TW200815001A - Benzimidazole carbamate composition - Google Patents

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 a method for protecting an animal from a parasitic infection.

Description

200815001 (1) IX. Description of the Invention [Technical Field of the Invention] The present invention relates generally to a pharmaceutical composition of benzimidazolyl carbamate for drinking water, a method for preparing the same, and a composition thereof. 'The use of agents for the control of parasites in animals, and methods for using them to protect animals from parasitic infections. Φ [Prior Art] Benzoimidazole was first developed as a plant antifungal agent and then used as a veterinary and human insect repellent (such as a worm). The benzimidazole family having anthelmintic activity includes thiazolyl benzimidazoles and benzimidazolyl carbamates. The benzimidazoles exhibit a very broad activity, especially the activity of anti-helminth parasites such as roundworms and aphids. Conventional benzimidazoles having anti-helminth activity are, for example, thiabendazole, ampendazole, and benzimidazolamide, such as pafenrazol, toluene #imidazole, flufenazole, fen Benzocarbazole, orphenoxazole, propoxyimidazole, albendazole, rivetazole and benzoxazole, all of which differ in the substituents on the benzimidazole core. Phenylhydrazine prodrugs have been developed which are metabolically converted into benzimidazoles which are capable of repelling insects. For example, phenylthioindane is a prodrug that can be converted to fenbendazole, while natobiamine produces albendazole. Benzimidazolamides are generally insoluble in water. In some common applications of these compounds, poor water solubility of benzimidazoles is a major obstacle. -5- 200815001 (2) Fenbenzazole (FBZ) is a benzimidazole carbazate that can be used as a veterinary anthelmintic in a variety of species including birds, pigs and cattle. The fenbenone is used to control nematodes (hcarM/a sp·), cecal sp., and Capillar ia sp., which are common in nematodes such as birds and pigs. * A large number of poorly water-soluble agents such as benzimidazolamides are given. High-density pigs and poultry are currently limited to pouring these drugs onto φ food or mixed with food for oral administration. . However, such medicated feeds require individual preparations on the farm or feed field and there is always a risk of cross-contamination with unmedicated feed. On the other hand, extra manpower is required to pour the feed. Therefore, it is preferable to administer the drug to the high-density animal worm by the drowning system, because it is easy to simultaneously administer a large number of animals. Many pig farms and poultry farms have been equipped with the required equipment for drinking water systems. The drinking water systems of these farms are complex systems consisting of tanks, ducts, spiral ducts, enclosure decanters and nipples. A common set of equipment can contain hundreds of meters of ducts and solenoids and hundreds of individual cups and drinking heads. The water system of the drinking water system of pigs or birds is following the laminar flow principle of the conveying pipe and the spiral pipe and is subjected to the so-called "shearing" force (which affects the flow rate). When such complex When a pipe system contains a compound that is insoluble in water, there is of course a risk of separation or precipitation of the drug. The efficiency of administration through the drinking water system is generally determined by the quality of the composition and the palatability of the drug. Provides the largest active ingredient -6- 200815001 (3) Availability, the smallest separation and precipitation of active ingredients in drinking water systems, drug delivery pumps, drinking water cups, etc. 'It can be accurately and evenly distributed in drinking water. The active compound and the active compound have inevitable stability. * So far, there is no convenient solution for veterinary drugs with poor water solubility (such as benzimidazolyl carbamate which meets the requirements of 1). For the use of such farm animals, φ International Patent Application No. WO 95/13065 discusses an aqueous fenflurene containing a Tween-type surfactant and a preservative. Suspension. In this aqueous suspension, fenbendazole will remain in suspension and will not agglomerate after storage for a period of time, and the particle size will not change. The particle size is on the order of about 1 micron. However, this An aqueous suspension of fenflurazole is not suitable for administration via a drinking water system as it is used in the above-mentioned large pig or bird cage. When the suspension is diluted to a drinking concentration of 60 ppm fenflurazole, a period of time The time will precipitate. These precipitates will prevent fenflurazole from spreading evenly in the water system and cause the drinking water system equipment, such as the drinking head, to be blocked. International Patent Application WO 0 1 /1 7504 A suspension emulsion composition for drinking water. However, in consideration of the uniform distribution of the properties, such compositions do not meet the requirements of the drinking water system. International Patent Application No. WO 00/50009 deals with water-stability or The insoluble compound is encapsulated into the liposome for drinking water. International Patent Application WO 95/1 6447 discusses an insect repellent composition for oral administration but not for use in a hydrophobic system, which contains micro Refassonne-7-200815001 (4) Radium (rafoxanide) and fenpropene granules with more than 98% of the average particle size below 20 microns. UK patent application GB 23 0 78 7 1 discusses a An industrial scale method for modulating a waterborne oxfendazole suspension without using any particle size reduction technique. * SUMMARY OF THE INVENTION The present invention generally relates to a stable and effective benzimidazolylamine-based phthalate aqueous composition. It is convenient to administer the drug through a hydrophobic system. Therefore, a part of the present invention provides a pharmaceutically acceptable benzoimidazolium carbamate pharmaceutically acceptable composition. The composition is characterized in that it contains an average effective particle size. A benzimidazolyl carbamate particle of less than about 450 nm and an aqueous suspension of a Tween-type surfactant. A certain part of the present invention further provides the use of the above composition for preparing an agent for controlling parasites in an animal body, which is administered by an animal drowning water. 〇# A part of the present invention provides a preparation for administration in drowning A method of pharmaceutical composition. The method comprises: i. dispersing the benzimidazolyl carbamate particles in a pharmaceutically acceptable carrier comprising a Tween type surfactant; and ii. granules of the benzimidazolyl carbamate particles The diameter is mechanically reduced to an effective average particle size of less than about 450 nm. A portion of the invention also provides a method of protecting an animal from parasitic infections. This method involves administering the above composition to the animal through the animal's drowning. This protective effect includes prevention, reduction of risk, delayed onset, and reduction. -8- 200815001 (5) Spread, improve, inhibit, and or eliminate parasitic infections and/or one or more of its symptoms. Those skilled in the art will be able to clarify the other advantages of the applicant's invention after reading this specification. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The detailed description of the preferred embodiments is only intended to enable other persons skilled in the art to understand the invention of the present invention, its principles, and its application and application, so that other persons skilled in the art can use various other forms (the most suitable) The invention is modified and implemented in a particular application. The detailed description and specific examples thereof set forth in the preferred embodiments of the invention are merely illustrative. Therefore, the invention is not limited to the preferred embodiments described in the specification, and may be modified in various ways. The inventors of the present invention have shown that the composition of the present invention, which is an aqueous suspension containing benzimidazolyl carbamate particles having an average effective particle diameter of less than about 450 nm and a Tween-type surfactant, is very stable. It is sufficient and can be homogeneously dispersed in the system to effectively administer the benzimidazolyl carbamate to the animal through the drinking water system. Through the novel composition, the benzimidazole urethane can be delivered to the target animal via a drinking water system by mixing or diluting the composition with a central sink or individual storage tank. Alternatively, the composition can be continuously injected into a high pressure or low pressure annular system of hydrophobic dispensing using a dose dispenser or dosing pump system or a proportional mixer dosing system. -9 - 200815001 (6) The dosing pump system relies on a pump that delivers the dosing concentrate to the water pipe at a typical dilution ratio of 1-5%. In the dosing pump system, an electronic dosing pump system such as KONTI-DOS from Buerkert or a mechanical dosing pump such as DOSATRON^JC power dosing pump, DOSMATIC 8 water drive-' proportional mixing applicator can be used. The changes in the on-site installation will take into account the situation of the water supply system itself: different materials (such as PVC, galvanized iron) and different lengths of closed or closed-end circuit systems and drinking fountains (which will be corrected for φ depending on the target animal) Type drinking fountains, drinking water heads, etc. In one embodiment, the benzimidazole carbamate has an effective average particle size of less than about 450 nm or less than 400 nm, and in other embodiments less than about 350 nm or less than about 300 nm. In other embodiments, the effective average particle size of the benzimidazolyl carbamate is less than about 250 nm, and in other embodiments less than about 200 nm. In one embodiment, the effective average particle size of the benzimidazolyl carbamate is between about 50 nm and 450 nm. In other specific examples, it is between about 100 nm and 400 nm. In other specific examples, it is between about 150 nm and 350 nm or between about 180 nm and 300 nm. In other embodiments, the effective average particle size of the benzimidazolyl carbamate is between about 1 90 nm and 22 0 nm, and in other embodiments about 200 nm. Alternatively, the benzimidazolamide may be formulated as an injection product for parenteral administration to an animal. As used herein, "particle size" refers to the number average particle size measured using particle size measurement techniques well known to those skilled in the art, such as laser sweeping cats, sinking field fullness photon correlation spectroscopy, or disc centrifugation. . -10- 200815001 (7) The particle size measurement can be performed using a Malvern Mastersizer 2000 equipped with Hydro 2000G or a Horiba LA-910 Laser Scanning Particle Size Analyzer. "Effective average particle size less than about 450 nm" means that at least 90% of the particles (D (0.90)) have a weight average particle size of less than 45 nm when measured by the above technique. Tween-type surfactant (polysorbate, sorbitan ester, poly-φ (oxy-1,2-ethanediyl) derivative, Tweens) is a water-soluble nonionic surfactant, which is derived From complex esters and ester-ethers of hexahydric alcohol, alkylene oxides and fatty acids formed by adding polyoxyethylene chains to sorbitol hydroxyl groups, and derived from sorbitol and using common fatty acids such as lauric acid, palmitic acid, hard Fatty acid and oleic acid partially esterified hexahydric anhydride (hexitol anhydride and hexides) ° In one embodiment, the Tween type surfactant is selected from one or more of Tween 20, Tween 40, Tween 60 or Tween 80 is also known in the pharmaceutical industry as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80. Polysorbate 20 (polyoxyethylated sorbitan monolaurate) is a lauric acid ester, and polysorbate 60 (polyoxyethylated sorbitan monostearate) is stearate. And a mixture of palmitic acid esters; and polysorbate 80 (polyoxyethylated sorbitan monooleate) is an oleate. Such tween-type surfactants are commercially available and/or can be made using techniques known in the art.

In a specific example, the Tween type surfactant is, for example, from ICI -11. 200815001 (8),

Specialty Chemicals, polyoxyethylene sorbitan monooleate (polysorbate 80, Tween 80) having the chemical name polyoxyethylene (20) sorbitan monooleate. The amount of the Tween-type surfactant in the composition is from about 0.1 to about 50% by weight. In some embodiments, the Tween-type surfactant has a concentration of from about 5 to about 20% by weight, from about 7.5 to about 15% by weight, or about 1% by weight. The compositions of the present invention contain one or more benzimidazolyl carbamates. φ Conventional benzimidazolyl carbamates are, for example, pacloconazole (see, e.g., U.S. Patent No. 3,480,642), mebendazole (see, e.g., U.S. Patent No. 3,657,267), fluorobenzoxazole (for example, U.S. Patent No. No. 3,65,267), fenbendazole (refer to, for example, U.S. Patent No. 3,954,79 1), orfendazole (see, for example, U.S. Patent No. 3,929,82 1), propionazole (see, for example, U.S. Patent No. No. 3,574,845), albendazole (see, e.g., U.S. Patent No. 3,915,986), rubene benzoxazole (sulfoximine albendazole) (Reference #, for example, U.S. Patent No. 3,9 1 5,9 8 6 And benzoxazole (see, e.g., U.S. Patent No. 4,639,463), all of which are different in the substituents on the benzoxazole core or prodrugs such as phenylthioindole and natotropium. In one embodiment, the benzimidazolyl carbamate is fenbendazole (see, e.g., U.S. Patent No. 3,954,79 1). In another embodiment, the benzimidazolyl carbamate is flufenazole (see, e.g., U.S. Patent No. 3,657,267). The benzimidazolyl carbamate is generally present in the composition in an amount of about 5 to About 50% by weight. In certain embodiments, the benzimidazolyl carbamate has a concentration of from -12 to 200815001 (9) of from about 10 to about 40% by weight, from about 15 to about 30% by weight, or from about 17.5 to about 25%. % by weight or about 20%. In some embodiments, the composition contains a pharmaceutically acceptable carrier. The carrier can be, for example, an aqueous carrier (preferably (pure) water). However, the present invention can be practiced with other liquid media such as aqueous salt solutions in which the benzimidazolyl carbamate is difficult to dissolve and disperse. Optionally, the composition may also contain an antifoaming agent such as dimethyl sulphuric acid (φ simethicone) emulsion 30% USP, sodium oleate, sodium octate or a mixture thereof. The antifoaming agent concentration is sufficient to prevent the composition of the present invention from forming bubbles upon dilution with water. In the present invention, the concentration of the dimethyl hydrazine emulsion is from about 0.2% by weight to about 1% by weight. In some embodiments, the concentration of the dimethyl hydrazine emulsion is about 0.5% by weight. Optionally, the composition may also contain a preservative. Such preservatives are well known to those skilled in the art and may be, for example, benzyl alcohol, sodium butyl paraben, sodium methylparaben, sodium propylparaben and mixtures of Φ. It is generally present in an amount of from about 0.01% by weight to about 3% by weight. In some embodiments, the concentration of the benzyl alcohol is from about 1.5% to about 2.5% by weight, or about 2% by weight. One aspect of the present invention is the use of the composition of the present invention for the preparation of a medicament for controlling parasites in an animal by drinking water from an animal. The invention also provides a method of protecting an animal from parasitic infections, wherein the method comprises administering to the animal a composition of the invention by drinking water from the animal. In one embodiment, the composition may also be treated with a benzimidazolyl carbamate-13-200815001 (10) ester compound such as fenbendazole via a drinking water system, particularly livestock (eg, cattle, poultry, and pigs). only). The composition (finished product) can be made into a medicated drowning water by a proportional mixer or a dispenser as is conventionally known. The applicator can be further diluted with water, for example, at a ratio of about 1:28 by the ratio of 1 ounce of final product* to obtain a benzimidazole urethane ester having a concentration of, for example, about 1 Torr to about 150 ppm " fenbendazole The medicine is drowning. In some embodiments, the benzimidazolyl carbamate (eg, fenflurazole φ azole) is at a concentration of from about 40 to about 120 ppm in the hydrating drip, which will depend on the effective dose, animal weight, and animal water. Depending on the amount and treatment time. In one embodiment, the concentrated premix composition is directly diluted to a concentration of from about 10 ppm to about 150 ppm. In some embodiments, the concentrated premix composition is directly diluted to a concentration of about 40 ppm to about 120 ppm benzimidazolamide (such as fenflurazole) and used directly in the water. Dosing (such as birds). In a specific specific example of a particular benzimidazolidinyl fenflurazole, the concentration is calculated for each of the treated birds provided by the drinking water volume normally taken by the bird during the 2 to 24 hour treatment period. The target amount of fenbendazole per unit weight (BW) is from about 1 mg to about 5 mg of fenbendazole per kilogram of body weight per day. This target dose will be determined by infection with the parasitic species to be treated and is well known for this technique. Concentrations need to be calculated separately when administered to other species. The time for treating birds with medicated drinking water is from about 2 to about 24 hours of treatment, and it is usually preferred to carry out a treatment for about 8 hours for 1 to 6 consecutive days. The duration of treatment should be calculated separately when administering to other species. -14- 200815001 (11) In the treatment of pigs, the final product is diluted to the desired concentration to obtain a drinking water containing an effective amount of benzimidazolyl carbamate such as fenflurazole for the prevention of helminth in pigs. This effective amount will depend on the infection of the parasitic species to be treated and is well known in the art. Alternatively, the compositions of the invention may be administered parenterally, such as by intravenous, intramuscular or subcutaneous injection. In another aspect, the invention provides a method of protecting an animal from infection with a pest, the method comprising administering to the animal a composition of the invention by a parenteral route. Parenteral treatment can also be used in other ways. Parenteral administration is particularly useful for the plasma and tissue content of benzimidazolidine carbamate (because of systemic action, benzimidazole carbamate must be taken up into the bloodstream). One such example uses benzimidazole to combat systemic parasitic infections, such as the larval stage of specific aphids (e.g., Echinococcus multicular is and E. granulosis). Essentially, the compositions of the present invention can be administered to all animal species such as pigs, cows, horses, goats, sheep, cats, dogs, birds and fish that require treatment or prevention of parasitic infections. Another aspect of the invention provides a method of making a composition of the invention. The method comprises dispersing the benzimidazolyl carbamate particles into a mixture comprising a pharmaceutically acceptable carrier and a Tween-type surfactant and mechanically reducing the particle size of the benzimidazolyl carbamate particles to be effective The average particle size is -15-200815001 (12) below about 450 nm. In one embodiment, the benzimidazole carbamate particle diameter system is reduced to less than about 400 nm, or about 3 50 ηι, in another embodiment less than about 250 nm, and the other to about 20 0 nm. In a specific example, the benzimidazole carbamate particle diameter system is reduced to φ between about 50 nm and 450 nm. Another specific example is between about 100 nm and about 400 nm. It is between about 150 to 350 nm, or between about 180. In another embodiment, the benzimidazolylcarbamic acid has an average particle size between about 190 nm and 220 nm, and provides mechanical force at about 200 nm to reduce the diameter of the benzimidazolyl carbamate particles to Effective methods of less than about 450 nm include spheres, and homogenization, as in the case of using MICROFLUIDIZER® (C 〇rp·), in a specific example, the mechanical particle size reduction is performed by grinding. Ball milling is a process that uses a honing medium, a drug, and a stable honing process. The materials are placed in a honing vessel so that the medium falls like a waterfall and the energy to reduce the particle size is reduced by compaction. The medium used for gravity and the quality of the friction medium must have a high density. Media honing is a high energy honing process. The effective average η of the drug particles or about 300 nm in the specific example of the effective average particle size of the small particles, and the effective specific average particle grinding of another specific nm to 300 nm ester particle is Media honing Microfluidics rotates the particle size of the drug at a low optimum rate of media elixirs and liquids. Provided by volume, so, stabilizer and liquid -16 - 200815001 (13) The body is placed in the tank and recycled to the tank containing the medium and the rotating shaft/impeller. The rotating shaft will agitate the medium, causing the drug to be pressed and sheared, and the particles of the drug become smaller. It is preferred because media honing can achieve the desired result in a relatively short period of time (i.e., to achieve the desired particle size reduction). In a specific example, a Dyno Mill Type KDL A or a Dyno Mill Multi Lab from WAB, Basel, and another honing machine are available from Hosokawa Alpine (Augsburg) _ Agitated Lab Ball Mill 90 AHM, available from Draiswerke DCP High Performance Media Mill Megavantis ACS from Inc. or DCP Super flow or Advantis from Btihler. When honing, the appearance consistency of the premix should be chosen to ensure an optimum balance between effective particle size breakage and media loss. The honing medium (beads) of the particle size reduction step (wet honing) is selected from coarse media which are preferably in the form of spheres or granules. In one embodiment, the honing medium has an average particle size of less than about 1 mm. In another embodiment, the honing medium has an average particle size of between about 〇5 and 0·7 mm. In another embodiment, the average particle size of the honing medium is about 0.5 m. In another embodiment, the honing medium has an average particle size of between about 0.25 and 0.3 mm. We do not believe that the choice of honing medium materials is decisive. It is known that chromium oxide (e.g., 95% or 93% ZrO with hydrazine) 'magnesium oxide, chromium citrate, and glass honing media can provide particles of a degree of contamination acceptable for the preparation of pharmaceutical compositions. However, other media such as stainless steel, titanium and alumina can also be used. A preferred medium density is preferably greater than about 3 g/cm3. -17- 200815001 (14) The length of wear varies widely and depends primarily on the particular machine and processing conditions chosen. When ball milling, processing times of up to 5 days or more may be required. On the other hand, use high shear media such as DYNO® MILL KDLA or DYNO® MILL Multi Lab or Agitated Lab B all

• Mill 90 AHM or DCP high-performance media honing machine Megavantis ACS, less than 1 day processing time (residence time is 1 minute to several hours) Φ can achieve the desired result. The length of honing time is determined by the particle size distribution specification; it will depend on various parameters such as the honing technique used, the type of method (continuous method of batch method or cycle product), batch size, bead size, bead quality, Rotator rotation speed and product flow rate, etc. The particles must be reduced in particle size at temperatures that do not significantly reduce the quality of the drug. Processing equipment can be cooled with conventional cooling equipment if needed. This method is conveniently carried out at room temperature and at a safe and effective processing pressure for the honing process. For example, atmospheric processing pressures are generally applicable to ball mills, agitated ball mills, and vibratory ball mills. Processing pressures of up to about 20 psi (1.4 kg/cm2) are generally suitable for media honing. In addition to the use of the MICRO FLUID IZER® process to produce particles of the next 450 nm, the homogenization method described in U.S. Patent No. 5,510,1 18 can also be used to reduce the particle size. When the particle size is reduced, the benzimidazolyl carbamate can be added to a substantially insoluble liquid dispersion medium to form a concentrated premix. Preferably, the dispersion medium used to reduce the particle size is an aqueous medium. -18- (15) (15) 200815001 The concentration of benzimidazolyl carbamate in the premix may vary from about 0.05 to about 0.6 g/ml (ie, from about 5 to about 60% (w/v) ). In certain embodiments, the benzimidazolyl carbamate is present in the premix at a concentration of between about 0.15 and about 0.50 g/ml, or between about 0.2 and about 0.4 g/ml. The premix can be placed directly into the mechanical device to reduce the average density of benzimidazolamide in the dispersion to less than about 450 nm. Preferably, the premix can be used directly when honing using a ball mill. Alternatively, the benzimidazolamide and the surfactant can be dispersed into the liquid medium by suitable agitation (such as a Cowles type stirrer) until homogeneously dispersed (the agglomerates are not visible to the naked eye and Has been further diluted). Preferably, when honing is carried out using a circulating media honing machine, the premix is preferably subjected to such pre-honing and dispersing steps. In one embodiment, the benzimidazolyl carbamate composition of the present invention is prepared using the following manufacturing procedure: preparing a premixed suspension (eg, 0.4 g/ml FBZ), which is pre-wet by wet honing The particle size of the suspension is reduced to less than 45 nm, and the premixed suspension is diluted with an aqueous pharmaceutically acceptable carrier until the final product (0.2 g/ml FBZ) is obtained, which can be directly added to the drinking water. Pharmaceutical composition. The antifoaming agent may be added to the premix or additionally to an aqueous carrier to prepare the final product. The premixed compound is diluted with a pharmaceutically acceptable carrier until the concentration of the benzimidazole carbamate in the final product is from about 5 to about 50 weight percent. Between. In some embodiments, the concentration is between about 1% by weight and about 30% by weight, between about 15% and about 25% by weight or about 20% by weight. -19- (16) (16) 200815001 The present invention provides a method for preparing a pharmaceutical composition for drinking water, wherein the composition comprises: benzimidazolamide with an effective average particle size of less than about 450 nm a granule, a Tween-type surfactant, a pharmaceutically acceptable carrier; which is prepared by the following steps: a. Dispersing the benzimidazolyl carbamate particles in a liquid dispersion medium containing a Tween-type surfactant And b. mechanically reducing the benzimidazole carbamate particle size to an average effective particle size of less than about 450 nm. In one embodiment, the mechanical particle size reduction is effected by media honing. In one embodiment, the pharmaceutical composition obtained in steps (a) and (b) above is further diluted with a pharmaceutically acceptable carrier to form an end product which can be directly added to the drinking water. The method comprises the steps of: a) dispersing the benzimidazolyl carbamate particles in a mixture comprising a pharmaceutically acceptable carrier and a Tween-type surfactant; b) administering a benzimidazole amide carbamate The particle size of the particles is mechanically reduced to an effective average particle size of less than about 450 nm to form a concentrated product mixture; c) a pharmaceutically acceptable carrier is added to the concentrated product to form a dilute product; and d) the final product is added Go to drinking water. EXAMPLES The following examples are for display only and are not intended to limit the remainder of the disclosure of this paragraph 20-200815001 (17). Example 1 Preparation of fenbendaz〇le according to the invention Composition 0. 2 g/ml fenflurazole (FBZ) drinking water suspension was prepared using the following three manufacturing steps: a) Preparation of a premixed suspension (0.4 g/ml FBZ) 'b) Wet honing this premixed suspension' and c) Dilute this premixed suspension to give the finished product (0.2 g/ml FBZ). Finished product formulation (〇.2 g/ml FBZ suspension) Substance fenflurazole 20.0 g Polysorbate 80 10.0 g Benzyl alcohol 2.0 g Dimethyl hydrazine emulsion 0.5 g Water to 100 ml A. Manufacturing pre- The suspension was mixed with the desired amount of the dimethylhydrazine oil emulsion and polysorbate 80 in a magnetic stirrer. For homogeneous mixing, heat it gently (less than 60 ° C). The desired amount of fenflurazole is then added under vigorous agitation (UlUa-Turrax) and the lost water volume is replenished to give a white homogeneous premixed suspension. In order to control the temperature of the product below 60 °C during the addition of fenbendazole, the beaker containing the product was placed in a cooling bath. -21 - 200815001 (18) Premixed suspension formulation substance fenbendazole 40 g polysorbate 80 20 g dimethyl hydrazine emulsion 30% USP 1 g pure water to 1 0 0 m 1 B. Wet Honing First, 450 ml of 0.25-0.3 mm glass beads (supplier VWR) was added to a 0.6 L DYNO® MILL KDL A container followed by 270 ml of the premixed suspension prepared in step A. The premixed suspension was wet honed for 45 minutes at a rotation rate of 4200 rpm using a polyurethane disk. During wet honing, the product temperature is maintained below 50 °C due to the use of a cooled double jacket to transfer heat away. The particle size of the fenflurazole suspension before and after honing was measured according to the following method using a Malvern Mastersizer 2000 equipped with a Hydro 2000G measuring chamber: under stirring (stirring speed 500 rpm, pumping speed 1000 rpm), measurement The background of the dispersant (water) contained in the dispersion unit. The FBZ suspension sample was then added until the opacity was 10 to 16%. The dispersion was first stirred with 100% ultrasonic for 2 minutes before measuring the particle size distribution. C. Dilution to obtain 0.2 g/ml FBZ suspension. Measure the volume of the wet honed premixed suspension'. Then add the required portion of 4% benzyl alcohol water to dilute the premixed suspension to obtain 0.2 g/ml fen. A suspension of benzoxazole (FBZ) in water. The obtained drinking water of the drinking water system was prepared using the obtained 〇·2 g/ml fenpropene-22-(19) 200815001 carbazole (FBZ) drinking water suspension. Example 2 Preparation of a fenflurazole composition according to the present invention A 0.2 g/ml fenflurazole (FluBZ) drinking water suspension was prepared using the following three manufacturing steps: a) Preparation of a premixed suspension (〇4 g/ml) • FluBZ), b) wet honing the premixed suspension, and c) diluting the premixed suspension to give the finished product (0.2 g/ml FluBZ). ι_Complete product formulation (0.2 g/ml FluBZ suspension) Substance quantity supplier fenbendazole 20.0 g Transchem Polysorbate 80 10.0 g Merck Benzyl alcohol 2.0 g Fluka Dimethyl hydrazine emulsion 0.5 g Dow Corning Pure water Make up to 100 ml - A. Make a premixed suspension. Mix the desired amount of the dimethyl hydrazine emulsion and polysorbate 80 with a magnetic stirrer in water. For homogeneous mixing, heat it gently (less than 60 ° C). The desired amount of fenflurazole is then added under vigorous agitation (Ultra-Turrax) and the lost water volume is replenished to give a white homogeneous premix suspension. In order to control the temperature of the product during the addition of fenbendazole to below 60 °C, the beaker containing the product was placed in a cooling bath. -23 - (20) 200815001 Formulation of Premixed Suspension Buprefen 40 g Polysorbate 8 0 20 g Dimethylhydrazine emulsion 30% USP 1 g Pure water to 100 ml B. Wet honing First 450 ml of 0.25-0.3 mm glass beads (VWR) were added to a 0.6 L DYNO® MILL KDL A vessel followed by 270 ml of the premixed suspension prepared in Step A. The premixed suspension was wet honed for 45 minutes at a spin rate of .4200 rpm using a polyurethane plate. Since the heat transfer is carried out with a cooled double jacket during wet honing, the product temperature is maintained below 50 °C. The particle size of the fenflurazole suspension before and after honing was measured according to the following method using a Malvern Mastersizer 2000 equipped with a Hydro 2000G measuring chamber: under stirring (stirring speed 500 rpm, pumping speed 1000 rpm), measurement The background of the dispersant (water) contained in the dispersion unit. The F B Z suspension sample was then added until the opacity was from 1 1 to 16%. The dispersion was first stirred with 100% ultrasonic for 2 minutes before measuring the particle size distribution. C. Dilution to obtain 〇·2 S/ml FluBZ suspension, measure the volume of the pre-mixed 1 suspension 'floating liquid' of the wet honing and then dilute the pre-mixed suspension with 4% benzyl alcohol water required by the required amount The liquid was used to obtain an aqueous suspension of 〇·2 g / m 1 fenbendazole (FBZ). Using the obtained 0. 2 g/ml fenfen-24-(21) 200815001 carbazole (FBZ) drinking water suspension to prepare the drinking water of the drinking water system. The particle size distribution of the FliiBZ composition of the present invention is 50%. Particle size 90% Particle size Particle size FluBZ 0.2 g/ml Suspension <13 0 nm < 3 2 0 nm Figure 10 shows the particle size of the fenflurazole suspension prepared in Example 2 distributed. φ Figure 11 shows the purification kinetics of drinking water administered with 60 ppm FluBZ (made in FluBZ suspension) obtained in the middle of the measurement chamber for 24 hours (according to WO 0 1 /1 7504, for visual optics) Scanning device TURBISCAN® (provided by French Formulaction)). Results: It was found that the water used for the fenflurazole suspension prepared in Example 2 during the 24 hour period measured by TURBISCAN® did not have significant physical instability. • Example 3 Another Wet Honing Method - Continuous Use of Recycled Premixed Suspension

First, 450 ml of 0.25-0.3 mm glass beads (supplier B. Braun Biotech International) was added to the 0.6 L DYNO® MILL KDL A vessel, followed by 270 ml of the premixed suspension prepared in Example 1 or 2, Step A. . The honing vessel is then connected to a pump to continuously feed the premixed suspension into the honing machine; the flow rate is set at about 1.3 L/h. When all the premixed suspension (500 ml) was separated from the honing medium by the honing machine from a 0.1 mm wide-25-200815001 (22) gap and discharged into a new container, a wet sputum was completed. Grinding cycle. The premixed suspension was subjected to a six-time honing cycle with a polyuratan disk and a rotational speed of 4200 rpm. Since the heat transfer is carried out with a double-layer cooling jacket during wet honing, the product temperature is maintained below 50 °C. ' The particle size of the fenflurazole suspension before and after honing is measured according to the following method using a Malvern Mastersizer φ 2000 equipped with a Hydro 2 0 00G measuring chamber. · Stirring (500 rpm, pumping speed 1000) The background 値 of the dispersant (water) contained in the dispersion unit was measured under rpm). The FBZ suspension sample was then added until the opacity was 10 to 16%. The dispersion was first stirred with 100% ultrasonic for 2 minutes before measuring the particle size distribution. The wet honed premixed suspension is then diluted as described in Example 1 or 2, Step C. Example 4 Another Wet Honing Method - Continuous Process for Recycling Premixed Suspensions First, 360 ml of 0·25-0·3 mm chrome oxide for hydrazine is first added to a L·6 L DYNO® MULTI LAB container. Beads (supplier Miihlmeier) were then attached to a pump to continuously feed the premixed suspension produced in Example 1 or 2, Step A, to a honing machine. The flow rate is set at about 37 L/h. This is a closed cycle: the premixed suspension (2 L) is continuously pumped from the feed vessel, and the premixed suspension is passed through the honing machine, separated from the honing medium by a 〇 1 mm wide gap and discharged to Feed container. The feed vessel is equipped with a stirrer to maintain the premixed suspension -26-200815001 (23) liquid homogenization. The premixed suspension was honed at a rotational speed of 10 m/s for 5 5 minutes using a D ΥΝ Ο ® -accelerator. Since the heat transfer is carried out with a double-layer cooling jacket during wet honing, the product temperature is maintained below 50 °C. The particle size of the fenflurazole suspension before and after honing was measured according to the following method using a Ma ver η M astersizer 2 000 equipped with a Hydr 〇200 0 G measuring chamber: stirring (stirring speed) The background enthalpy of the dispersant (water) contained in the dispersion unit was measured at 500 rpm and a pumping speed of 1000 rpm. φ Then add the FBZ suspension sample until the opacity is 1 〇 to 1 6%. The dispersion was first stirred with 100% ultrasonic for 2 minutes before measuring the particle size distribution. The wet honed premixed suspension is then diluted as described in Example 1 or 2, Step C. Example 5 Comparison of the particle size of the composition of the present invention and the composition manufactured by WO 95/1 3065 The composition of WO 9 5/1 3 065 was prepared according to the procedure A of Example 1. The particle size was wet honed (unconstituted in WO 95/13065) and in accordance with the Frauenhofer method using a Malvern Master sizer GMAL 01 equipped with a Hydro 2000G measuring chamber (the composition of the invention prepared according to step AB of Example 1) ) measured. The wet honing reduces the effective particle size of the fenbendazole particles to less than 200 nm. Unwet honing and 粒径 粒径 粒径 硏 之 之 粒径 粒径 ( ( ( FB FB FB 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 2 0 0 nm -27 - 200815001 (24) Figure 1 shows the particle size distribution after wet honing and wet honing. Figure 2 shows the 60 ' obtained in the middle of the measurement room for 24 hours. PPm Purification power of FBZ (made of FBZ suspension) for the drinking water • Academic characteristics (measured according to WO 0 1/1 7504, with the visual optical scanning device TURBISCAN® (supplied by French Formulaction)). • The TURBISCAN® unit uses a multi-light scattering basis to detect all changes in the dispersion system (eg, cleanliness, precipitation, etc.). It is a vertical scanning visual analyzer consisting of a read head that moves along a flat-bottomed cylindrical chamber to scan the entire sample height. The read head itself consists of a pulsed near-infrared source and two synchrotrons (the transmission detector receives the light passing through the product's backscatter detector and receives the light backscattered by the product). The read head reads the transmitted and backscattered data every 4 0 // m and can read up to a height of 80 mm. The properties obtained can characterize product homogeneity, particle concentration, and • average diameter. The results obtained are expressed as a function of the percentage of backscattered light or percent of transmitted light as a function of sample height (in mm). The results obtained along the product are repeated at a programmable frequency to give a product fingerprint overlay that characterizes the stability or instability of the product (whether identical or different from each other). Results: found during the 24-hour period measured by TURBISCAN® The fenflurazole suspension prepared in Example 1 was administered with hydrazine without any signs of physical instability (no purification, no precipitation). -28-200815001 (25) Example 6 Comparison of the physical stability of the composition of the present invention and the composition manufactured by WO 95/1 3 065 The composition of the present invention is referred to as "a thorough wet honing FBZ suspension" It was prepared as in Example 1. Another fenbendazole suspension was prepared as described in WO 9 5/1 3 065 (referred to as FBZ coarse suspension). Another * composition, referred to as "slightly wet honked FBZ suspension", was prepared according to the same manufacturing procedure as described in the examples, but was prepared using milder wet honing conditions: premixing 1 L The suspension was mixed with 490 ml of 0.5 mm glass beads for a three-time grinding with a U-Ban plate and a rotation speed of 3200 rpm. Such wet honing conditions produce an intermediate particle size distribution between the "more thorough wet honing FBZ suspension" and the FBZ coarse suspension. FBZ coarse suspension (without wet honing) and FBZ suspension (slightly wet honed and more thoroughly wet honed) particle size distribution D (0.50) D (0.90) FBZ coarse suspension (according to WO 95/ 1 3 065 ) <2430 nm <24710 nm FBZ 0.2 g/ml The suspension was slightly wet honed and thoroughly wet & tempered <3 50 nm < 120 nm < 1030 nm < 200 nm Figure 3 The figure shows these particle size distributions. These preparations are diluted with water to give, for example, fenbendazole medicated drinking water having a concentration of 60 ppm for the treatment of birds. The physical stability of the obtained medicated drinking water was examined by means of a visual optical scanning device TURBISCAN8 as described in Example 5. -29- 200815001 (26) The results of the TURBISCAN® evaluation are shown in Figure 4, which shows the purification kinetics obtained by measuring the four formulations in the middle of the measurement chamber for 24 hours. Results: 24 hours analysis with TURBISCAN® was found During the period of administration, the medicated drinking water administered with the fenflurazole suspension prepared in Example 1 showed no signs of physical instability, but the medicated drinking water was administered according to the crude suspension of fenflurazole prepared according to WO 95/13065. Significant purification occurs. φ This purification is consistent with the formation of the precipitate detected about 6.5 hours after the start of the study. A slightly moisturized suspension showed moderate stability characteristics. The degree of purification was consistent with the result of detecting the precipitate after 14 hours of standing. Example 7 Relative physical stability of a composition of the invention with a commercially available suspoemulsion product (SOLUBENOL®, Janssen-Cilag, Beerse Belgium) φ The commercially available suspoemulsion product SOLUBEOL® was diluted with water to give, for example, a concentration 85.6 ppm of fenbendazole for the treatment of birds and medicated drinking water. The particle size distribution is summarized in the following table, and the composition of the present invention (FBZ suspension) described in Example 1 is referred to as a reference, and is schematically shown in Fig. 5. FBZ 0.2 g/ml suspension liquid phase is smaller than S Ο LU Β ΕΝ Ο L ® particle size distribution 50% particle diameter D (0.50) 90% particle diameter D (0.90) SOLUBENOL® <13700 nm < 29800 nm FBZ 0.2 g/ml suspension < 120 nm < 200 nm -30 - 200815001 (27) The physical stability of the medicated water prepared with SOLUB ΕΝ OL® was the same as in Example 2. The operating instructions are based on TURBISCAN®. The results of the TURBISCAN® evaluation are shown in Figure 6, which shows the purification dynamics obtained by detecting the medicated water prepared from the SOLUBENOL® formulation in the middle of the measurement chamber for 24 hours. % ' Result: SOLUBENOL® medicated water has a significant decontamination effect' but the φ syrup prepared with the fenflurazole suspension of Example 1 was used during the 24-hour analysis with TURBISCAN® There is no sign of physical instability. Example 8: Fiprophenyl-Zole Suspension Prepared with Different Surfactants The FBZ suspension was prepared as described in the Examples below with the following ingredients. Substance functional company phenacazole active ingredient Intervet a ) Polysorbate 20 Suspension Merck b) Polysorbate 40 Suspension Merck c ) Polysorbate 60 Suspension Merck d) Polysorbate 80 Suspension VWR e ) Poloxamer 1 8 8 Suspension Uni q em a Dimethylhydrazine emulsion 3 0 ° / 〇 USP Defoamer Dow Corning Benzyl alcohol preservative F luka Pure water to 100 ml Pharmacy water Stability Evaluation Immediately before analysis, the FBZ suspension containing the suspension was diluted to 60 ppm with water and measured with Turbiscan at room temperature for 24 hours to determine the difference -31 - 200815001 (28) Physical stability of the medicated water (transmitted light and Backscattered light). A premixed suspension containing poloxamer 1 88 was prepared by the procedure described in Example 1 with the following modifications. The poloxamer was first melted, mixed with the dimethyl hydrazine emulsion, and then fenflurazole was added; after stirring, the mixture became too viscous * thick enough to pass through the honing machine. Particle size distribution φ The particle size distribution of the different suspensions before wet honing and after wet honing was measured and is shown in the table below. Particle size distribution (// m ) FBZ suspension after wet honing wet 硏Z0(0.50) D(0.90) D(0.95) D(0.50) D(0.90) D(0.95) Polysorbate 20 1.89 17.74 23.74 0.12 0.25 0.37 Polysorbate 40 2.18 28.39 49.69 0.13 0.32 0.81 Polysorbate 60 2.06 26.85 41.07 0.13 0.33 0.62 Polysorbate 80 2.44 32.64 50.46 0.12 0.20 0.23 poloxamer 188 2.23 29.03 41.84 - - -

After wet honing, all polysorbate compositions exhibited a fine and narrow particle size distribution. Physical stability evaluation of the medicated water. Immediately prior to analysis, the FBZ suspension containing the suspending agent was diluted with water to 60 ppm and measured under the same analytical procedure as in Example 3 for 24 hours at room temperature to determine the physical stability of the different medicated waters. Sex (-32- (29) 200815001 transmitted light and backscattered light). The TURBISCAN® evaluation results are shown in Figure 7, which shows the purification dynamics obtained by detecting the medicated water prepared from the FBZ 0.2 g/ml suspension containing different suspensions in the middle of the measurement chamber for 24 hours. Results: The medicated water prepared by dilution of the FBZ suspension containing poloxamer 188 was physically unstable. A precipitate layer that grows at 0.77 # m/min can be detected, but this precipitate layer is not detected in other dosing waters containing different polysorbate esters. The change in transparency of the medicated water containing the tested polysorbate in 24 hours is less than 10% acceptable. Example 9 A fenbyl oxazole suspension prepared from various concentrations of polysorbate 80. The FBZ suspension was prepared as described in Example 1 with the following composition. Fenbenzoxazole active ingredient 2 0.0 g

Polysorbate 80 Suspension 5,10 or 15 g Dimethylhydrazine oil emulsion 30% USP Defoamer 0.5 g Benzyl alcohol preservative 2.0 g _Pure 7 underfill to 100 ml Particle size distribution measurement Wet honing The particle size distribution of the different FBZ suspensions before and after wet honing is shown in the table below. -33- 200815001 (30) Particle size distribution (β m) D(0.50) after wet honing D(0.90) D(0.95) D(0.50) D(0.90) D(0.95) FBZ suspension containing 5% Polysorbate 80 2.45 32.08 55.87 0.13 0.20 0.22 Containing 10% Polysorbate 80 2.44 32.64 50.46 0.12 0.20 0.23 Containing 15% Polysorbate 80 2.16 30.64 51.10 0.11 0.19 0.22 After wet honing, All FBZ suspensions exhibit a fine and narrow # particle size distribution. Physical stability evaluation of the medicated water The FBZ suspension containing the suspending agent was diluted with water to 60 ppm and measured with Turbiscan at room temperature for 24 hours to determine the physical stability of the medicated water (transmitted light and backscattered light). . The physical stability of the dosing water was investigated by means of TURBISCAN® according to the same analytical operating instructions of Example 5. • The TURBISCAN® evaluation results are shown in Figure 8, which shows the purification dynamics obtained by detecting the effluent water prepared from a FBZ 0.2 g/ml suspension containing different concentrations of sorbitol 80 in the measurement chamber for 24 hours. RESULTS: The medicated water containing different concentrations of polysorbate 80 did not detect the sinking layer. This good physical stability can be confirmed by the light transmission pattern. The maximum variation is equivalent to 1% after 24 hours, which is acceptable. Example 10 Wet honing of 20% and 40% suspension of fenbendazole The composition of the present invention referred to as "FBZ 0.2 g/ml suspension" is based on -34-200815001 (31) Manufacture of Example 3 Another fenbendazole suspension was prepared according to WO 95/13065 (referred to as "FBZ coarse suspension") and subjected to the following wet honing. First, in the DYNO8MILL MULTI LAB0.6 L container, first add 360 ml 0.3 mm Ming'anding oxidized pin glass beads (supplier ' Muhlmeier ), then connect the honing vessel to the pump to continuously feed the FBZ coarse suspension. In the honing machine, the flow rate is set at about 112 L/h φ. This is a closed cycle: the premixed suspension (2 L) is continuously pumped from the feed vessel, and the premixed suspension is passed through the honing machine, separated from the honing medium by a 1 mm wide gap and discharged to Feed container. The feed vessel is equipped with a stirrer to keep the premixed suspension homogeneous. The premixed suspension was honed with a DYNO®-accelerator at a rotational speed of 10 m/s for 5 minutes. Since the heat transfer is carried out with a double-layer cooling jacket during wet honing, the product temperature is maintained below 50 °C. The particle size distribution of the fenflurazole suspension was measured as described in Example 3 to measure the particle size of the FBZ 0.2 g/m 1 suspension liquid phase compared to the wet honed FBZ coarse suspension D (0.50 ) D (0.90) Wet honed F Β ζ coarse suspension <13 0 nm < 300 nm FBZ 0.2 g/ml suspension <13 0 nm < 290 nm Result: honing contains 20% w/v FBZ "FBZ crude suspension" end product or honing premixed suspension containing 40% FBZ and diluting to obtain the final product of "FBZ 0·2 -35- 200815001 (32) g/ml suspension '' Particle size distribution. Example 11 Conductor tube experiment with fenbendazole The composition of the present invention, referred to as "FBZ 0.2 g/ml suspension," was prepared as described in Example 2 (the honing step was performed from Mtihlheimer 42 0 ml 0.3 mm yttrium yttrium oxide beads, cycled twice at a flow rate of 1 L/h. FBZ 0.2 g/ml suspension ί Graft phase particle size distribution compared to FBZ coarse suspension D ( 0 · 5 0 D ( 0.90 ) F Ζ Ζ 悬浮 & 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 13 13 13 13 13 13 13 13 13 13 5 5 5 5 5 5 5 5 5 5 5 5 3 0 6 5 (referred to as "FBZ coarse suspension"). The particle size distribution of the fenbendazole suspension was prepared according to Example 3. Stability and homogeneity simulation of the medicated water of the two compositions The on-site condition of the medicated water distribution was tested for 3 hours. These studies were carried out with locally supplied drinking water. The medicated water was prepared in the dosage tank with the desired amount of the composition and hydrophobic water to obtain a concentration of 60 ppm fenpropene. The azole medicated water is used, for example, for bird treatment. The tank is connected to a 25-meter long delivery tube via its bottom sluice outlet. It is set at about 3.5 L/h. During the delivery period, the dosing water is periodically sampled at the end of the drug delivery tank (surface) and the 25-meter-long delivery tube. -36- 200815001 (33) The sample will be analyzed for fenflurazole content. The medicated water was not stirred. Further, visually inspect the drug delivery tank and the delivery tube for any precipitate formation. The results are shown in Fig. 9, which shows the change in FBZ concentration of the two administration waters sampled from the drug delivery tank and the end of the delivery tube. 'Results··In the two studies, neither the drug delivery tank nor the delivery tube detected 'precipitation; however, at the end of the experiment, the medicated water at the bottom of the dosing tank containing the FBZ crude suspension administration tank was thicker. This instability is consistent with the analytical result φ: it shows that the FBZ concentration of the medicated water prepared with the FBZ coarse suspension is greatly reduced during the delivery period compared to the homogeneous stable medicated water prepared with the FBZ 0.2 g/ml suspension. Example 12 Field Experiments Pigs and birds were prepared as "FBZ 0.2 g/ml suspension" and the compositions of the invention were prepared according to Example 1. Two on-site studies were conducted to evaluate the homogeneity and stability of the FBZ 2·2 g/ml suspension in the dosing water under field conditions. # A study was carried out on a pig farm with a feed tank, a closed loop circuit of approximately 60 m long (from PVC and stainless steel ducts), and another study with an electronic dosing pump (from Buerkert) KONTI-DOS) and a 220-meter-long terminal water supply system (made of galvanized iron and plastic tubes) are used in turkey farms. The general study procedure for each study was the same: medicated water was prepared from drinking water from the farm with a pH range between about 7.2 and 8.2 and a total hardness between 7.3 and 13.7 ° dH. FBZ concentration in water (parts per million) is based on a single dose of 5 mg FBZ/kg body weight, animal body weight and the estimated three-hour period -37-200815001 (34) (dosing tank) and eight hour period (dosing pump) The amount of drinking water is made. The sample water was taken from the bottom and top of the tank and the established head and decanter of the water supply system every 30 to 60 minutes during the administration. The contents of the dosing tank are not stirred during the entire period of administration. * Check the dosing tank and the drinking head or decanter for any active ingredients or *precipitate formed by the excipient. More water samples were taken approximately 24 hours after the discontinuation of administration to assess whether φ potentially had residual FBZ content. Next, all water samples were analyzed for FBZ content using an efficient HPLC method. Results: All analytical results (actual FBZ content) were consistent with nominal (calculated) concentrations. There is a consistent FBZ concentration in both the dosing tank and the water pipe during the two or eight hours of dosing. The concentration of FBZ in the samples collected from the bottom of the tank and the top of the tank is not different. No precipitation or suspension of particles was observed in the tank. There is no sedimentation and there is no obstruction of the drinking head. Water sampled 24 hours after discontinuation of administration* The sample does not have any measurable FBZ residue (below the detection limit of less than about 0.4 ppm), indicating that the novel FBZ suspension does not form any residue in the hydrophobic system. Things. The results of these on-site studies are summarized in the table below. -38- 200815001 (35) Average FBZ concentration reported in the on-site study' Concentration average FBZ concentration as a function of time [ppm] Dosing/pre: Dilution tank drinking head / decanter A1 A2 BCDEFG Pig name 192 Actual 193.3 188.3 180.6 181.7 193.3 186.7 176.0 190.3 Name of turkey 2395 81 Actual 2443.4 2413.1 82.7 84.6 78.4 83.3 72.2 76.8 The conclusion from the site study was: FBZ 0.2 g/ml suspension in the selected pig and bird farms The representative water supply system can be evenly distributed in the administration water and since there is a consistent FBZ concentration during administration, accurate administration can be ensured. In this patent (including the scope of the patent application), the words "comprises" and "comprising" are to be construed as being inclusive and not exclusive. These explanations are the same as those provided by US patent law. All of the references cited in this patent are hereby incorporated by reference in their entirety for all purposes for the purposes of the disclosure of The present invention can be used and implemented in a variety of forms (as they may be best suited to the needs of a particular application). Therefore, the present invention is not limited to the specific examples above, and various modifications may be made. -39- 200815001 (36) [Simple description of the diagram] Figure 1 represents the particle size distribution of fenflurazole (FBZ) suspension without wet mashing and after wet honing. 'Fig. 2 represents the purification kinetics of 60 ppm FBZ dosing water (grinded with FBZ suspension) obtained in the middle of the measurement chamber with TURBISCAN® minutes and hours. φ Figure 3 represents the particle size distribution of the FBZ coarse suspension (without wet honing) and the suspension (slightly wet honing and more thorough wet honing). Figure 4 is a representation of 60 ppm FBZ dosing water obtained by TURBISCAN® in the middle of the measuring chamber (wet blasting with FBZ coarse suspension) and FBZ suspension (slightly wet honing and grinding) The kinetics of purification by honing). Figure 5 represents the particle size distribution of SOLULUNOL® and FBZ fluids. φ Fig. 6 represents 8 5 · 6 ppm fenbendazole dosing water (made with Salouben SOLULUNOL) obtained by TURBISCAN® in the middle of the measuring chamber and 6〇ppm FBZ medicinal drinking water Purification kinetics (prepared from suspension) Figure 7 represents 60 ppm FBZ dosing in the middle of the measurement chamber with TURBISCAN® (diluted with FBZ suspension containing different interfacial agents) Physical stability of the system. Figure 8 represents the TURBISCAN® in the middle of the measurement room; 60 ppm FBZ dosing water obtained in f hours (with different concentrations of grinding (f 24 wet 硏FBZ f 24 (not bottom wet suspension) f 24 Connaught (physical stability of FBZ T 24 active T 24 poly-40- (37) (37) 200815001 sorbitol ester 80 FB Z suspension dilution) Figure 9 represents FBZ coarse suspension The concentration of FBZ in the medicated drinking water was 3 hours during the delivery of the effluent and FBZ 0.2 g/ml suspension; the sample was taken from the drug delivery tank and the end of the 25-meter long delivery tube. The first 〇 diagram is representative The particle size distribution of the fenflurazole suspension prepared in Example 2. The figure 1 1 represents the test In the intermediate chamber T U R BI S C A N⑧ analysis 2 of 4 hours to give 60 ppm FluBZ medicated drinking water (available in FluBZ 0.2 g / ml suspension) was purified of dynamics.

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Claims (1)

200815001 (1) X. Patent application 1. A pharmaceutical composition for administering benzimidazolyl carbamate to drinking water, characterized in that the composition contains a benzene having an effective average particle diameter of less than about 450 nm. An aqueous suspension of imidazole urethane granules and a Tween type boundary surfactant. The composition of claim 1, wherein the benzimidazole urethane particles have an effective average particle diameter of less than about 300 nm. Φ 3 The composition of claim 1 or 2, wherein the Tween-type surfactant contains polysorbate 80. 4. The composition of claim 1 or 2, wherein the Tween-type surfactant is present in an amount of from about 0.1 to about 50% by weight. 5. The composition of claim 1 or 2, wherein the benzoxanthene amide comprises fenbendazole. 6. The composition of claim 5, wherein the fenflurazole is present in an amount of from about 5 to about 50% by weight. Φ 7. The use of the composition of claims 1 to 6 for the manufacture of a medicament for administration to an animal via an animal's drowning water for controlling parasites in an animal. 8. A method of preparing a pharmaceutical composition for drinking water, wherein the method comprises: 'dispersing the benzimidazolyl carbamate particles in a mixture comprising a pharmaceutically acceptable carrier and a Tween-type surfactant And mechanically reducing the particle size of the benzimidazolyl carbamate particles to an effective average particle size of less than about 450 nm. The method of claim 8, wherein the method further comprises: dispersing the benzimidazolyl carbamate particles in a pharmaceutically acceptable carrier and a Tween-type interfacial activity a mixture of agents; * mechanically reducing the particle size of the benzimidazolyl carbamate particles " to an effective average particle size of less than about 45 nm to form a concentrated product mixture; a pharmaceutically acceptable carrier It is added to the concentrated product to form a dilute product φ : and the final product is added to the drinking water. 10. The method of claim 8 or 9, wherein the mechanically reducing the particle size is performed by media honing. -43-