AU691990B2 - Equine anthelmintic formulations - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

TO BE COMPLETED BY APPLICANT Name of Applicant: VIRBAC SA.

Actual Inventor(s): Vincent Beuvry and Michael Forster Address for Service: Barker Blenkinship Associates Patent Attorneys PO Box 34, CHATSWOOD NSW 2067 "Invention Title: EQUINE ANTHELMINTIC FORMULATIONS Details of Associated Provisional Application Nos: PM9699 28 November 1994 The following statement is a full description of this invention, including the best method of performing it known to me:-

IA

EQUINE ANTHELMINTIC FORMULATIONS The present invention relates to a formulation for the control of parasitic infestations in Equidae and in particular to a formulation for simultaneous treatment of roundworms and tapeworms.

Avermectins and Milbemycins are currently used in the treatment and control of roundworms and bots in horses and ponies although these compositions are known to be inactive against tapeworms. The widespread use of the anthelmintic Ivermectin has recently been linked with a rise in the prevalence of the equine tapeworm Anoplocephala Peifoliata.

Anoplocephala Peifoliata is found mainly in the caecum but tends also to cluster in the ileum near the ileocecal valve where it is associated with ulceration and reactive inflammation of the ileal wall. This clustering results in ulceration of the mucous membrane and inflammation with thickening and induration of the deeper layers of the intestinal wall. These pathological changes probably account for some cases of persistent diarrhoea and may predispose to intussusception of the ileum into the caecum or rupture of the bowel wall in the vicinity of the ileocecal valve.

It is therefore desirable to prepare a formulation which has activity against cestodes and nematodes infestation in horses. It is accordingly an object of the present invention to provide a novel veterinary formulation adapted to control both cestodes and nematodes in equine animals.

According to the present invention there is provided an anthelmintic composition for equine use comprising Praziquantel in combination with a second active chosen from a group comprising Avermectins and Milbemycins.

Ld R~Pll~mrma~i~a~r~ass 2 Trials have indicated that Praziquantel in combination with an Avermectin or a IVMbemycin has been administered with a surprising increase of the anthelmintic spectrum due to the administration in combination. Furthermore a synergistic effect has been observed to the extend that when in combination with Avermectins or Milbemycins the required dosage rate for Praziquantel in equine animals is between 0.5 and 2.0 mg/kg. This synergistic activity observed was even higher with a paste formula.

It has however been observed that Praziquantel may be administered to equine animals in higher dosage rates without adverse effects and in this regard dosage rates of up to mg/kg of body weight have been tested.

Praziquantel combined with another anthelmintic has already been claimed in the Patent GB 2252730 by Ancare Distributors Limited but these associations are not synergistic and only increase the anthelmintic spectrum in sheep. According to Ancare Distributors Limited associations the recommended dose rate ofPraziquant"l is between 2.0 and 7.5 mg/kg.

According to the present invention, it has been ,,,overed that the association between Praziquantel and an Avermectin or a Milbemycin shows a surprising synergy in the treatment of horse tapeworms It allowed the use of Praziquantel against Anoplocephala Peifoliata at a dose rate between 0.5 and 2.0 mg/kg. These dosages are significantly lower than in the already described formulations.

Kitano in the Patent EP59074 claims associations of macrolide anthelmintic agents and a variety of several anthelmithic agents like benzimidazole, salicylamide and isoquinoline compounds with enhanced anthelmintic activity. However Kitano studies on Cestodes did not show any evident synergy of any association on Anoplocephala Perfoliala.

According to the present invention, the activity of Praziquantel against Anoploce)phala Perfoliata is increased in association with an Avermectin or a Milbemycin compound.

Il~b %msBl~m~Lnammsu~oPaarnaanraa~- Moreover, the association exhibits higher synergistic activity as a paste formula which allowed a better biodisponibility of Praziquantel in horses.

Praziquantel (2(Cyclohexylcarbonyl)-1,2,3,6,7, 1 b-hexahydro-4H-pyrazino iso quinolin -4-one) is a relatively insoluble material in water and consequently the applicant has devised formulations for administration of the compound subject of this invention in the form of paste, drench, tablet or pellet.

Examples of formulations in accordance with the present invention will be described hereafter without limiting the generality of the invention as above described.

The range of active percentages of a typical formula in accordance with this invention could be as indicated thereunder: Praziquantel 0.1-30% w/v c r and Ivermectin or Abamectin 0.05-5% w/v 0.05-5% w/v Moxidectin or 0.05-5% w/v Doramectin and one or more of the following the composition: 0.05-5% w/v ingredients to enhance stability and/or other characteristics of Surfactants Preservative Viscosity agents Stabilisers Flavours/Colours Iverrmectin is a semnisynthetic derivative of the Avermiectins. Ivermnectin contains at least of 22,23-dihiydroaveriiectin Bla and less than 20% of 22,23-dihydroavermnetin Bilb.

Ivermectin is disclosed in Au~stralian Patent 519569.

Abamectin or Avermectin B I contains at least 80% of Avermectin B I a and not mnore than 20% of Avermectin Bib. Abamnectin is disclosed in Au~stralian Patent 513641.

Moxidectin [spiro (I1,5-methano-2Hral 3G, 1 7H-furo(4,3,2-pg)(2,6) benzodioxacyclo Oct adectin-1 13,2'-(2H)pyran-7-onie,20,20b-dihiydroxy-6' (1 ,3-dirnethlyl-T'-buteny)=4'- (met hoxyi no)-3 4'5 7, 10,11,14,15,1 7a, 20,20a, 20b-tetradecahydro-5 '6,8,1 9teramethyl-(6R-(2aZ,4E, 5' SE, 1 13S*, I5R"', I7aR*,20R*,20bS*)] is a new broad spectrumn endectocide.

Dorarnectin 25-cyclohexyl-5-O-demethiyl-25-de- 1(nmethiylpropyl)avermectin Ala is an Avermectin.

EXAMPLE I ABAMYECTIN-PRAZIQUANTEL PASTE FOR HORSES ABAMECTIN (AVERMECTIN BI1) 0.4g PRAZIQUANTEL 50 g DIETHYLENE GLYCOL PALMITO STEARATE 80 g SODIUM METABISULFITE Ig SORBITOL SOLUTION (NON-CRYSTALLISING) 120 g GLYCEROL FORMAL 60 ml POLYETHYLENE GLYCOL 400 60 ml METHYL HYDROXYBENZOATE 0.5 g PROPYL HYDROXYBENZOATE 0.05 g BENZYL ALCOH-OL log OAT MEAL FLOUR 300 g PURIFIED WATER q.s. to I litre, D~Br~-~I~ZIII~D~L~Y--pua~~ l raul-- The manufacture of the formulations of Example 1 is in accordance with the following procedure: 1. Heat 400 ml of Purified Water in a separate container to 80 degrees 85 degrees Celsius.

2. While mixing, add and dissolve Methyl Hydroxybenzoate and Propyl Hydroxybenzoate.

Continue mixing until all has dissolved.

3. While mixing, add Sorbitol Solution. Maintain the temperature at 70 degrees Celsius.

4. In a separate container, add Glycerol Formal, Polyethylene Glycol 400, Benzyl Alcohol.

Start mixing while warming to 35 degrees 40 degrees Celsius.

While mixing, add Abamectin. Continue mixing until all has dissolved. Maintain Stemperature at 35 degrees 40 degrees Celsius.

6. In the ointment tank, add half of the Oat Flour, the Praziquantel, then start mixing.

on Continue mixing for 5-10 minutes until a homogeneous blended powder is formed. The add the rest of the Oat Flour and continue mixing.

7. While mixing the powders, add the solution from step 5 in a thin stream. When all is added, continue mixing until an homogenous mass is formed.

8. Melt Diethylene Glycol Palmitostearate in a separate container. While mixing the solution form step 3, add the melted wax and continue mixing to form an homogeneous emulsion.

Stop heating and mix to cool to 40 degrees 45 degrees Celsius.

9. Add and dissolve Sodium Metabisulphite in the emulsion.

While mixing the mass from step 7, add gradually and in a thin stream the emulsion from step 9. The emulsion when added should be at 40 degrees 45 degrees Celsius.

11. When all is added, continue mixing for 10-15 minutes.

12. Complete the batch to volume with Purified Water while mixing. Continue mixing for minutes. Stop when the batch temperature is not higher than 30 degrees Celsius. Check on Specific Gravity (1.05 1.09).

I,-g 6 13. Homogenise the batch.

14. Pack in syringes.

Combinations with other Avermectins or Milbemyicn type compounds can be formulated in a manner similar to that of Example 1.

EXAMPLE 2 ABAMECTIN-PRAZIQUANTEL PASTE FOR HORSES We use the ingredients, dosages and manufacturing process of Example 1 except for Abamectin= 2 g instead of 0.4 g.

EXAMPLE 3 ABAMECTIN-PRAZIQUANTEL PASTE FOR HORSES We use the ingredients, dosages and manufacturing process of Example 1 except for Abamectin= 4 g instead of 04 g.

EXAMPLE 4 ABAMECTIN-PRAZIQUANTEL PASTE FOR HORSES We use the ingredients, dosages and manufacturing process of Example 1 except for Abamectin= 8 g instead of 0.4 g.

EXAMPLE 5 ABAMECTIN-PRAZIQUANTEL PASTE FOR HORSES We use the ingredients, dosages and manufacturing process of Example 1 except for S ORSES IVERMECTIN 2 g PRAZIQUANTEL 50 g GLYCEROL FORMAL 250 ml TWEEN 80 120 g BENZYL ALCOHOL 30 g XANTHAM GUM 1 g PURIFIED WATER q.s. to 1 litre ra -r I- Other Avermectins such as Abamectin or Doramectin or Milbemycins such as Moxidectin may be used in place of Ivermectin.

EXAMPLE 7 IVERMECTIN PRAZIQUANTEL ORAL DRENCH FOR

HORSES

We use the ingredients, dosages and manufacturing process of Example 6 except for Ivermectin= 4 g instead of 2 g.

EXAMPLE 8 IVERMECTIN PRAZIQUANTEL ORAL DRENCH FOR

HORSES

We use the ingredients, dosages and manufacturing process of Example 6 except for Ivermectin= 8 g instead of 2 g.

EXAMPLE 9 ABAMECTIN PRAZIQUANTEL TABLET FOR HORSES S 1 Tablet/200 kg body weight per Tablet ABAMECTIN 40 mg PRAZIQUANTEL 200 mg SODIUM STARCH GLYCOLLATE 12 mg HYDROXY PROPYL CELLULOSE 4 mg LACTOSE 178 mg COLLOIDAL SILICON DIOXIDE 4 m; MAGNESIUM STEARATE 2 mg Other Avermectins or Milbemycins can be used instead of Abamectin.

I--

TRIALS

Trials of formulations in accordance with the present invention have been conducted in Australia.

The method of evaluating the activity of the formulation was a modified critical test (Lyons et al. 1986) which involved killing the horses at 24 hours after treatment.

Efficacy is the number of worms count dead and removed versus the number of worms count alive and not removed (scolex attached for Anoplocephala petfoliata).

EXAMPLE 10 TRIAL 1 A trial involving Abamectin paste (lmL per 20 kg of body weight equivalent to 0.2 mg of Abamectin per kg Praziquantel paste (0.1 to 5 mg of Praziquantel per kg of body weight and formulations in accordance with examples 1, 2, 3, 4 and Eleven groups often horses per group were involved in the study. Area of origin of the horses was well known for having internal parasitism problem and specifically tapeworms (Anoplocephala perfoliata) infestation.

A high level of efficacy was demonstrated by the combination formula of Example 2, 3, 4 and I against roundworms, arthropod parasites and tapeworms.

Synergistic activity of Praziquantel and Abamectin shows 100% removal of Anoplocephala perfoliata with 0.2 mg of Abamectin per kg B.W. and 1 mg of Praziquantel per kg B.W.

-I -d~ EFFICACY OF TI-LB FORMULATION OF EXAMPLE 1, 2, 3, 4 and 5 AGAINST NEMATODES, ARTHROPOD PARASITES AND CESTODES IN HORSES IN A CRITICAL TRIAL.

Anthelmintic Dosage Efficacy Efficacy Efficacy Efficacy mg/kg Strongylidae, Gasterophilus spp. Parascaris equoruni Atioplocephala Aba~nectin 0.2 100 100 100 0 Praziquantel -0.1 0 0 0 0 Praziquantel 0.5 0 0 0 27 Praziquantel 1 0 0 0 58 Praziquantel 2 0 0 0 71 *Praziquantel 5 0 0 0 83 Abarnectin 0.2 100 100 100 :Praziquantel 0.1 39 Abarnectin 0.2 100 100 100 Praziquantel 0.5 Abanmectin 0.2 100 100 100 *Praziquiantel 1 100 :Abamnectin 0.2 100 100 100 PraziqUantel 2 0 *Abamnectin 0.2 100 100 100 Praziquantel 5 a EXAMPLE 11 TRIAL 2 A trial involving Ivermectin drench (I mL per 10 kg of body weight equivalent to 0.2 rng of Ivermectin per kg Praziquantel drench. (0.5 to 2 mg of Praziquantel per kg of body weight and formulations in accordance with example 6, 7 and 8.

Seven groups of 6 horses per group were involved in the study. Area of origin of the horses was well known for having internal parasitism problem and specifically tapewormns (A nop/ocephala perfoliata) infestation.

A high level of efficacy was demonstrated by the combination formula of Exmple 7 and 8 against roundworms, arthropod parasites and tapeworms.

Synergistic activity of Praziquantel and Ivermectin shows 100% removal of Anop/ocephala peifoliala with 0.2 mg of Ivermectin per kg B.W. and 2 nig of Praziquantel per kg 13W.

EFFICACY OF THE FORMULATION OF EXAMPLE 6, 7 AND 8 AGAINST NEMATODES, ARTHROPOD PARASITES AND CESTODES IN HORSES IN A CRITICAL TRIAL.

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999 Anthelmintic Dosage Efficacy Efficacy Efficacy Efficacy mg/kg Strongylidae Gasierophi his spp. Parascaris equoriom Anoplocephala _________perfoliala Ivermectin 02100 100 100 0 -Praziquantel 0.5 0 0 0 21 -PraziqUantel 1 0 0 0 43 Praziquantel 2 0 0 0 59 Ivermectin 0.2 100 100 100 Praziquantel 0.5 68 Ivermectin 0.2 100 100 100 -Praziquantel 1 91 Ivermectin 0.2 100 100 100 -Praziquantel 2 100

Claims (9)

1. A methiod br controlling and treating infestations by Anoplocephala perfoliata in equine anirnals comprising orally administering to Wad aniLmals a w3mposition compring a dose of 0.5 to 2.0 nmg of praiuanteI per kilogram of animal body weight togetber Aith an zfffctive dose of an anthelmintic agent selected from avermectins or ,.nycin~ or derivatesthereof~

2. A metbo4 a~rxrding to clam I hereof wherein the anthelmintic agent is an avermectin.

3, A method according to claim 2 hereof wherein the avennectin is sbaniectiz,

4. A method according to clam 2 hereof wherein the anthelinintic agent is ivermectin. A method Eiccording to clam I hereof wherein the authelmintic agent is moxdecin.

S06-04-199 i6t 3 DARIKR BLENKINSHIP GI612407649 p. 12

6. A method in accordance with claim 3 hereof wherein the abamectin is administered at a dose of about 0.2 mg per kilogram of animal body weight:.

7. A method in accordance with claim 4 hereof wherein the ivermectin is administered at a dose of about 0.2 mg per per kilogram of animal body weight.

8, A method in accordance with any one of the preceding claims wherein the composition is administered in the form of a paste.

9# 999 "DATED this 3rd day of April 1998. w 9 a VIRBAC S.A. B by their Patent Attorneys Barker Blenkinship Associates TOTAL P.03 ABSTRACT An equine anthelmintic composition for oral use comprising an effective amount of praziquantel in combination with an effective amount of at least 0 0 one anthelmintic agent selected from a group comprising avermectins or '0o0 rmilbemaycins, 00 0 0*0*S6 06 a 0e 44 4