GB2117241A - Anthelmintic preparations - Google Patents

Abstract

A veterinary preparation comprising an effective amount of an anthelmintic agent, preferably fenbendazole, and a non-toxic amount of selenium salt, preferably sodium selenate, effective to prevent selenium deficiency in an animal. Preferably, a non-toxic amount of a cobalt salt effective to prevent cobalt deficiency in an animal is also included. By combining selenium with an anthelmintic agent, the safety margin for selenium is greatly increased.

Description

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UK Patent Application,,,, 2 1 1 7 2 41 A (21) Application No 8308849 (22) Date of filing 30 Mar 1983 (30) Priority data (31) 8209347 (32) 30 Mar 1982 (33) United Kingdom (GB) (43) Application published 12 Oct 1983 (51) INT CL3 A61K 33/04 31/41 45/06 (52) Domestic classification ASB 180 190272 273 27Y36X36Y 381 38Y 480 482 483 484 485 48Y 513 51Y 546 54Y 552 55Y 565 56Y 575 57Y 586 58Y 616 61Y 642 644 645 64Y 670 67Y J (56) Documents cited G B 0741704 .DTD:

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A5B (71) Applicant Hoechst UK Limited (Great Britain), Hoechst House, Salisbury Road, Hounslow, Middlesex (72) Inventors John Anthony Ganley, David George McBeath, Celia Margaret McTaggart, Peter William Wells (74) Agent and/or Address for Service Abel and Imray, Northumberland House, 303--306 High Holborn, London WCIV 7LH (54) Anthelmintic preparations (57) Veterinary preparations comprising an anthelmintic agent and a selenium salt have an increased safety margin with regard to the selenium. The selium salt is preferably sodium selanate, selanite or selanide and the anthelmintic agent is preferably a benzimidazole anthelmintic agent. The preparation may also contain a cobalt salt.

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ATA SPECIFICATION No. 2 117 241 A .DTD:

Front page, abstract second column, for The selium salt is preferably sodium selanate, selanite or selanide read The selenium salt is preferably sodium selenate, selenite or selenide Page 1, line 23, for verterinary read veterinary Page 1, line 29, for is (.first occurrence) read it Page 1, l'ine 34, for Expansa, read expansa, Page 1, line 53,}for patassium read potassium Page 2, line 27, for fenbenazole read fenbend- azole Page 2, 1)ine 45, for of (first occurrence) read or Page 3, line 36,]or slt read salt Page S, line 27, [or selonium read selenium Page 11, l/he 35, for selenate read selenite THE PATENT OFFICE20th January, 1984 gO Fo ___x bo ____x 1 GB 2 117 241A 1 i, SPECIFICATION .DTD:

Anthelmintic preparations The present invention relates to anthelmintic preparations, particularly for the treatment of ruminants.

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As clinical and sub-clinical nematode infections can cause serious economic loss, due to death, 5 reduced weight gain and lowered milk yield, anthelmintic treatment of ruminants is now a routine practice. Treatment is also undertaken to reduce pasture larval contamination and thus aids in ensuring optimal grassland usage.

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In some cases, however, even after anthelmintic treatment, animals still fail to thrive. It is now considered that this may be caused by mineral deficiencies resulting from soils and pastures deficient in 10 minerals. Cobalt is one mineral that may be lacking in the diet of ruminants, particularly in the spring, when there is pasture dominance of rapidly growing grasses, which have a lower cobalt content than more slowly growing grasses. Cobalt participates in the production of vitamin B12 in the rumen, and deficiency results in loss of appetite and loss of bodyweight, and the animal may finally waste away. In the ewe, in addition to weight loss, milk yield falls and there is a reduction in fleece quality. Selenium is 15 also an essential element, but its exact metabolic function is uncertain. Deficiency is associated with muscular dystrophy, unthriftiness, and infertility in female animals.

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It has, therefore, been proposed to administer trace elements, particularly cobalt and selenium, to animals. Some of the trace elements, however, are toxic, and it is possible to overdose animals. This is particularly so with selenium, the oral LDso of which is only 0,5 mg/kg. The present invention is based on 20 the surprising observation that a preparation comprising both selenium and an anthelmintic agent has a very greatly increased safety margin with regard to the selenium.

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Accordingly, the present invention provides a verterinary preparation which comprises an anthelmintic agent and a selenium salt, preferably in admixture or conjunction with a carrier suitable for use in a veterinary preparation. Preferably, the preparation also comprises a cobalt salt. 25 The anthelmintic agent may be suitable for treating worms and/or flukes, and is preferably a benzimidazole anthelmintic, for example, parbendazole, oxfendazole, oxibendazole, thiabendazole, albendazole, cambendazole, mebendazole, flubendazole or fenbendazole. As a general rule, the less soluble a benzimidazole anthelmintic, the more active is is. Accordingly, fenbendazole, oxfendazole and albendazole are more active than thiabendazole, parbendazole and cambendazole and are, therefore, 30 preferred.

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Fenbendazole is a" broad spectrum anthelmintic with excellent efficacy against adult, larval and egg stages of all important gastro-intestinal and respiratory nematodes of ruminants. In addition, it is effective against both scolices and segments of M. Expansa, the cestode affecting sheep and cattle.

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It is non-teratogenic, and so can be used safely in animals at any stage of pregnancy. Having no 35 adverse effect on fertility, it can be used around the time of service and in the breeding male. It has a very high safety margin (sheep: 1000 times the recommended dose, cattle: 50 times the recommended dose). Moreover, it is non-toxic to handlers. Oxfendazole and albendazole have substantially the same spectrum of activity as fenbendazole, but have a lower therapeutic index. Fenbendazole (methyl-5phenylthio-2-benzimidazole carbemate) is particularly preferred as the anthelmintic agent for the 40 preparation of the present invention.

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A preparation of the invention may be in liquid or solid form. A liquid preparation may be a solution, but is generally a suspension, preferably a fairly mobile suspension. Other forms of preparation suitable for dosing animals may be used, for example, tablets, bolus tablets and pastes; and powders and granules for reconstitution as solutions or suspensions prior to use. Moreover, animals may be 45 dosed by the addition of an anthelmintic agent, a selenium salt and, preferably also a cobalt salt, directly to the feed. A preparation of the invention, accordingly, may be in a form suitable for addition to an animal feedstuff. The invention further comprises an animal feedstuff that has been augmented by the incorporation of an anthelmintic agent, a selenium salt and, preferably, also a cobalt salt.

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In a preparation of the invention, the selenium salt may be insoluble or soluble, soluble salts being 50 preferred, for example, alkali metal and ammonium salts. The selenium may be in the form of a selenate, selenite or selenide. Examples of selenium salts are sodium, potassium and ammonium selenate, sodium, patassium and ammonium selenite, and sodium and potassium selenide. Selenates are generally preferred as they are the most soluble, and sodium selenate is particularly preferred. The cobalt salt also may be insoluble or soluble, examples of cobalt salts being cobalt carbonate, cobalt 55 chloride, cobalt nitrate and cobalt sulphate. Cobaltous or cobattic salts may be used. Soluble cobalt salts are preferred. In a liquid preparation, the selenium salt and, when present, the cobalt salt, is preferably in solution to ensure a uniform distribution of these elements throughout the preparation and therefore to improve dose to dose reproducibility.

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One or more further physiologically active substance(s) may be present in a preparation of the 60 invention, for example, selected from vitamins and, especially, other trace elements, for example, copper, zinc and magnesium.

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One or more carriers suitable for veterinary preparations may be present in addition to the active substances to aid manufacture and/or to confer desirable properties on the final preparation. Such 2 GB 2 117 241A 2 materials include pH adjusters, pH buffers, wetting agents, suspending agents, thickening agents, stabilising agents, solubilisers, antimicrobial preservatives, lubricants and distintegration agents. Water is generally the basis for a solution or suspension.

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A suspension of the invention may be prepared by mixing the ingredients with water using a high speed mixer/homogeniser until a uniform dispersion is achieved. The p.H of the suspension is usually 5 adjusted to the range 5.5 to 6.5 and especially to 5.9 to 6.0 to optimise product stability. The suspension preferably includes ingredients to ensure an elegant product by retarding sedimentation and/or aiding resuspension on shaking, for example, a thixotropic agent, e.g. colloidal silicon dioxide, and/or a thickening agent, e.g. carboxymethyl cellulose. The selenium salt is preferably added as a solution to avoid dust problems on handling. 10 Other preparation forms, for example, tablets, powders and granules, may be prepared in a conventional manner.

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In a voterinery preparation of the invention the anthelmintic agent is preferably present in an excess by weight, calculated on the weight of elemental selenium, and advantageously the anthelmintic agent and the selenium component are present in a weight ratio of at least 3:1, the selenium being 15 calculated as elemental selenium.

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In a veterinary preparation of the invention for cattle the anthlemintic agent is preferably present in an amount of from 150 to 1500 parts by weight; and the selenium salt is preferably present in an amount, calculated as elemental selenium, of 0.75 to 18.75 parts by weight. Such a preparation may also comprise a cobalt salt, the cobalt salt preferably being present in an amount, calculated as 20 elemental cobalt, of 0.75 to 37.5 parts by weight.

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In a veterinary preparation of the invention for sheep and goats, the anthelmintic agent is preferably present in an amount of from 100 to 400 parts by weight; and the selenium salt is preferably present in an amount, calculated as elemental selenium, of 1 to 20 parts by weight. Such a preparation may also comprise a cobalt salt, the cobalt salt preferably being present in an amount, calculated as 25 elemental cobalt.

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In a suspension of the invention the fenbenazole content is, for example, in the range of from 10 to mg/ml for sheep and goats, especially 25 mg/ml. For cattle, the fenbendazole content is, for example, from 20 to 200 mg/ml, especially 1 O0 mg/ml. If a different anthelmintic agent is used, the dose should be substantially equivalent to that given above for fenbendazole. (The recommended doses 30 of most anthelmintic agents for sheep, goats and cattle are generally well known.) The content of selenium in a suspension of the invention, calculated as elemental selenium is, for example, within the range of from O. 1 to 2.0 mg/ml, especially 0.4 mg/ml for sheep and goats, and within the range of for from 0.1 to 2.5 mg/ml, especially 2.0 mg/ml for cattle. The cobalt content, also calculated as the elemental substance is, for example, from 0.1 to 5.0 mg/ml, especially from 0.9 to 1.0 35 mg/ml for sheep and goats, and from 0.1 to 5.0 mg/mi, especially 2.5 mg/ml for cattle. If desired, however, the selenium content can be increased considerably, for example, up to 10 mg/ml, for sheep, goats and cable.

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A suspension of the invention for sheep and goats preferably comprises 25 mg of fenbendazole, 0.4 mg of elemental selenium and 0.95 mg of cobalt per ml. With this preparation, the recommended 40 dose is 1 ml/5 kg body weight.

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A suspension of the invention for cattle preferably comprises 100 mg of fenbendazole, 2.0 mg of elemental selenim and 2.5 mg of elemental cobalt per ml. The recommended dose of this preparation is 7.5 ml per 100 kg body weight.

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In a tablet of bolus tablet of the invention, thedoses of the various ingredients may be calculated 45 pro rata from the doses given above, knowing the body weight of the intended recipient of the dose, for example, in a tablet suitable for administration to a 50 kg sheep, the fenbendazole content is generally from 1 O0 to 400 rag, especially from 250 to 300 mg, the content of elemental selenium is generally from 1 to 20 mg, especially from 3 to 5 mg; and the cobalt content, calculated as elemental cobalt, is generally from 1 to 50 mg, especially from 9 to 10 mg. Tablets may be scored to assist the 50 administration of divided doses to smaller animals, and multiple doses may be given to larger animals.

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The optimum dose of the various ingredients for solid preparations e.g. tablets and bolus tablets for cattle can be calculated similarly from the data given above for suspensions.

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As indicated above, appropriate amounts of other anthelmintic agents, can be readily calculated.

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It will be appreciated that as an alternative to presenting the anthelmintic agent and the selenium 55 to an animal in a single preparation, these two components may be formulated separately and administered simultaneously or substantially simultaneously. The present invention accordingly also provides a pack which comprises an anthelmintic agent and, in conjunction or close juxtaposition therewith, a selenium salt. The anthelmintic agent is in the form of a veterinary preparation and is preferably in admixture or conjunction with a carrier suitable for use in a veterinary preparation. The 60 preparation may be liquid or solid, and example of preparation forms are given above. As indicated above, suspensions are generally preferred. The content of the anthelmintic agent is preferably as indicated above. The selenium salt may be formulated either alone or in admixture or conjunction with a carrier suitable for veterinary use in solid or liquid form, for example, as tablet, bolus tablet or paste, as a solution or suspension, or as a powder or granules for reconstitution as a solution or suspension prior to 65 3 GB 2 117 241 A 3 use. It is advantageous to provide the selenium in a unit dose form suitable for addition either to the suspension containing the anthelmintic agent or to water, preferably purified water. Tablets and sachets containing the appropriate amount of a selenium salt are examples of suitable dosage forms. The amounts of selenium to be incorporated can be calculated from the data given above.

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The cobalt salt may be present either as a component of the anthelmintic preparation or as a 5 component of the selenium preparation, or separately.

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Examples of both selenium salts and cobalt salts are given above.

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The anthelmintic agent-containing preparation and the selenium-containing preparation should be provided in conjunction with one another or in close juxtaposition to one another for example, the two should be provided close to hand. Preferably, the two components are joined together, one is attached 10 to the othei, or both are provided in the same container. The selenium containing preparation, for example, tablets or a sachet containing a powder or granules for reconstitution, may be physically attached to the anthelmintic preparation, for example, a pack of bottle of tablets, or a bottle of liquid preparation. The two components may be provided together in a container, for example a box or carton.

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Both components may be solid, both may be liquid, or one may be solid and one may be liquid. As 15 indicated above, liquid forms may be preferred for the anthelmintic preparation, and a pack may comprise a bottle of anthelmintic suspension together with a bottle of selenium-containing preparation or a solid selenium preparation, for example, tablets or one or more sachets of powder or granules for reconstitution. Other preparation forms may be provided analogously.

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The two preparations should be accompanied by instructions regarding their use. The instructions 20 should indicate that the two preparations should be administered simultaneously or substantially simultaneously, with the selenium component preferably being administered immediately after the anthelmintic component.

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The instructions should indicate that the selenium component can be added to the anthelmintic component, if this is appropriate. The selenium component can be administered separately, the. 25 appropriate dose of both components should be indicated. It may be convenient to provide the selenium component in units suitable for reconstitution in a predetermined amount of either water or anthelmintic suspension. The user may then decide whether to add the selenium component to the anthelmintic preparation, or to make it up with water and use it separately.

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The present invention also provides a method of treating a ruminant comprising administering to 30 the ruminant a preparation of the invention. When the ruminant is a sheep or a goat, the anthelmintic agent is preferably administered in an amount of from 100 to 400 mg/50 mg body weight of the ruminant and the selenium salt is preferably administered in an amount, calculated as elemental selenium, of 1 to 20 mg/50 mg body weight of the ruminant.

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When the ruminants are cattle, the anthelmintic agent is preferably administered to the cattle in 35 an amount of from 150 to 1500 mg/100 kg body weight of the cattle; and the selenium sit is preferably administered to the cattle in an amount, calculated as elemental selenium of 0.75 to 18.75 mg/1 O0 kg body weight of the cattle.

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The preparation may be ready for administration for example, a suspension or tablet, or the preparation may be produced from a pack of the invention. 40 The present invention further provides a method of treating a ruminant, which comprises administering to the ruminant simultaneously or substantially simultaneously an anthelmintic agent as defined herein and a selenium salt as defined herein. The amounts of the anthelmintic agent and of the selenium salt to be administered are preferably as defined above.

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The recom mended treatment times for sheep with a preparation of the invention are as follows: 45 Ewes: in the period within 4m6 weeks of lambing. In addition, further treatments may be given approximately 4m6 weeks after lambing and prior to service--the former to assist in reduction of pasture larval contamination and the latter to improve bodily condition and, therefore, conception rate. Such additional treatments by providing cobalt and selenium will aid in body condition maintenance and improve fertility. 50 Lambs: at 4--6 weeks of age and monthly thereafter to maintain optimal growth rate. Treatments may have to be more frequent in areas where Nematodirus infection occurs.

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Brought-in treat on arrival and thereafter as for ewes/lambs, but particularly (as with all sheep) when Sheep: moving to clean pasture.

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Treatment of cattle could be carried out as follows: 55 Calves in their first grazing season: in a set stocked system, dose at 3 and 6 weeks post turnout and again at housing. Alternatively, dose and move to clean pasture in mid- summer, and dose again at housing.

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Cattle in subsequent grazing seasons: dose prior to movement to clean pasture and at housing.

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Cows: dose prior to calving. 60 As indicated above, we have found, surprisingly, that the safety margin for selenium administration is increased greatly when the selenium is combined with an anthelmintic agent, particularly fenbendazole. The LDso of elemental selenium per os in sheep is considered to be 0.5 mg/kg (W. M. Allen, Institute for Research on Animal Diseases, Compton), where as we have found that administration of oral dose levels of elemental selenium of up to 2.0 mg/kg were tolerated, no signs of 65 4 GB 2 117 241 A 4 drug toxicity being observed in any of the treated animals. This decrease in toxicity was quite unexpected, and we believe that there is a safety margin of at least 25 times the recommended dose of the preparation of the invention. This is of considerable practical importance, as there is risk of killing livestock by administering an overdose of selenium using trace element preparations currently available, whereas it is virtually impossible to administer a fatal dose of selenium using a preparation of the 5 present invention, the following Examples illustrate the invention.

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The anthelmintic agents denoted by their generic names are as follows.

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Fenbendazol: 5-Phenyl-thio-2-benzimidazolecarbamic acid methylester Oxfendazol: 5-Phenylsulfinyl-2-benzimidazolecarbamic acid methylester Albendazol: 5-Propyl-thio-2-benzimidazolecarbamic acid methylester 10 Oxibendazol: 5-Propoxy-2-benzimidazolecarbamic acid methylester Parbendazol: 5-Butyl-2-benzimidazolecarbamic acid methylester Mebendazol: 5-Benzoyl-2-benzimidazolecarbamic acid methylester Flubendazol: 5-(4-Fluorobenzoyl)-2-benzimidazolecarbamic acid methylester Cambendazol: 2-(4-Thiazolyl)-5-benzimidazolecarbamic acid isopropylester 15 Thiabendazol: 2-(4-Thiazolyl)-benzimidazole EXAMPLE 1 .DTD:

Composition per ml Fenbendazole 25.000 mg Colloidal silicon dioxide Sodium methylhyroxybenzoate Sodium.pro.pylh.ydroxybenzoate 30.000 mg 20 Sodium carboxymethyl cellulose 1.994 mg Polyvinylpyrrolidone 0.216 mg Sodium citrate 14.506 mg 19.342 mg 31.350 mg 25 Citric acid 31.250 mg Cobalt sulphate hepthydrate 4.500 mg Sodium selenate decahydrate 60% w/w solution 3.167 mg Purified water to 1.0 ml Procedure A mixing vessel was charged with water that had been filtered through a 0. 45 m filter. The following ingredients were added, with mixing to disperse them: citric acid, sodium citrate, cobalt sulphate, sodium selenate solution, sodium methylhydroxybenzoate, sodium propylhydroxybenzoate and colloidal silicon dioxide. The following ingredients were added via an in-line homogenisation unit: 35 sodium carboxymethyl cellulose, polyvinylpyrrolidone and fenbendazole. Circuiation through the in-line homogeniser was oontinued until a uniform dispersion was achieved. The pH was checked and adjusted to 5.9 with citric acid if necessary. The resulting pink suspension was felled into 2 litre containers.

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This suspension contains 0.4 mg/ml elemental selenium and 0.904 mg/ml elemental cobalt.

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EXAMPLE 2 40 .DTD:

Determination of efficacy and toxicity levels MATERIALS AND METHODS:

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Animals: Twenty, six to eight month old lambs were made available for the purpose of this investigation. The lambs were allocated to five groups (n = 4) on the basis of mean faecal egg counts determined on each of three successive days. 45 Prior to treatment, all lambs were weighed. Lambs were maintained at grass as a single group for the duration of the study.

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= GB 2 117 241 A 5 TREATMENTS:

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Group 1: Untreated controls Group 2: Treated with 5 mg/kg fenbendazole as Panacur 2.5% Suspension (Commercial batch, "'Panacur", is a Trade Mark) Composition of Panacur 2.5%: as described in Example 1 with the omission of the selenium and cobalt components.

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Group 3: Treated with 5 mg/kg fenbendazole as a developmental formulation (see below) Group 4: Treated with 25 mg/kg fenbendazole as a developmental formulation (see below) Group 5: Treated with 50 mg/kg fenbendazole as a developmental formulation (see below) All treatments were administered per os.

DEVELOPMENT FORMULATION Procedure: As described in Example 1 Composition per ml:

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Fenbendazole Colloidal silicon dioxide Sodium methylhyroxybenzoate Sodium propylhydroxybenzoate Sodium carboxymethyl cellulose Polyvinylpyrrolidone Sodium citrate Citric acid Cobalt sulphate hepthydrate Sodium selenate decahydrate Purified water 25.000 mg 30.000 mg 1.994 mg 0.216 mg 14.506 mg 19.542 mg 31.590 mg 31.350 mg 4.500 mg 4.700 mg to 1.000 ml Groups 4 and 5 thus received five and ten times respectively the recommended dose of fenbendazole and cobalt, and 12.5 and 25 times respectively the recommended dose of selonium.

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Parasitological examinations:

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Faecal egg counts were performed using the modified McMaster technique on samples taken directly from the rectum of lambs pre-treatment and at seven, eleven, eighteen and twenty five days post 30 treatment.

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Groups 1,2 and 3 were slaughtered at eleven days post treatment and postmortem examinations carried out. The abomasum, small intestine and large intestine of each animal were removed and the contents collected. The abomasal mucosa was digested in a pepsin/hydrochloric acid mixture for six hours. Numbers of helminth species present were calculated from aliquot samples of the organ contents 35 (abomasal digests being examined in toto).

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Clinical examinations:

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Clinical examinations were carried out on all lambs daily post treatment for the duration of the s;(udy.

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RESULTS: 40 No signs of drug-associated toxicity were noted in any of the treated animals.

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Faecal egg counts of all lambs are given in Table 1. Treatment with the commercially available or experimental formulations virtually eliminated faecal egg excretions.

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Worm counts obtained from lambs in Groups 1--3 at slaughter are recorded in Table I1.

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A mixed nematode burden was present in the untreated lambs--Haemonchus, Ostertagia and 45 6 GB 2 117 241 A 6 Trichostrongylus spp. being present in the abomasum; Cooperia, Nematodirus and Trichostrongylus spp. in the small intestine and Chabertia and Trichuris spp. in the large intestine.

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Treatment with both formulations virtually eliminated nematode burdens, there being no significant difference in efficacy between the two formulations.

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CONCLUSIONS: 5 .DTD:

1. Inclusion of the trace elements, cobalt and selenium, in Panacur 2.5% Suspension had no deleterious effect on anthelmintic efficacy.

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2. Oral dose levels of up to 1.9 mg/kg of elemental cobalt (as CoSo34. 7H=O) and 2.0 mg/kg of elemental selenium (as Na2SO4.10H20) were tolerated, no signs of drug toxicitybeing noted in any of the treated lambs. 10 G6 2 117 241 A Group TABLE 1 .DTD:

Mean Trichostrongylid egg counts in lambs pre and post treatment Lamb Weight No. (KG) 844 32.0 --3 1500 Faecaleggcont(epg)onTreatmentday --2 -1 ' +7 +11 --18 2400 1950, 2150 2350 +25 822 36.0 350 900 800 400 866 26.5 650 1900 350 650 400 812 32.0 t NIL NIL NIL I 870 823 856 880 35.0 250 350 650 NIL NIL 33.0 700 350 1000 NIL NIL 32.0 1500 1650 1300 NIL NIL 38.0 1250 700 1100 NIL NIL i 1 i i 851 27.0 1050 878 28.0 350 826 32.5 750 2 28.5 650 I 1100 1650 NIL 500! 2000! 50 600 750 NIL 650 1050 NIL I I I 835 29.5 550 650 843 31.0 700 800 824 34.5 700 1000 892 i 33.0 NIL NIL 450 NIL 1650 NIL 1050 NIL NIL NIL NIL NIL NIL NIL NIL NIL NIL t NIL NIL NIL NIL NIL NIL NIL NIL 889 23.5 NIL NIL 896 33.5 NIL NIL 814 32.0 NIL NIL 811 25.0 NIL NIL, + Groups 1--3 slaughtered at day 11 post treatment.

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Group 5 lamps served for safety evaluation only.

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NIL NIL NIL NIL NIL NIL NIL NIL NIL NIL NIL NIL t NIL NIL NIL NIL NIL NIL NIL NIL I" I 8 GB 2 117 241 A 8 Groups Lamb No.

TABLE II .DTD:

Total Worm Counts at Post Mortems of Groups 1--3 No. of Worms Recovered ABOMASUM Early Adult/ SMALL Larval Stages Dev. Stages INTESTINE I I! I I LARGE INTESTINE 844 822 866 812 F MEAN 82 19,400 38 1,860 16,700 0 i 150 11,900 690 5,300 i 380 320 36 9,528 4,568 103 870 823 856 1 0 0 0 0 0 0 0 0 0 0 0 880 0 I I MEAN 0.3 I I I I 0 0 0 i 0 0 0 % reduction compared to controls i 99.2 100 100 100 1 I I 851 0 0 130 0 878 0 0 0 0 826 0 0 110 0 2 0 0 MEAN % reduction compared to controls 0 0 r 0 I" 98.7 100 J 9 GB 2 117 241 A 9 EXAMPLE 3 .DTD:

Composition per millilitre Fenbendazole Fumed silicon dioxide Sodium methylhyroxybenzoate Sodium propylhydroxylbenzoate Sodium carboxymethyl cellulose Polyvinylpyrrollidone (PVP) Sodium Citrate BP Citric Acid BP Cobalt Sulphate.7H20 Sodium Selenate.10 H20 Purified Water Procedure 100.000 mg 30.000 mg 1.883 mg 0.205 mg 13.720 mg 18.294 mg 29.837 mg 1. 649 mg 11.925 mg 9.349 mg 880.000 mg A 2,500 1 mixing vessel was charged with water filtered through a 0.45 filter. The following 15 ingredients were added in order, with mixing to disperse them: citric acid, sodiumcitrate, cobalt sulphate, sodium selenate solution, sodium methylhydroxybenzoate, sodium propylhydroxybenzoate and colloidal silicon dioxide.

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The following ingredients were added via the in-line homogenisation unit: sodium carboxymethylcellulose, polyvinylpyrrolidone and fenbendazole. Circulation through the in-line 20 homogeniser was continued until a uniform dispersion was achieved.The pH was checked and adjusted to 5.9 with citric acid if necessary. The resulting pink suspension was filled into 2 litre containers.

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Each millilitre of this suspension contains 2.0 mg elemental selenium and 2.5 mg elemental cobalt.

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This suspension is suitable for cattle. The suggested dose is 7.5 ml per 1 O0 kg body weight. 25 EXAMPLE 4 .DTD:

Composition per ml Albendazole Colloidal silicon dioxide Sodium methylhydroxybenzoate 25.000 mg 30.000 mg 1.994 mg Sodium propylhydroxybenzoate Sodium carboxymethyl cellulose 0.216 mg 14.506 mg Polyvinylpyrrolidone 19.342 mg Sodium citrate Citric acid Cobalt sulphate. 7H20 Sodium selenate. 10H20 31.590 mg 31.350 mg 4.500 mg 3.167 mg Purified water to 1.0 ml GB 2 117 241 A 10 Procedure The preparation was made up by a procedure analogous to that described in Example 3.

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Each ml of suspension contains 0.4 mg of elemental selenium and 0.94 mg of elemental cobalt. This suspension is suitable for administration to sheep or goats. The suggested dose is 1 ml per 5 kg body weight.

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EXAMPLE 5 .DTD:

Procedure Composition per ml Albendazole Fumed silicon dioxide Sodium methylhydroxybenzoate Sodium propylhydroxybenzoate Sodium c arboxymethyl cellulose Polyvinylpyrrolidone (PVP) Sodium citrate BP Citric acid BP Cobalt sulphate. 7H20 Sodium selenate. 10H20 Purified water 100.000 mg 30.000 mg 1.883 mg 0.205 mg 13.720 mg 18.294 mg 29.837 mg 1. 649 mg 11.925 mg 9.349 mg 880.000 mg The composition was made up using a procedure analogous to that described in Example 3. Each millilitre of suspension contains 2.0 mg of elemental selenium and 2,5 mg of elemental cobalt. This suspension is suitable for administration to cattle. The suggested dose is 7.5 mg per 100 kg body weight.

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EXAMPLE 6 .DTD:

Composition per ml Oxfendazole Colloidal silicon dioxide Sodium methylhydroxybenzoate Sodium propylhydroxybenzoate Sodium carboxymethyl cellulose Polyvinylpyrrolidone Sodium citrate Citric acid Cobalt sulphate. 7H20 Sodium selenate. 10H20 Purified water 22.650 mg 30.000 mg 1.994 mg 0.216 mg 14.506 mg 19.342 mg 31.590 mg 31.350 mg 4.500 mg 3.167 mg to 1.0 ml t 11 GB 2 117 241 A 11 Procedure The above composition was made up using a procedure analogous to that described in Example 3. Each millilitre of this suspension contains 0.4 mg of elemental selenium and 0.94 mg of elemental cobalt, and is suitable for administration to sheep or goats. The suggested dose is 1 ml per 5 kg body weight.

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EXAMPLE 7 .DTD:

Procedure Composition per millilitre Oxfendazole Fumed silicon dioxide Sodium methylhydroxybenzoate Sodium propylhydroxybenzoate Sodium carboxymethyl cellulose Polyvinylpyrrolidone (PVP) Sodium citrate BP Citric acid BP Cobalt sulphate. 7H20 Sodium selenate. 10H20 Purified water 90.600 mg 30.000 mg 1.883 mg 0.205 mg 13.720 mg 18.294 mg 29.837 mg 1.649 mg 17,887 mg 14.023 mg 880,000 mg The above composition was made up using a procedure analogous to that described in Example 3. Each miililitre of this suspension contains 3.0 mg of elemental selenium and 3.75 mg of elemental cobalt. The suspension is suitable for administration to cattle, and the recommended dose is 5 ml per 1 O0 kg body weight.

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EXAMPLE 8 .DTD:

Composition per millilitre Fenbendazole Fumed silicon dioxide Sodium methylhydroxybenzoate Sodium propylhydroxybenzoate Sodium carboxymethyl cellulose Polyvinylpyrrollidone Sodium citrate Citric acid Cobalt sulphate. 7H20 Sodium selenate. 5H20 Purified water to 100.000 mg 30.000 mg 1.883 mg 0.205 mg 13.720 mg 18.294 mg 29.837 mg 1. 649 mg 11.925 mg 6.662 mg 100.000 mg 12 GB 2 117 241A 12 i Procedure The preparation was made up by a procedure analogous to that described in Example 3. Each millilitre of suspension contains 2.0 mg of elemental selenium and 2.5 mg of elemental cobalt. The suspension is suitable for administration to cattle at a recommended dose of 7.5 mg p'er 100 kg body weight.

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EXAMPLE 9 (A) The preparation of Example 1 was made up, omitting the selenium and cobalt components, which were replaced by the equivalent weight of purified water. The resulting suspension was filled into 2 litre bottles. Sachets were prepared, each containing 4.5 g of cobalt sulphate. 7H20 and 3.i 7 g of sodium selenate 10HO. The bottles and sachets were packaged into boxes at the rate of one bottle 10 and two sachets per box, together with instructions.

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(a) to mix the contents of one sachet with one litre of suspension before administration to sheep at a recommended dose of 1 ml per 5 kg body weight, or (b) to mix the contents of each sachet with 1 litre of water, preferably purified water, and to administer the resulting preparation to sheep substantially simultaneously with the anthelmintic 15 suspension, each being administered at a recommended dose of I ml per 5 kg body weight. The selenium/cobalt preparation is preferably administered after the anthelmintic preparation. The contents of the sachet may be made up in a different volume of water, if this is more convenient. The recommended dose should then be calculated pro rata.

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(B) The preparation of Example 6 was made up analogously to the procedure described in (A) 20 above, i.e. omitting the selenium and cobalt components, which were packaged into sachets as described in (A). The anthelmintic suspension was filled into 5 litre bottles, and bottles and sachets were packaged into boxes at the rate of one bottle and 5 sachets per box. Instructions as set out in (A) were included in each box.

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(C) The preparation of Example 4 was made up as described in (A) above, but only the selenium 25 component of Example 4 was replaced by purified water. Sachets were made up as described in (A) above, containing 3.17 g of sodium selenate. 10H20. Bottles and sachets were packaged in boxes at the rate of one 2 litre bottle of suspension and two sachets per box. Instructions were included in each box, as specified in (A) above.

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(D) The preparation of Example 1 was made up as described in (A) above, but only the selenium 30 component of Example 1 was replaced by purified water. Sachets were made up as described in (A), containing 3.17 g of sodium selenate. 10H20. Bottles and sachets were packaged into boxes at the rate of one 2 litre bottle of suspension and two sachets per box.. Instructions were included in each box, as specified in (A) above.

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EXAMPLE 10 35 (A) The preparation of Example 3 was made up with the omission of the selenium and cobalt components, which were replaced by the equivalent weight of purified water. The resulting suspension was filled into 5 litre bottles. Sachets were prepared, each containing 11.9 g of cobalt sulphate 7 HzO and 9.3 g of sodium selenate. 10H20. The bottles and sachets were packaged into boxes at the rate of one bottle and five sachets per box, together with instructions to mix the contents of each sachet with 40 either (A) one litre of the anthelmintic suspension or (b) one litre of water, preferably purified water. In the case of (a), the resulting combined preparation is to be administered to cattle at a recommended dose of 7.5 ml per 100 kg body weight. (It is suggested that for convenience, the contents of all five sachets can be admixed with the contents of the 5 litre bottle of suspension). In the case of (b), the instructions point out the requirement for the substantially simultaneous administration of the 45 anthelmintic suspension and the selenium/cobalt preparation, and suggest that the selenium/cobalt preparation is administered immediately after the anthelmintic suspension. The recommended dose for each preparation is 7.5 ml per 100 kg body weight. The instructions also point out that in case (b) the sachets may be made up in a different volume of water, if desired. The recommended dose should then be calculated pro rata. 50 (B) The preparation described in Example 5 was made up as described in (A) above i.e. with the replacement of the selenium and cobalt components by the equivalent weight of purified water. Sachets containing the selenium and cobalt salts were made up as described in (A) above. The anthelmintic suspension, filled into 2 litre bottles, and the sachets were packaged into boxes at the rate of one bottle and two sachets per box, together with instructions as set out in (A) above. 55 (C) The preparation of Example 7 was made up as described in (A) above but with the replacement of the selenium component only by the equivalent weight of purified water, and filled into 5 litre bottles.

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Sachets were prepared, each containing 14.02 g of sodium selenate. 10H20. The bottles and sachets were packaged into boxes at the rate of one bottle and five sachets per box, together with instructions.

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The instructions were as in (A) above except that the recommeded dose of the combined preparation of 60 of one selenium sachet made up in one litre of water is 5 ml per 100 kg body weight.

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13 GB 2 117 241A 13 (D) The preparation of Example 8 was made up as described in (A) above i. e. with the replacement of the selenium and cobalt components with the equivalent weight of purified water, and filled into litre bottles. Sachets were prepared, each containing 6,662 g of sodium selenite. 5 H=O and 11.925 g of cobalt sulphate. 7 H20. The bottles and sachets were packaged into boxes at the rate of one bottle 5 and five sachets per box, together with instructions as specified in (A) above.

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(E) The preparation of Example 3 was made up as described in (A) above but with the replacement of only the selenium component and not the cobalt component by the equivalent weight of purified water, and filled into 5 litre bottles. Sachets were prepared, each containing 9.35 g of sodium selenate 10H20. Sachets and bottles were packaged into boxes at the rate of one bottle and five sachets per 10 box. Instructions as set out in (A) above were also included in each box.

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EXAMPLE 11 .DTD:

The preparation of Example 3 was tested for anthelmintic efficacy in cattle. There was also used a comparative preparation that did not contain selenium or cobalt.

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Comparison preparation:

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Composition per ml.

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Fenbendazole 100.000 mg Fumed silicon dioxide 30.000 mg Sodium methylhydroxybenzoate 1.883 mg Sodium propylhydroxybenzoate 0.205 mg Polyvinylpyrrollidone (PVP) 18.294 mg Sodium Citrate BP 29.837 mg Citric Acid BP 1.649 mg Purified water 901.274 mg 25 The comparison preparation was made up as described in Example 3.

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Method A group of 23 heifers was made available for this study. The cattle had been at grass over the summer and had recently been housed when sampled for allocation to treatment group. Cattle in all three groups were housed in one pen. 30 Faeces samples were collected from all the heifers on two successive days, and were examined for the presence of worm eggs. On the basis of these worm egg counts the heifers were allocated to one of three treatment groups as shown in Table 1.

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On the day after second sampling, the cattle were weighed and treated appropriately as indicated in Table 1. Thereafter, faeces samples were collected from the cattle on days 4, 7 and 17 following 35 treatment.

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Faecal worm egg counts were carried out using the modified McMaster technique.

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Results The nematode eggs observed in the faeces samples were of the strongyle species and the results of faecal egg counts for all the heifers are shown in Table 2. Both anthelmintic preparations were shown 40 to result in elimination of faecal egg excretion.

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Conclusions .DTD:

The inclusion of selenium and cobalt does not affect the anthelmintic efficacy of the preparation of Example 3.

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Sodium carboxymethyl cellulose 13.720 mg 20 14 GB 2 117 241 A 14 Animal L1282 Bl175 Y1252 R1396 Q1342 W1331 L1279 W1307 Y1267 L1246 W1372 L1245 L1271 W1342 Ll184 L1237 W1340 W1336 W1281 L1232 W1339 Number TABLE III .DTD:

Faecal Worm Egg Counts prior to treatment Day --2 Day --1 Weight (kg) X -50 250 400 750 450 550 500 350 300 250 550 400 300 325 550 450 250 150 450 500 450 300 283 233 350 380 40O 420 415 330 330 380 370 400 340 400 370 360 440 650 400 440 250 200 300 450 600 360 -- 380 -- 50 370 300 200 330 257 221 Dose (ml) 271 30, Treatment P reparation of Example 3 Comparative Preparation Controls Untreated GB 2 117 241 A 15 Animal L1282 B1175 Y1252 R 1396 Q1342 W1331 L1279 W1307 Y1267 L 1246 W1372 L1245 L1271 W1342 L1184 L1237 W 1340 W1336 W1281 L1232 W1339 Not sampled Number TABLE IV .DTD:

Faecal Worm Egg Counts following treatments Treatment Day 4 Osy 7 Day 19 Preparation of Example 3 m m Comparative Preparation Controls Untreated m X q 700 450 30O 257 550 450 35O 228 m 55O 300 400 20O 290 16 GB 2 117 241 A 16 EXAMPLE 12 .DTD:

The safety of the composition of Example 3 on oral administration to cattle was investigated:

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A total of 16 cattle were treated orally with the preparation of Example 3. Eight Friesian heifers weighing between 330 and 420 kg were treated with the preparation at the recommended dose bf 7.5 ml per 1 O0 kg body weight. Four Friesian cattle weighing between 930 and 990 kg were treated 5 orally with the preparation at five times the recommended dose i.e. 37.5 ml per 1 O0 kg. A further four Friesen cattle weighing between 870 and 1030 kg were treated orally with the preparation at ten times the recommended dose i.e. 75 mg per 100 kg. Table 1 shows the computed and actual dose administered relative to live weight.

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The cattle were observed daily for a period of 21 days following treatment for any signs at adverse 10 effect.

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Results and Conclusions .DTD:

No signs of adverse toxicity were observed in cattle treated with up to ten times the recommended dose of the formulation.

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Oral administration of up to 20 mg/kg of selenium and 25 mg/kg of cobalt in combination with 75 mg/kg of fenbendazole was carried out in cattle with no adverse effect observed.

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TABLE V .DTD:

Volumes of preparation of Example 3 administered in safety tests Calculated Dose Dose Administered Animal Number Weight (kg) (ml) (ml) L1282 Bl175 350 26.2 380 28.5 Y1252 400 30.0 30 R1396 420 31.5 32 Q1342 415 31.1 31 W1331 330 24.8 L1279 330 24.8 26 W1307 380 28.5 28 990 372 950 357 930 349 930 349 870 1 O30 960 925 652 774 721 695 380 360 36O 360 660 780 720 700 17 GB 2 117 241 A 17 .CLME:

Claims (1)

1. CLAIMS .CLME:

   1. A veterinary preparation which comprises an anthelmintic agent and a selenium salt.

   .CLME:

   2. A veterinary preparation as claimed in claim 1, wherein the anthelmintic agent and the selenium salt are in admixture or conjunction.

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   3. A veterinary preparation as claimed in claim 1 or claim 2, which also comprises a carrier 5 suitable for use in a veterinary preparation, 4. A veterinary preparation as claimed in any one of claims 1 to 3, which also comprises a cobalt salt.

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   5. A veterinary preparation as claimed in any one of claims 1 to 4, wherein the anthelmintic agent is a benzimidazole anthelmintic agent. 10 6, A veterinary preparation as c!aimed in claim 5, wherein the anthelmintic agent is fenbendazole.

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   7. A veterinary preparation as claimed in claim 5, wherein the anthelmintic agent is albendazole.

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   8. A veterinary preparation as claimed in claim 5, wherein the anthelmintic agent is oxfendazole.

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   9. A veterinary preparation as claimed in claim 5, wherein the anthelmintic agent is thiabendazole, parbendazole, cambendazole, oxibendazole, mebendazole or flubendazole. 15 10. A veterinary preparation as claimed in any one of claims 1 to 9, wherein the selenium salt is soluble.

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   11. A veterinary preparation as claimed in claim 10, wherein the selenium salt is an alkali metal salt or an ammonium salt.

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   12. A veterinary preparation as claimed in any one of claims 1 to 11, wherein the selenium salt is 20 a selenate, selenite or selenide.

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   13. A veterinary preparation as claimed in claim 12, wherein the selenium salt is sodium selenate.

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   14. A veterinary preparation as claimed in any one of claims 4 to 13 wherein the cobalt salt is soluble.

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   15. A veterinary preparation as claimed in any one of claims 4 to 13, wherein the cobalt salt is 25 cobalt chloride, nitrate, carbonate or sulphate.

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   16. A veterinary preparation as claimed in any one of claims 1 to 15, in solid form.

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   17. A veterinary preparation as claimed in claim 16, in the form of a tablet, a bolus, or a paste.

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   18. A veterinary preparation as claimed in claim 16, in the form of a powder or granules for reconstitutlon as a solution or suspension prior to use. 30 19. A veterinary preparation as claimed in any one of claims 1 to 15, in liquid form.

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   20. A veterinary preparation as claimed in claim 19, in the form of a solution.

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   21. A veterinary preparation as claimed in claim 19, in the form of a suspension.

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   22. A veterinary preparation as claimed in any one of claims 1 to 21, which also comprises one or more further physiologically active substance(s). 35 23. A veterinary preparation as claimed in claim 18 or claim 21, which comprises one or more ingredients selected from thickening agent, and agents for retarding sedimentation and agents for aiding resuspension of the suspension per se or of a suspension after reconstitution from a powder or granules.

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   24. A veterinary preparation as claimed in any one of claims 1 to 23, wherein the anthelmintic 40 agent is present in an excess by weight, calculated on the weight of elemental selenium.

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   25. A veterinary preparation as claimed in claim 24, wherein the anthelmintic agent and the selenium component are present in a weight ratio of at least 3:1, the selenium being calculated as elemental selenium.

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   26. A veterinary preparation as claimed in any one of claims 1 to 25, for sheep and goats, wherein 45 the anthelmintic agent is present in an amount of from 100 to 400 parts by weight; and wherein the selenium salt is present in an amount, calculated as elemental selenium, of 1 to 20 parts by weight.

   .CLME:

   27. A preparation as claimed in claim 26, which comprises a cobalt salt, wherein the cobalt salt is present in an amount, calculated as elemental cobalt, of 1 to 50 parts by weight.

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   28. A veterinary preparation as claimed in any one of claims 1 to 25 for cattle, wherein the 50 anthelmintic agent is present in an amount of from 150 to 1500 parts by weight; and wherein the selenium salt is present in an amount, calculated as elemental selenium, of 0.75 to 18.75 parts by weight.

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   29. A preparation as claimed in claim 28, which comprises a cobalt salt, wherein the cobalt salt is present in an amount, calculated as elemental cobalt, of 0.75 to 37.5 parts by weight. 55 30. A preparation as claimed in any one of claims 1 to 29, in a form suitable for incorporation with an animal feedstuff.

   .CLME:

   31. An animal feedstuff which comprises an anthelmintic agent, a selenium salt and, optionally, a cobalt salt.

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   32. An animal feedstuff as claimed in claim 31, wherein the anthelmintic agent is as defined in any 60 one of claims 5 to 9, the selenium salt is as defined in any one of claims 10 to 13, and the optional cobalt salt is as defined in claim 14 or claim 15.

   .CLME:

   33. A veterinary pack comprising an anthelmintic agent and a selenium salt, the anthelmintic agent and the selenium salt being separately packaged.

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   34. A veterinary pack as claimed in claim 33, additionally comprising a cobalt salt. 65 18 GB 2 117 241A 18 J 35. A pack as claimed in claim 33 or claim 34, wherein the anthelmintic agent is as defined in any one of claims 5 to 9.

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   36. A pack as claimed in any one of claims 33 to 35, wherein the anthelmintic agent is in the form of a veterinary preparation as defined in any one of claims 16 to 21.

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   37. A pack as claimed in any one of claims 33 to 36, wherein the selenium salt is as defined in any 5 one of claims 10 to 13.

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   38. A pack as claimed in any one of claims 33 to 37, wherein the selenium salt is in the form of a veterinary preparation as defined in any one of claims 16 to 21.

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   39. A pack as claimed in any one of claims 34 to 38, wherein the cobalt salt is as defined in claim 14orclaim 15. 10 40. A veterinary pack as claimed in any one of claims 33 to 39, for sheep or goats, wherein the anthelmintic agent is present in the pack in an amount of from 100 to 400 parts by weight; and wherein the selenium salt is present in the pack in an amount, calculated as elemental selenium, of 1 to 20 parts by weight.

   .CLME:

   41. A veterinary pack as claimed in claim 40, which comprises a cobalt salt, wherein the cobalt 15 salt is present in the pack in an amount, calculated as elemental cobalt, of 1 to 50 parts by weight.

   .CLME:

   42. A veterinary pack as claimed in any one of claims 33 to 39, for cattle, wherein the anthelmintic agent is present in the pack in an amount of from 150 to 1500 parts by weight; and wherein the selenium salt is present in the pack in an amount, calculated as elemental selenium, of 0.75 to 18.75 parts by weight. 20 43. A veterinary pack as claimed in claim 42, which comprises a cobalt salt, wherein the cobalt salt is present in the pack in an amount, calculated as elemental cobalt, of 0.75 to 37.5 by weight.

   .CLME:

   44. A pack as claimed in any one of claims 33 to 43, wherein the anthelmintic package and the selenium package are joined together, or one is attached to the other, or both are provided in the same container. 25 45. A pack as claimed in any one of claims 33 to 34, which also comprises instructions that require the administration of the anthelmintic component and the selenium component simultaneously or substantially simultaneously.

   .CLME:

   46. A pack as claimed in claim 45, wherein the instructions require the administration of the selenium component immediately after the anthelmintic component when the two components are not 30 administered simultaneously.

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   47. A pack as claimed in claim 45, wherein the instructions require the admixture of the anthelmintic component and the selenium component.

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   48. A pack as claimed in'any one of claims 33 to 47, wherein the selenium salt is in unit dosage form suitable for admixture with a unit dose of the anthelmintic agent. 35 49. A veterinary preparation as claimed in claim 1, substantially as described in any one of Examples 1,3, and 4 to 8 herein.

   .CLME:

   50. A pack as claimed in claim 33, substantially as described in Example 9 or Example 10 herein.

   .CLME:

   51. A method of treating a ruminant comprising administering to the ruminant a preparation as claimed in any one of claims 1 to 29 or claim 49. 40 52. A method as claimed in claim 51, wherein the ruminant is a sheep or a goat, and wherein the anthelmintic agent is administed in an amount of from 100 to 400 mg/50 body weight of the ruminant and wherein the selenium salt is administered in an amount, calculated as elemental selenium, of 1 to rag/50 body weight of the ruminant.

   .CLME:

   53. A method as claimed in claim 51, wherein the ruminant is cattle and wherein the anthelmintic 45 agent is administered to the cattle in an amount of from 150 to 1500 mg/100 kg body weight of the cattle; and the selenium salt is adminstered to the cattle in an amount, calculated as elemental selenium, of 0.75 to 18.75 mg/100 kg body weight of the cattle.

   .CLME:

   54. A method as claimed in claim 51, wherein the preparation is produced from a pack as claimed in any one of claims 33 to 48 or claim 50. 50 55. A method of treating a ruminant, which comprises administering to the ruminant simultaneously or substantially simultaneously an anthelmintic agent as defined in claim 10 or in any one of claims 5 to 9 and a selenium salt as defined in claim 1 or any one of claims 10 to 13.

   .CLME:

   56. A method as claimed in claim 55, wherein the ruminant is a sheep or a goat and the amounts of anthelmintic agent and selenium salt administered are as defined in claim 52. 55 57. A method as claimed in claim 55, wherein the ruminant is cattle, and the amounts of anthelmintic agent and selenium salt administered are as defined in claim 53.

   .CLME:

   Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1983. Published by the Patent Office, Southampton Buildings, London, WC2A lAY0 from which copies may be obtained.

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