GB2195081A - Anthelmintic drench - Google Patents

Abstract

An oral drench contains 1.425 to 1.575% w/v levamisole hydrochloride and 0.57 to 0.63% w/v menichlopholan (niclofolan).

Description

SPECIFICATION Anthelmintic composition This invention relates to a veterinary composition having broad spectrum anthelmintic properties.

In particular, the invention relates to an oral drench having broad spectrum anthelmintic properties.

Levamisole hydrochloride (L-(-)-6-phenyl-2,3 ,5,6,-tetrahydroimidazo-[2, 1 -b]thiazole hydrochloride) is a rapidly acting and rapidly excreted anthelmintic which exerts its effects by inducing paralyses (spastic contractions) on susceptible parasites. Levamisole hydrochloride exerts its anthelmintic properties on such parasites as tapeworm segments, Dictyocaulus viviparus (Strongylus micru rus-Hoose-both mature and immature forms), stomach and bowel worms such as Haemonchus, Ostertagia, Trichostrongylus, Oesophagostomum, Chabertia and Bunostomum species.

These parasites, once paralysed are expelled from the animal by coughing or gut movements, as appropriate. Levamisole hydrochloride is absorbed rapidly into the blood stream and is rapidly eliminated from the body. Twenty four hours after oral drenching approximately 90% of levamisole hydrochloride will have been excreted.

Studies carried out have indicated that subcutaneous injection of levamisole hydrochloride is more efficient than oral drenching in cattle, since therapeutic levels are reached more rapidly and approximately 90% of the drug is excreted after five hours following administration of a single dose. However, adverse reactions are more common with subcutaneous injection than with oral drenching. Examples of these reactions are: (i) inflammation at the site of injection; (ii) friskiness in cattle; and (iii) risk of overdosage which can lead to toxicity thus causing muscle tremors, spastic paralysis and/or asphyxia. Partly because of this oral drenching of levamisole hydrochloride has become the more effective form of administration.

Levamisole hydrochloride is sold as a drench under the Trade Mark LEVASOL by Janssen Pharmaceutica. The drench contains levamisole hydrochloride at a concentration of 1.5% and is indicated for the treatment of parasitic gastro-enteritis and lungworm in cattle and sheep.

Recommended dosages are for cattle 25 ml per cwt. body weight. The maximum dosage being 150 ml. In the case of sheep the recommended dosage is 5 ml for sheep up to 33 Ib. in weight; 10 ml for sheep having weights in the range 33-55 Ib.; 15 ml for sheep having weights in the range 55-75 Ib.; 20 ml for sheep of weights over 75 Ib; and 30 ml for sheep over 2,000 Ib in weight.

Menichlopholan or niclofolan (5,5'-dichloro-3,3,-dinitro[l,l'-biphenyl]-2,2'-diol) is an anthelmintic and fasciolicide which is highly effective against mature flukes in the bile ducts of infested ruminants. Menichlopholan exerts its fasciolicidal effect principally by uncoupling oxidative phosphorylation in the parasites. It is presumed that there is a reduction of the 3,3'-nitro groups on the phenyl rings to the corresponding amino groups. The presence of the nitro groups imparts toxicity to the molecule. It is postulated that menichlopholan is excreted into the urine and faeces as a phenolic conjugate of the amino reduction product. Menichlopholan is also eliminated in the milk of lactating cows.

A number of studies have been carried out to determine the effectiveness of menichlophoian as a flukicide. The results are shown in Table 1.

TABLE I EFFECTIVENESS OF MENICHLOPHOLAN AS A FLUKICIDE NAME DOSE STAGE OF GROWTH % EFFECTIVENESS OF FLUKE Lee, O' 5 mg per kg mature fluke High efficiency Nuallain 5 mg per kg and Power immature fluke 40-57% Veterinary Record (up to 100 mm in length) February 5, 1966 Vol. 78 No. 6 5 mg per kg larger immature 53-100% Boray 8 mg per kg 4 weeks old 92.5% Australian Veterinary 8 mg per kg 6 weeks old 99.7% Journal Vol. 43 8 mg per kg 8 weeks old 99.7% July 1967 16 mg per kg 4 weeks old 100% 4 mg per kg 8 weeks old 58.4% 4 mg per kg 12 weeks old 100% Boray and 8 mg per kg 4 weeks old up to 92% (Safety Index 1.5) Happich Australian 6 mg per kg 6 weeks old up to 92% (Safety Index 2.0) Veterinary Journal 2.7 mg per kg 12 weeks old up to 92% (Safety Index. 4.4) Vol. 44 February 1968 KNAPP 6 mg per kg not known 100% American Journal of Veterinary 3 mg per kg not known 100% (one trial) Research Vol. 26 No. 114 3 mg per kg not known 93% (one trial) It will be observed from Table 1 that menichlopholan is principally active against mature flukes.

It is an object of the present to provide an anthelmintic composition having a broad spectrum of activity and which is effective against both immature and mature flukes.

It is a further object of the present invention to provide an anthelmintic composition which has a high level of acceptability and tolerance in ruminant animals.

Accordingly, the invention provides an oral drench having anthelmintic properties, said drench comprising levamisole hydrochloride in an amount of from 1.425 to 1.575% w/v and menichlopholan in an amount of from 0.57 to 0.63% w/v.

The drench preferably has a pH in the range of 3.2 to 4.2.

The oral drench according to the invention is preferably in the form of a suspension.

The oral drench preferably includes one or more suspending agents. Suitable suspending agents include siiica such as that sold under the Trade Mark AEROSIL 200 or polyethelene glycol (Mn 8,000). U.S.P. as sold under the Trade Mark MACROGOL. The use of such suspending agents may necessitate the use of an anti-foaming agent such as poly(dimethylsiloxane) as sold under the Trade Mark SIMETHICONE.

The oral drench according to the invention may also include a surfactant such as TWEEN 20 (polysorbate 20) (TWEEN is a Trade Mark).

The pH of the drench according to the invention is suitably controlled by the use of an organic acid such as citric acid.

Other additives for inclusion in the drench according to the invention include stabilisers such as disodium edetate, sodium phosphate and sodium metabisulphite and colouring agents such as tartrazine (E 102).

The oral drench according to the invention may be administered orally using conventional dosing equipment such as a drenching gun.

The oral drench according to the invention is suitable for use as a broad spectrum anthelmintic which is highly effective against: Fascioliasis (liver fluke) in the bile ducts of cattle and sheep; tapeworm segments in sheep; immature and mature stages of all major stomach and bowel worms, including Haemonchus, Ostertagia, Trichostrongylus species in the abomasum and Trichostrongylus, Oesophagostomum, Chabertia and Bunostomum species in the intestine; and immature and mature stages of Dictyocaulus viviparus in the lungs (Hoose).

The invention will be further illustrated by the following Example.

EXAMPLE An oral drench was prepared from the following ingredients: Ingredient t (w/v) Levamisole HC1. BP. (Vet) 1.50 Menichlopholan 0.60 Citric Acid Ph. Eur Monohydrate 1.380 Disodium Edetate BP 0.020 Sodium Phosphate BP 0.964 Sodium Metabisulphite 0.10 Tartrazine E102 0.0037 Aerosil 200 2.0 Simethicone 0.025 Polyethylene Glycol 8,000 (Macrogol) U.S.P. 0.50 Tween 20 (Polysorbate 20) 1.0 Water q.v. 100 The various ingredients were added to the water with stirring. The levamisole hydrochloride, citric acid, disodium edetate, sodium phosphate, sodium metabisulphite and tartrazine are added first of all in any order. The Aerosil 200, Simethicone and polyethylene glycol are then added and lastly the menichlopholan wetted with Tween 20.

As with the active ingredients levamisole hydrochloride and menichlopholan, the concentration of the other ingredients can vary within + or -5% of the values specified in the above formulation in the oral drench according to the invention.

The oral drench so prepared is suitable for use as a broad spectrum anthelmintic as indicated above. Before dosing each animal the container containing the oral drench must be thoroughly shaken to ensure an even dispersion of the active ingredients. Animal weights must be calculated before dosing commences to ensure the dose per animal is estimated accurately. The effects of over-dosage include lethargy, loseness of faeces, blindness, hyperventilation and collapse. With weak or emaciated animals, animals with severe liver damage or young stock, professional advice should, of course, be sought before dosing. Furthermore, animals should not be dosed with the oral drench according to the invention in the last month of gestation. Cattle, sheep and goats should not be slaughtered for human consumption for forty days after dosing with the oral drench of Example 1.Milk from treated animals should not be used for human consumption for twenty four hours after dosing.

METHOD FOR ANALYSIS OF THE ORAL DRENCH CONTENT: (Nominal) Levamisole HC1. 1.5% w/v Menichlopholan 0.6% w/v PROCEDURE: (a) Levamisole: Measure 25 ml of the suspension accurately with a pipette. It is necessary to wash the pipette as the suspension adheres to the glass walls. The suspension is made alkaline with 2 M NaOH, indicated by the solution turning red. The suspension is then mixed and extracted four times with 25 ml of chloroform. The suspension should not be shaken too vigorously at this stage. The combined chloroform fractions are dried with anhydrous sodium sulphate and 50 ml of glacial acetic acid added to the residue. The resulting solution is titrated with 0.1 M HALO4 (perchloric acid) using 1-naphtholbenzein solution as indicator.The end point is indicated by the solution changing from brown to an emerald green colour. One ml of 0.1 M HALO4 is equivalent to 24.08 mg levamisole hydrochloride. The HALO4 should be standardised with freshly prepared potassium hydrogen phthalate (use 25 ml; 0.05 M) (b) Menichlopholan: 10 ml of the suspension is taken and made alkaline with 2 M NaOH. The suspension is then made up to 100 ml with water. The suspension is diluted 1 in 100 and the absorbance read at 458 nm in a 1 cm cell. The content of menichlopholan is calculated spectrophotometrically by treating an authentic sample in a similar manner, i.e. 60 mg diluted to 100 ml and made alkaline with 2 M NaOH followed by a further 1/100 dilution with water.

Suitable dosages for cattle, sheep and goats are indicated in Table 2.

TABLE 2 LIVEWEIGHT DOSE Cattle: Up to 75 kg (Approx. 1 1/2 cwt) 25 ml 76 - 125 kg (1 1/2 - 2 1/2 cwt) 50 ml 126 - 175 kg (2 1/2 - 3 1/2 cwt) 75 ml 176 - 225 kg (3 1/2 - 4 1/2 cwt) 100 ml 226 - 300 kg (4 1/2 - 6 cwt) 125 ml 301 kg and over 150 ml (6 cwt and over) Sheep Up to 15 kg (Approx. 33 lb) 5 ml 16 - 25 kg (34 - 55 lb) 10 ml and 26 - 35 k.g (56 - 75 lb) 15 ml 36 - 45 kg (76 - 99 lb) 20 ml Goats 46 - 65 kg (100 - 132 lb) 25 ml 66 - 85 kg (133 - 187 lb) 30 ml Very heavy sheep over 85 kg 35 ml FIELD TRIALS Tests were carried out on the oral drench as prepared in Example 1 to evaluate the tolerance and acceptability of the suspension in cattle at the normal dosage and also to observe any evidence of drug induced toxicity at elevated dosage levels.

Sixteen cattle were used in the trial. All were female animals, either Hereford crosses or Fresian crosses. The liveweights varied within the range 295 kg-375 kg.

All animals were suitably restrained in a crush and dosed orally using a drenching gun following the manufacturer's labelled instructions. All animals were individually weighed before dosing. Five animals received the normal therapeutic dosage, six animals received twice the therapeutic dosage, and five animals received three times the normal therapeutic dosage. The normal therapeutic dosage is 1 ml per 2 kg, equivalent to 7.5 mg/kg levamisole hydrochloride and 3 mg/kg menichlopholan.

The animals were observed at set intervals of time over a period of twenty four hours following treatment. The oral drench was shaken to ensure adequate suspension prior to testing each animal.

The results are shown in Table 3.

TABLE 3 FIELD TRIAL RESULTS Observation Times Weight Dose therapeutic + 1 + 2 + 4 + 10 + 12 + 24 + 32 Breed (kg) Volume Dose Hour Hours Hours Hours Hours Hours Hours FR X 300 150 ml 1 X Normal Normal Normal Normal Normal Normal Normal FR X 295 150 ml 1 X Normal Normal Normal Normal Normal Normal Normal H X 370 150 ml 1 X Normal Normal Normal Normal Normal Normal Normal H X 310 150 ml 1 X Normal Normal Normal Normal Normal Normal Normal H X 370 150 ml 1 X Normal Normal Normal Normal Normal Normal Normal H X 335 300 ml 2 X Normal Normal Normal Normal Normal Normal Normal FR X 375 300 ml 2 X Normal Normal Normal Normal Normal Normal Normal FR X 305 300 ml 2 X Normal Normal Normal Normal Normal Normal Normal FR X 335 300 ml 2 X Normal Normal Normal Normal Normal Normal Normal FR X 345 300 ml 2 X Normal Normal Normal Normal Normal Normal Normal FR X 320 300 ml 2 X Normal Normal Normal Normal Normal Normal Normal FR X 320 450 ml 3 X Normal Normal Normal Normal Normal Normal Normal FR X 360 450 ml 3 X Normal Normal Normal Normal Normal Normal Normal FR X 345 450 ml 3 X Normal Normal Normal Normal Normal Normal Normal H X 320 450 ml 3 X Normal Normal Normal Normal Normal Normal Normal H X 335 450 ml 3 X Normal Normal Normal Normal Normal Normal Normal FR X = Fresian cross H X = Hereford cross RESULTS: It was found that the oral drench of Example 1 was extremely well tolerated by all animals, including those which received three times the therapeutic dose. No adverse effects were noted in any of the animals. There was no sign of head shaking, atoxic incoordination or lethargy in any of the animals treated. Specifically, no evidence of departure was observed in any of the treated animals. All animals were observed to be grazing normally.

The oral drench of Example 1 contains 3 mg/kg menichlopholan and has a safety index of 4.0.

As indicated above, the oral drench according to the invention is suitable for use a broad spectrum anthelmintic. It is highly effective against both immature and mature stages of fluke. It is also less toxic than an oral drench containing either levamisole hydrochloride or menichlopholan per se and, accordingly, is more effective therapeutically.

Claims (11)

1. An oral drench having anthelmintic properties, said drench comprising levamisole hydrochloride in an amount of from 1.425 to 1.575% w/v and menichlopholan in an amount of from 0.57 to 0.63% w/v.

2. An oral drench according to Claim 1, which contains 1.5% w/v levamisole hydrochloride and 0.6% w/v menichlopholan.

3. An oral drench according to Claim 1 or 2, which has a pH in the range 3.2 to 4.2.

4. An oral drench according to any one of the preceding claims, which has a pH of 3.7.

5. An oral drench according to any preceding claim, which is in the form of a suspension.

6. An oral drench according to Claim 5, which includes a suspending agent.

7. An oral drench according to Claim 6, wherein the suspending agent is submicroscopic pyrogenic silica made at 1100 C, in an amount of from 1.5 to 2.5% w/v.

8. An oral drench according to Claim 7, which additionally includes as a further suspending agent polyethylene glycol in an amount of from 0.024 to 0.026% w/v.

9. An oral drench according to any one of Claims 6 to 8, which additionally contains one or more additives selected from a defoaming agent, a surfactant, a stabiliser, a flavouring agent and/or a colouring agent.

10. An oral drench according to Claim 1, substantially as hereinbefore described with particular reference to the accompanying Example.

11. Use of an oral drench according to any one of Claims 1-10 in the treatment of helminth infestation in ruminants.