wet milling conditions: ground 1 l of the premix suspension with 490 ml of 0.5 mm glass beads for only 3 milling cycles with polyurethane discs and a rotor speed of 3200 rpm These wet milling conditions allowed a distribution to be obtained

25 of the intermediate particle size compared to the "most wet milled FBZ suspension" and the gross FBZ suspension.

Particle size distribution of a suspension of raw FBZ (not wet milled) and FBZ suspensions (lightly ground and more wet) 30

D (0.50)

D (0.90)

Gross FBZ suspension / according to WO 95/13065

: 2430 nm : 24710 nm

0.2 g / ml suspension of slightly wet milled ground more wet wet FBZ

: 350 nm: 120 nm : 1030 nm: 200 nm

Figure 3 graphically depicts these particle size distributions.

The preparations were diluted with water to obtain a concentration of 60 ppm of similar fenbendazole, by

35 example, to medicated water for the treatment of poultry. The physical stability of the resulting medicated water was studied with the aid of the TURBISCAN® macroscopic optical scanning device as described in Example 5.

The results of the TURBISCAN® evaluation are illustrated in Figure 4, which shows the clarification kinetics 40 detected in the middle part of the measuring cell for 24 hours for each of the three preparations.

Results TURBISCAN® did not measure signs of physical instability for medicated water prepared with a suspension of fenbendazole, manufactured according to Example 1 during the 24-hour analysis, while significant clarification occurred with medicated water prepared with a suspension of fenbendazole stupid

45 manufactured in accordance with WO 95/13065. This clarification corresponds to the formation of a detectable sediment layer approximately 6.5 hours after the start of the study. This slightly wet milled suspension had an intermediate stability profile. Its level of clarification corresponded to the detection of a sediment layer only after 14 hours of rest.

Example 7 comparative physical stability of a composition according to the invention and a product of a commercial suspoemulsion (SOLUBENOL®, Janssen-Cilag, Beerse Belgium)

The SOLUBENOL® commercial suspoemulsion product was diluted with water to obtain a concentration of 85.6 ppm of flubendazole similar, for example, to medicated water for the treatment of poultry. its

The particle size distribution is summarized in the following Table, and is plotted in Figure 5 with the composition according to the invention (FBZ suspension) described in Example 1 as a reference.

Particle size distribution of a 0.2 g / ml suspension of FBC compared to SOLUBENOL®

(D (0.50) 50% particle size

D (0.90) 90% particle size

SOLUBENOL®

: 13700 nm : 29800 nm

0.2 g / ml suspension of FBZ

: 120 nm : 200 nm

The physical stability of medicated water prepared with SOLUBENOL® was studied with the help of TURBICAN®

5 according to the same analysis instructions as in Example 2. The results of the TURBISCAN® evaluation are illustrated in Figure 6, which shows the clarification kinetics detected in the intermediate part of the measuring cell for 24 hours for medicated water prepared with the SOLUBENOL® preparation. Results Significant clarification occurred with water medicated with SOLUBENOL®, while TURBISCAN® did not measure signs of physical instability for medicated water prepared with a suspension of

10 fenbendazole manufactured according to Example 1 during the 24-hour analysis.

Example 8: Suspension of fenbendazole manufactured with various surfactants

FBZ suspensions were manufactured as described in Example 1 with the following ingredients. fifteen

Substance Function Company

Fenbendazole Active substance Intervet a) Polysorbate 20 Merck suspension agent b) Polysorbate 40 Merck suspension agent c) Polysorbate 60 Merck suspension agent d) Polysorbate 80 VWR suspension agent

e) Poloxamer 188 Uniquema Suspending Agent 30% Simethicone Emulsion Dow Corning USP Defoaming Agent Benzyl Alcohol Preservative Fluka Purified Water Up to 100 ml

Evaluation of the physical stability of medicated water

FBZ suspensions with suspending agents were diluted to 60 ppm with water just before

20 analysis and the physical stability (transmitted or counterdispersed light) of the different medicated waters was measured for 24 hours at room temperature with Turbiscan. The premix suspension containing Poloxamer 188 was manufactured with the following deviations compared to the procedure described in Example 1. Poloxamer 188 was melted before mixing with the simethicone emulsion and then by adding fenbendazole, the mixture was it became viscous in this way while stirring in such a way that it was not

25 feasible to pass it through the mill.

Particle size distribution

The particle size distribution of various suspensions was measured before and after wet milling and is reported in the following table.

Particle size distribution (μm) Before wet milling After wet milling

D (0.50) D (0.90) D (0.95) D (0.50) D (0.90) D (0.95)

Suspension of FBZ With Polysorbate 20 1.89 17.74 23.74 0.12 0.25 0.37 With Polysorbate 40 2.18 28.39 49.69 0.13 0.32 0.81 With Polysorbate 60 2, 06 26.85 41.07 0.13 0.33 0.62 With Polysorbate 80 2.44 32.64 50.46 0.12 0.20 0.23

With Poloxamer 188 2.33 29.03 41.84 ---

All polysorbate compositions exhibited a fine and narrow particle size distribution after wet milling. 35 Evaluation of the physical stability of medicated water

The suspensions of FBZ with the suspending agents were diluted to 60 ppm with water just before the analysis and the physical stability (transmitted and counter-dispersed light) of the different medicated waters was measured for 40 24 hours at room temperature with TURBISCAN® according to the same analysis instructions as in the

Example 3. The results of the TURBISCAN® evaluation are shown in Figure 7, which show the clarification kinetics detected in the middle part of the measuring cell for 24 hours for medicated waters prepared with 0.2 g suspensions. / ml of FBZ containing the various suspending agents.

5 Results. The medicated water characterized from the dilution of the FBZ suspension containing Poloxamer 188 is physically unstable. This was confirmed by detecting a sediment layer that grows at 0.77 µm / min while no sediment layer could be detected for the other medicated waters that contained the various Polysorbates.

The water medicated with the polysorbates tested shows an acceptable transmission variation below 10% for 24 hours.

Example 9 Suspension of fenbendazole manufactured with various concentrations of Polysorbate 80

FBZ suspensions were manufactured as described in Example 1 with the following ingredients

Fenbendazole Active substance 20.0 g Polysorbate 80 Suspending agent 5, 10 or 15 g Emulsion of 30% simethicone USP Defoaming agent 0.5 g Benzyl alcohol Preservative 2.0 g Purified water Up to 100 ml

Particle size distribution

The particle size distribution of various FBZ suspensions was measured before and after wet milling and is reported in the following table.

Particle size distribution (μm) Before wet milling After wet milling

D (0.50) D (0.90) D (0.95) D (0.50) D (0.90) D (0.95)

Suspension of FBZ With Polysorbate 80 2.45 32.08 55.87 0.13 0.20 0.22 With Polysorbate 80 2.44 32.64 50.46 0.12 0.20 0.23 With Polysorbate 80 2, 16 30.64 51.10 0.11 0.19 0.22

All FBZ suspensions had a fine and narrow particle size distribution after wet milling.

Evaluation of the physical stability of medicated waters

The suspensions of FBZ with the suspending agents were diluted to 60 ppm with water just before the analysis and the physical stability (transmitted and counter-dispersed light) of the different medicated waters was measured for 24 hours at room temperature with Turbiscan. The physical stability of medicated water was studied with the help of TURBISCAN® in accordance with the same analysis instructions as in Example 5.

The results of the TURBISCAN® evaluation are shown in Figure 8, which show the clarification kinetics

35 detected in the middle part of the measuring cell for 24 hours for medicated waters prepared with the 0.2 g / ml suspensions of FBZ containing the various concentrations of polysorbate 80.

Results: No sediment layer could be detected for medicated waters containing the different concentrations of Polysorbate 80. This good physical stability was confirmed by the transmission variation graph: the maximum variation corresponds to 1% after 24 hours, That is acceptable.

Example 10 Wet milling of a 20% and 40% fenbendazole suspension

A composition according to the invention, called "0.2 g / ml suspension of fenbendazole such as described in Example 3, was manufactured.

A suspension of fenbendazole was manufactured as described in WO 95/13065 (called "crude FBZ suspension") and was ground wet as follows.

First, the 0.6 l vessel of the DYNO® MILL MULTI LAB was loaded with 360 ml of 0.3 mm zirconium oxide beads stabilized with yttrium (Muhlmeier supplier), and then connected to a pump in order of continuously feeding the mill with a suspension of raw FBZ. The flow rate was adjusted to about 112 l / h. It was in a closed circuit: the premix suspension (2 l) was continuously pumped from the feed vessel, carried through the mill, separated from the crushing media by means of a 0.1 mm hole and discharged into the feeding container The feed vessel was equipped with an agitator to maintain the homogeneous premix suspension. 55 minutes of grinding with DYNO®-Accelerators and a rotor speed of 10 m / s were applied to the premix suspension.

5 During the wet grinding process, the product temperature was kept below 50 ° C due to heat transfer with the double cooling jacket.

The particle size distribution of the Fenbendazole suspensions was measured as described in Example 3.

10 Particle size distribution of a 0.2 g / ml suspension of FBZ compared to the wet-ground raw FBZ suspension.

D (0.50)

D (0.90)

Wet milled raw FBZ suspension

: 130 nm : 300 nm

0.2 g / ml suspension of FBZ

: 130 nm : 290 nm

15 Results. The milling of the final product of "crude FBZ suspension" containing 20% w / v of FBZ or milling of the premix suspension containing 40% FBZ to be diluted in the final product of "0.2 g suspension / ml of FBZ ”resulted in an equivalent particle size distribution.

Example 11 Test with the suspension of fenbendazole in conduits

A composition according to the invention, called "0.2 g / ml suspension of FBZ" was manufactured as described in Example 2 (the milling step was carried out with 420 ml of zirconium oxide beads 0.3 mm stabilized with Mühlheimer yttrium, two cycles were carried out with a flow rate of 1 l / h.

25 Particle size distribution of a 0.2 g / ml suspension of FBZ compared to the crude FBZ suspension

D (0.50)

D (0.90)

Gross FBZ suspension

: 1910 nm : 13180 nm

0.2 g / ml suspension of FBZ

: 130 nm : 270 nm

A suspension of fenbendazole was manufactured as described in WO 96/13065 (referred to as

30 “suspension of gross FBZ”). The particle size distribution of fenbendazole was measured as described in Example 3.

The stability and homogeneity of the medicated water prepared with both compositions was tested for a period of 3 hours simulating the distribution of medicated water under field conditions. These studies are

35 carried out with drinking water from the local water supply.

Medicated water was prepared with the required amount of the composition and drinking water in the medication reservoir in order to obtain a concentration of 60 ppm of fenbendazole, similar, for example, to medicated water for the treatment of poultry. The reservoir was connected to a 25 m transparent pipe through the

40 outlet from the bottom of the tank. The flow rate was adjusted to approximately 3.5 l / h. medicated water was sampled periodically in the medication reservoir (on the surface) and at the end of the 25 m pipe during the distribution period.

The samples were analyzed in terms of fenbendazole content. The medicated water was not stirred during the

45 distribution period. In addition, the medication reservoir and the pipeline were visually checked for any sediment formed. The results are illustrated in Figure 9, which show the variation in the concentration of FBZ of both sampled medicated waters from the medication reservoir and the end of the pipe.

Results In both studies, no sediments were detected in the medication reservoir and the pipeline; without

However, in the medication reservoir containing the medicated water with the raw FBZ suspension, the medicated water had a more concentrated appearance in the lower part of the reservoir at the end of the trial. This instability was confirmed by the analytical results that showed a drastic decrease in the concentration of FBZ over the period of distribution for the medicated water prepared with the suspension of raw FBZ, in contrast to the medicated, homogeneous and stable water prepared with the 0.2 g / ml suspension of FBZ.

Example 12 Field test in pigs and poultry

A composition according to the invention called "0.2 g / ml suspension of FBZ" was manufactured as described in Example 1. Two field studies were carried out to evaluate the homogeneity and stability of the suspension. 0.2 g / ml FBZ in medicated water when used in field conditions.

A study was carried out on growing pigs with a medication tank, a closed circuit water system (made of PVC and stainless steel pipes) approximately 60 m long and the other study on growing turkeys with a electronic dosing pump (KONTI-DOS from Buerkert) and a system

10 dead end water supply (made of galvanized iron and plastic pipes) of approximately 220 m in length.

The general study procedures were the same for each study: medicated water was prepared using the drinking water available on farms with pH values that vary between 7.2-8.2 and a total hardness that varies

15 between 7.3 and 13.7º dH. FBZ concentrations in water were prepared in parts per million (ppm) based on a single dose of 5 mg of FBZ / kg body weight, animal body weights and estimated water consumption in all three (medication reservoir) and eight o'clock (dosing pump) hours.

Samples of medicated water were taken every 30 to 60 minutes during administration between the bottom and the

20 upper part of the tank and teats and drinking fountains were predefined along the water supply system. The contents of the deposit were not stirred throughout the entire administration period.

The tank and the teats or drinking troughs were inspected for any type of sediment formed by the active substance of any of the excipients.

25 Additional water samples were withdrawn approximately 24 hours after cessation of administration to evaluate potential FBZ content residues. All water samples were subsequently analyzed for the FBZ content using a validated HPLC method.

30 Results. All analytical results (actual FBZ concentrations) were in line with the nominal concentrations (calculated). Consistent concentrations of FBZ were achieved in the reservoirs and along the water pipes for two to eight hours of administration. There were no differences in FBZ concentrations in the samples taken between the bottom and the top of the tanks.

35 In the deposits, no sedimentation or flotation of particles was observed. There was no settling or blockage of the teats. Water samples taken 24 hours after cessation of administration do not show any measurable FBZ residue (below the detection limit of approximately 0.4 ppm), indicating that the new FBZ suspension does not form any residue in the water systems. drinking water The following table summarizes the results of these field studies.

40 Average FBZ concentrations reported from field studies

study

Conc. Average FBZ concentrations [ppm] over time

Deposit medication / predilution

Teats / drinkers

A1

A2 B C D AND F G

Pigs

nominal  192

real

193.3 188.3 180.6 181.7  193.3  186.7 176.0  190.3

Turkeys

nominal  2395 81

real

2443.4 2413.1 82.7 84.6  78.4  83.3 72.2  76.8

The conclusion of these field studies is that the 0.2 g / ml suspension of FBZ is distributed so

45 homogeneous in the medicated water in water supply systems representative of the selected pig and poultry farms and that an accurate dosage is ensured during administration since consistent concentrations of FBZ were produced during the defined administration period.

Claims (11)

1. A pharmaceutical composition for administration to drinking water of a benzimidazole carbamate characterized in that the composition comprises an aqueous suspension comprising: 5 benzimidazole carbamate particles having an effective average particle size of less than about 450 nm, and a Tween type surfactant.

2.

 The composition of claim 1, wherein the average effective particle size of the benzimidazole carbamate particles is less than about 300 nm.

3. The composition of claim 1 or 2, wherein the Tween surfactant comprises polysorbate 80.

Four.

 The composition of any one of claims 1 to 3, wherein the Tween type surfactant is present in an amount of between about 0.1 to about 50% by weight.

5. The composition of any one of claims 1 to 4 wherein the benzimidazole carbamate comprises fenbendazole. The composition of claims 1 to 5, wherein fenbendazole is present in an amount of between about 5 to about 50% by weight. 7. Use of the composition of claims 1 to 6 in the manufacture of a medicament for controlling a parasite in an animal administering the medication to the animal through the animal's drinking water. 25 8. A method for preparing a pharmaceutical composition for administration in drinking water, where the method comprises: dispersing benzimidazole carbamate particles in a mixture comprising a vehicle 30 pharmaceutically acceptable and a Tween type surfactant, and mechanically reduce the particle size of the benzimidazole carbamate particles to an effective average particle size of less than about 450 nm. 9. The method of claim 8, wherein the method further comprises: Dispersing benzimidazole carbamate particles in a mixture comprising a pharmaceutically acceptable carrier and a Tween type surfactant; mechanically reduce the particle size of the benzimidazole carbamate particles to an effective average particle size of less than about 450 nm to form a product mixture 40 concentrate; adding a pharmaceutically acceptable carrier to the concentrated product form to form a diluted product; and add the final product to the drinking water. 10. The method of claim 8 or 9, wherein the mechanical reduction of the particle size is carried out by means of a media mill. 11. Use of the composition of any of claims 1-6 in the manufacture of a medicament for protecting an animal from a parasitic infection, wherein said composition is to be administered to the animal through the animal's drinking water. 12. Use of the composition of any of claims 1-6 in the manufacture of a medicament for protecting an animal from a parasitic infection, wherein said composition is to be administered to the animal by the parenteral route.   particle particle particle   particle particle particle particle of particle