IE920446A1

IE920446A1 - Formulations comprising praziquantel and another anthelmintic

Info

Publication number: IE920446A1
Application number: IE920446A
Authority: IE
Inventors: Colin Manson Harvey
Original assignee: Ancare New Zealand Ltd
Priority date: 1991-02-12
Filing date: 1992-02-11
Publication date: 1992-08-12
Also published as: NZ237086A; NZ247278A; GB9202978D0; IE69667B1; GB2252730B; GB2252730A

Abstract

Anthelmintic compositions containing praziquantel (a pyrazinoisoquinoline derivative; (2(Cyclohexylcarbonyl))- 1,2,3,6,7,-11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one) together with at least one other anthelmintic. Formulations are described containing; (i) praziquantel and levamisole, (ii) praziquantel and albendazole, (iii) praziquantel and oxfendazole, (iv) praziquantel and moxidectin, (v) praziquantel and ivermectin. The avermectin component may be replaced by Milbemycin D, or other milbemycins.

Description

This invention relates to pharmaceutical compositions for the treatment of helminthiasis in warm-blooded animals, more particularly cattle, sheep, goats, and other domesticated herbivores.

BACKGROUND Helminthiasis is a widely occurring disease in farmed animals. It commonly causes clinical disease and has significant adverse economic effects on farming economies when present at subclinical levels. Over the past twenty-five years a number of initially successful anthelmintic agents, with relatively specific effects on the metabolism of smaller or larger groups of endoparasites have been discovered, trialled, and used successfully to control helminthiasis on farms. Various groups of compounds have a greater or lesser spectrum of activity - that is to say they are able to destroy a wider or smaller range of parasite. For example, the widely used ivermectin is active against parasitic roundworms and also against some ectoparasites, yet it is inactive against tapeworms because of a difference in their biochemical constitution. Triclabendazole is active only against the liver fluke Fasciola hepatica.

Unfortunately, resistance to the effects of particular compounds or related families has usually developed with time, after repeated use of the same compound, and has become one of the major problems in the use of these anthelmintic agents. In fact, the growth of drench resistance seems to be overtaking the ability of scientists to develop new drenches. The spread of sheep measles (cysts of the taenia ovis species of tapeworm) is one such problem.

There is a need, therefore, for alternative anthelmintic formulations having the breadth of activity of the benzimidazole drugs (for example) but which slows the advancement of drench resistance.

OBJECT It is an object of this invention to provide novel pharmaceutical compositions having anthelmintic activity. 4734CS3.292 In one aspect the invention shall comprise a composition including an effective amount of the anthelmintic praziquantel together with effective amounts of at least one other anthelmintic.

Preferably the other anthelmintic is selected from the group comprising the avermectins; milbemycins; levamisole; tetraraisole; or a substituted benzimidazole carbamate.

Praziquantel (2(Cyclohexylcarbanyl))-l,2,3,6,7,-llb‘hexahydro-4H-pyrazino[2,la]tsoquinolin-4-one) has for many yean been used to control cestode infestations and schistosomiasis in humans. The siuprising discovery that the efficacy of praziquantel can be enhanced in domesticated animals by simultaneous administration with other anthelmintics has been exploited in the present invention, which offen improved efficacy in the control of cestodes, together with simultaneous control of nematode infestations.

Examples of suitable benzimidazole drugs include drugs such as mebendazole, fenbendazole, oxfendazole, albendazole, cambendazole, parbendazole, oxibendazole, flubendazole and cyclobendazole.

Preferably, in the case of compositions incorporating levamisole, the composition has a pH less than 4.0 and in the most preferred aspect the pH is about 3.0.

Optionally, the composition may contain other veterinary products (including other anthelmintics).

A further aspect is to provide a method for treating helminthiasis in animals with compositions comprising praziquantel and at least one other anthelmintic.

When administered to sheep we prefer to administer the composition as & drench having an effective amount of praziquantel in the range of 4 to 4 mg/kg of body weight.

Since praziquantel is a relatively insoluble material, we have devised formulations for administration in the form of drenches and examples are included in this specification.

We have previously found that combining benzimidazole drenches with levamisole drenches results in an unstable product due to the different pH values needed to maintain -3 the stability of the individual products. Mixtures of levamisole as the hydrochloride together with praziquantel are stable, provided that the pH of the mixture is lower than approximately 4.

These and other aspects of the invention, which will be considered in all its novel aspects, will be apparent from the following description, which is given by way of example only.

GENERAL FORMULATION A typical formula for this invention would include the following active ingredients: praziquantel AND benzimidazole OR levamisole OR ivermectin OR moxidectin OR doramectin active in a range of activity from 0.5-15% w/v active in a range of activity from 1 -15% w/v active in a range of activity from 1 - 10% w/v active in a range of activity from 0.05 - 1% w/v active in a range of activity from 0.05 -1% w/v active in a range of activity from 0.05 - 1 % w/v and one or more of the following ingredients to enhance stability and characteristics of the composition: viscosity agents surfactants sanitizers acidifiers stabilizers -4 EXAMPLE 1: Praziquantel/Levamisole HCl Drench pH of 3.4 Density at 20 °C = 1.025 kg/1 Viscosity @ 20 °C Ingredient Water (hot) Polyoxystearate 40USP/NF PEG 6000* praziquantel Defoamer RD Water (cold) Potassium sorbate BP Citric Acid (anhyd) BP Levamisole HCl BP Xanthan Gum USP/NF Mono propylene glycol BP Colloidal anhydrous silica BP Formalehyde solution BP = 20 sec. (Ford no. 4 cup) gm/100ml 2.0 2.50 3.00 1.88 0.20 to 100 ml 0.18 0.30 3.75 0.20 0.40 1.00 0.20 100.00 *PEG 6000 is an abbreviation for Polyethylene Glycol 6000 USP/NF.

We have found that it is possible to make an acidified praziquantel drench in which the stability of levamisole can be maintained without affecting the praziquantel component. The acidity of the resulting product is preferably of a pH of less than 4.0, preferably around 3.0. A lower pH down to 2.0 is preferable if minerals are added to the drench. We have found that the pH of the above examples will vary slightly on a batch by batch basis. -5 Manufacturing Instructions for Composition of Example 1 1. Praziquantel premix - measure the hot water into a premix vessel, add the PEG 6000 and polyoxystearate 40 and mix until fully melted (approximately 65’C). Use external heating if required. Add the praziquantel and Defoamer RD and silverson until smooth and lump free. 2. Measure the bulk of the cold water into the production tank, add the potassium sorbate, citric acid, and levamisole hydrochloride and stir to dissolve. 3. Add the hot praziquantel premix to the production tank and stir until fully dispersed and lump-free. 4. Premix the Monopropylene glycol and Xanthan Gum, add to the batch and silverson until dispersed and until the viscosity has fully developed.

. Add the colloidal anhydrous silica and silverson until fully dispersed. 6. When the batch temperature is below 40’C add the formalin and stir to dissolve. 7. Add the remaining water to make up to volume. 8. Take a test sample for laboratory analysis.

The procedure called silversoning” is essentially mixing or dispersing in a device providing high shear rates within the fluid. -6 EXAMPLE 2: Praziquantel/Albendazole Drench By way of a second embodiment, a combination with an albendazole would be prepared using the following constituents: Water (hot) gm! 100ml 2.00 PEG 6000 2.50 Polyoxystearate 40 3.00 Albendazole 2.38 Defoamer RD 0.20 Praziquantel 2.50 Water (cold) to 100ml Potassium sorbate 0.18 Citric acid 0.30 Xanthan Gum USP/NF 0.20 Monopropylene glycol 0.40 Formalin 0.20 Colloidal anhydrous silica 1.00 100 ml The pH of such a suspension is expected to be in the range of from 3.5 to 5.5.

Combinations with other benzimidazole-type compounds can be formulated in a manner similar to that of Example 2. -7 EXAMPLE 3: Praziquantel/Ivermectin Drench Combinations with avermectin-related compounds can be made as non-aqueous or aqueous suspensions depending on the stability of the avermectin compound. For example, a formulation including ivermectin and praziquantel could be: Ivermectin Praziquantel Propylene glycol Water gmllOOml 0.1 1.88 40.00 to 100ml The suspension would have a neutral pH.

Other avermectins such as doramectin or moxidectin may be used in place of ivermectin.

It is also possible to prepare a solution of praziquantel with appropriate organic solvents.

The resulting product is not only stable but also allows the farmer to obtain control of a wider range of parasites.

EXAMPLE 4: Praziquantel/Oxfendazole A combination with an albendazole would be prepared using the following constituents: Water (hot) gmllOOml 2.00 PEG 6000 2.50 Polyoxystearate 40 3.00 Oxfendazole 2.265 Defoamer RD 0.20 Praziquantel 2.50 Water (cold) to 100ml Potassium sorbate 0.18 Citric acid 0.30 Xanthan Gum USP/NF 0.20 Monopropylene glycol 0.40 Formalin 0.20 Colloidal anhydrous silica 1.00 100 ml EXAMPLE 5: Praziquantel/Moxidectin gm!100ml Praziquantel 2.0 Moxidectin 0.10 Propylene glycol 20.0 Xanthan Gum USP/NF 0.2 Water to 100 ml 100ml EXAMPLE 6: Praziquantel/Ivermectin gm!100ml Praziquantel 2.0 Ivermectin 0.08 Ethanol 20.0 Propylene glycol to 100ml 100 ml - 9 In addition, it is possible to include in the composition other veterinary products including ectoparasiticides, as well as other endoparasiticides, minerals, and trace elements as required. In the following trials reference will be made to the praziquantel/levamisole formulation of Example 1. In some of the trials the formulation of Example 1 may include minerals and trace elements.

The compositions may be administered to mammals preferably by mouth as a drench, and as a single dose.

TRIALS The formulation of Example 1 has been shown in a series of New Zealand trials to be highly effective in controlling benzimidazole resistant roundworms and tapeworms in sheep.

While levamisole has been well researched for the control of helminths in sheep, there historically has been little information on praziquantel in the ovine. Thomas & Gonnert [Research in Veterinary Science (1978) 24,20] report a high efficacy in the control of Moniezia spp at a dose of 2.5mg/kg, while other studies against liver tapeworm (Stilesia hepatica) demonstrated efficacy at 15mg/kg.

A recent study by C. Bauer [Veterinary Record (1990) 127, 353-354] demonstrated an adequate efficacy against Moniezia expensa in Iambs at a dose of 3.75mg/kg. Based on this study a praziquantel dose of 3.75mg/kg was chosen. -10 TRIAL I Summary Two groups of milk lambs - slaughter at ten days. The formulation of Example 1 at a dose of 2ml/10kg of body weight. epg Reduction % Formulation of Example 1 Control Strong 98% (800%) Nem.

% Reduction worm Haemonchus spp 100% counts versus controls Ostertagia spp 97% Nematodirus spp 100% Trichostrongylus spp 100% Cooperia 100% Moniezia Scoleces 100% Segments 98% A high level of efficacy was demonstrated by the formulation of Example 1 against roundworms and tapeworms.

TRIAL REPORT I OBJECTIVE To assess by dosing and slaughter trial the efficacy and dose compatibility of the formulation of Example 1 on lambs in the control of tapeworm and roundworm.

MATERIALS The formulation of Example 1 TRIAL DESIGN Two groups of lambs were divided into two random groups as follows: -π Group 1 Dosed with the formulation of Example 1 Dose rate 2 ml/lOkg bodyweight Lambe Nos. 43,42,55,23,14, 61,45,47 All lambs were tagged, weighed and faecal sampled predosing.

All lambs were slaughtered at 10 days post treatment and tapeworm and nematode worm counts done on the abomasum and small intestine.

Reaction of animals at drenching observed and no effects noticed EGGS/GRAM 10 DAY CRITICAL SLAUGHTER WORM COUNTS Tag No. Wgt. Dose Strong. Nem. Strong. Nem. Haem. Ostert. Trich. Nema. Trich. Coop. MONIEZIA kgs ml Scolex Segments ml.

GROUP 1 - LEVITAPE 4ml/1 Okg 43 22 8.8 250 - - - 500 - - - - - 42 24 9.6 50 - - - - - - - - - 55 20 8.0 350 - - - 200 - - - - - 23 15 6.0 650 - - - - - - - - - 14 16 6.4 2200 - - - - 400 - - - - - 61 17 6.8 300 - - - - - - - - 45 22 8.8 250 5 47 19 7.6 200 50 - - - - - - - MEAN 531.2 - 62 137.5 - - - . 0.6 GROUP 2-CONTROL 37 20 1650 - 3750 - 150 14000 - 200 2200 400 8 3 20 16 1000 - 2800 - 250 1400 - - 1000 200 8 100 5 -26 900 1400 - 40 6000 - - 2600 400 3 1 11 19 600 950 180 800 - 600 200 - - 17 20 600 2650 - 70 3000 - 100 700 500 2 8 63 17 400 2400 - 140 5800 - 100 2000 800 2 45 51 18 100 950 10 1600 - 100 600 100 2 60 32 18 200 450 30 2400 - - 500 200 2 35 MEAN 681.2 - 6168.7 - 878 4375 - 62.5 1 275 350 3.3 31.5 -12 The tabulated results above show for each result the weights of the lambs, the dose administered, the faecal egg counts predosing and the 10 day worm counts. The efficacy of the formulation of Example 1 on Moniezia expansa is demonstrated. The levamisole shows no diminution in its efficacy on the common nematodes in lambs.

TRIAL Π Summary Three groups of lambs - slaughter at ten days.

Group 1 Formulation of Example 1 - lml/5kg Group 2 Albendazole - lml/5kg Group 3 Control - untreated % epg Reduction Formulation of Example 1 Albendazole Control Strong 15% 45% (788%) Nem 100% + + % Reduction Haemonchus spp 60% 30% worm counts Ostertagia spp 82% 96% versus Nematodirus spp 85% (23%) controls Trichostrongylus spp 100% 25% Cooperia spp Moniezia — Scoleces 99% 19% Segments 100% 23% Clear evidence of resistant nematodes to levamisole and albendazole. Albendazole resistant moniezia were cleared by the formulation of Example 1. -13 TRIAL REPORT II OBJECTIVE To assess by dosing and slaughter trial the efficacy and dose compatibility of the formulation of Example 1 on lambs in the control of tapeworm and roundworm.

MATERIALS 1. Formulation of Example 1 8mg/kg levamisole/3.75 mg/kg praziquantal 2. Albendazole TRIAL DESIGN Three groups of lambs were divided into three random groups as follows: Group 1 - 8 Lambs, Group 2-8 Lambs, Group 3-7 Lambs.

Group 1 Dosed with the formulation of Example 1 (3.75 mg/kg praziquantal) (8mg/kg levamisole) Dose rate 1 ml/1 kg body weight Lamb Nos. 50,54, 37,75, 35,35, 30, 61, 52 Group 2 Albendazole lml/5kg Lamb Nos. 48, 64, 56, 33, 60, 58,44, 59 Group 3 Control Lamb Nos. 40,32,57,49,43,46, 51 All lambs were tagged, weighed and faecal sampled predosing.

Reaction of animals at drenching observed and no effects noticed. -14 Tag No. Wgt. kgs Dose Strong. Nem. ml EGGS/GRAM 10 DAY CRITICAL SLAUGHTER WORM COUNTS Strong. Nem. Haem. Ostert. Trich. Nema. Trich. Coop. MONIEZIA Scolex Segments ml.

GROUP 1 -LEVITAPE 11(1 ml/5kg) 50 16 3.0 1900 100 - - - 100 - 100 - - - 54 14 3.0 50 - - - - 30 - - - - 37 14 3.0 450 - - - - - - - - - 75 13 3.0 600 - - - 10 - - - .. - - 35 14 3.0 350 50 750 - - 200 - 100 - 1 - 30 14 3.0 900 - 2850 - 100 1900 - - - - - - 61 12 2.5 300 - - - 20 - - - - - - 52 26 5.0 300 Missing MEAN 606.3 18.8 514 14.3 318.6 32.8 - 0.14 GROUP 2 - ALBENDAZOLE (1 ml/5koi 48 16 - 750 50 - 30 100 - 100 - - 55 - 64 14 - 500 - 30 100 - 20 - - 4 - 56 14 - 450 150 - - - - 700 - - 11 40 33 13 - 150 400 - 20 - - 1000 100 - 34 10 60 14 - 2250 - 1000 200 40 100 - 100 - - 39 27 58 14 - 900 700 50 20 - 100 100 - - 16 14 44 12 - 700 150 50 100 200 - 100 - - 29 3 59 26 - 950 400 - - - 10 - - 4 - MEAN 768.7 418.8 37.5 30.0 62.5 12.5 266.3 112.5 - 24.0 11.

GROUP 3-CONTROL 40 450 1350 - 40 1200 - 300 100 - 24 15 32 850 7300 500 60 2500 -- 400 200 - 3 - 57 500 950 50 30 1000 -- 300 - - 18 1 49 .. 1750 150 20 400 - - - - 52 45 43 750 1050 - 30 3200 - 200 100 - 49 30 46 450 13450 - 40 2200 -- 100 500 - 32 2 MEAN 485.7 4308.0 116.0 36.61750 -. 216.6 150.0 - 29.6 15.5 -15 The tabulated results above show for each result the weights of the lambs, the dose administered, the faecal egg counts predosing and post dosing and the 10 day worm counts. The efficacy of the formulation of Example 1 on Moniezia expansa is demonstrated. The levamisole and albendazole group results shows efficacy on the common nematodes in lambs is not as high as desired as resistance appears to be present to both these actives.

The albendazole was not effective in its efficacy against Monezia expansa. The formulation of Example 1 shows a very successful level of elimination of this tapeworm when in combination with levamisole.

TRIAL REPORT III LOCATION OBJECTIVE To assess by dosing and slaughter trial the efficacy and dose compatibility of the formulation of Example 1 on lambs in the control of tapeworm and roundworm.

MATERIALS 1. The formulation of Example 1 including minerals and trace elements such as copper, cobalt, selenium, iodine and zinc. 8mg/kg levamisole/3.75 mg/kg praziquantal with Minerals 2. Albendazole (Valbazen) TRIAL DESIGN Three groups of lambs were divided into three random groups as follows: Group 1-8 Lambs, Group 2-8 Lambs, Group 3-8 Lambs Group 1 Dosed with the formulation of Example 1 including minerals and trace elements such as copper, cobalt, selenium, iodine and zinc. (3.75 mg/kg praziquantal) (8mg/kg levamisole) - 16Dose rate 1 ml/5 kg body weight Lamb Nos. 17,20,23,33, 36, 37, 102, 108 Group 2 Albendazole lml/5kg Lamb Nos. 12,21, 26, 39, 43,46, 51, 103 Group 3 Control Lamb Nos. 10,11,18, 32,41, 49, 105, 109 All lambs were tagged, weighed and faecal sampled predosing. All lambs were slaughtered at 9 days post treatment and tapeworm and nematode worm counts done on the abomasum and small intestine.

Reaction of animals at drenching observed and no effects notice.

EGGS/GRAM 10 DAY CRITICAL SLAUGHTER WORM COUNTS Tag No. Wgt. Dose Strong. Nem. Strong. Nem. Haem. Ostert. Trich. Nema. Trich. Coop. MONIEZIA kgs ml Seolex Segments ml.

GROUP 1 -LEVITAPE 11(1 ml/5kg) 17 28 6.0 150 - - - - - - -- -- - - 20 22 4.5 50 - - - - - - - -- - - - 23 20 4.0 200 -- 50 - - - - - - - - - 33 26 5.0 - -- - - -- - -- - - - 36 26 5.0 50 - 100 - - - - - - _ - - 37 24 5.0 50 - 50 -- 102 23 4.5 200 - 108 32 6.5 50 - - - - - - - - - MEAN 93.78 37.5 - 17gR9UP2;,ALBENDftZgLm5hg) 12 26 5.0 50 - 5 - 160 - - - - - 3 10 21 22 4.5 - - - - 10 - - - - 5 - 26 28 5.5 100 - - - 50 - - - - 39 24 5.0 100 - - - 20 - - - - 1 - 43 26 5.0 150 -- 50 - - - - - 1 5 46 30 6.0 - - 50 - - -- - - - - 35 51 28 5.5 100 -- - - - - - -- - - 5 103 20 4.0 300 - 450 - - - .. MEAN 100.0 13.1 86.3 - .. - 6.9 11.8 SRQUP3-CQttIBaL 22 100 600 - 650 100 - - 700 200 6 110 11 24 250 2250 - 1400 400 - - 2200 4000 2 85 18 22 - 400 - 880 300 - 100 1800 3200 2 80 32 30 50 - - 400 600 - 100 200 300 8 15 41 26 100 50 - 50 100 - - 200 - - - 49 22 50 950 - 560 200 - 100 - - 105 24 150 - 1400 - 700 100 - - 1600 4800 2 55 109 26 - - 1150 - 970 200 - - 800 1400- 40 MEAN 87.5 850 - 701.3250 - 375 9375 1738 2.5 48.

The tabulated results above show for each result the weights of the lambs, the dose administered, the faecal egg counts predosing and post dosing and the 9 day worm counts. The efficacy of the formulation of Example 1 including minerals and trace elements on Moniezia expansa is demonstrated. The albendazole group results shows efficacy on the common nematodes in lambs is not as high as desired as resistance appears to be present to this active for Haemonchus contortus.

The albendazole was not effective in its efficacy against Monezia expansa. The formulation of Example 1 shows a very successful level of elimination of this tapeworm when in combination with levamisole, with no dimunition in efficacy by levamisole against the common nematodes in lambs. ia. Λ .

VARIATIONS A range of compositions have been described suitable for the treatment or prevention of helminthiasis in sheep and goats. The trials show dose rates of 3.75 mg/kg of praziquantel and 8mg/kg of levamisole. We have discovered that the dose rate of the formulation of Example 1 can be reduced, thereby reducing the dose rate of praziquantel to about 2mg/kg whilst preventing sheep measles in lambs. Preferred dose rates for lambs and sheep are in the range of 2-7.5 mg/kg of live body weight of praziquantel, giving a comparable range of levamisole of 4-16 mg/kg of live body weight.

Any of the avermectins: ivermectin, moxidectin, doramectin, could be replaced by Milbemycin D or other members of the Milbemycin family (Merck Index # 6112,11th Edition).

Finally it will be appreciated that various other alterations and modifications may be made to the foregoing without departing from the scope of this invention as set forth in the following claims.

Claims

1. WHAT WE CLAIM IS:

1. An anthelmintic composition including an effective amount of the anthelmintic praziquantel together with effective amounts of at least one other anthelmintic.

2. An anthelmintic composition as claimed in claim 1 wherein the other anthelmintic is selected from the group comprising the avermectins; milbemycins; levamisole; tetramlsoie; or a substituted benzimidazole carbamate.

3. An anthelmintic composition as claimed in claim 1 wherein the composition includes levamisole, and the composition has a pH of less than 4.0

4. Ah anthelmintic composition as claimed in claim 3 wherein the pH is about 3.0.

5. An anthelmintic composition as claimed in claim 1 wherein the formulation is a drench and contains from 0.3 to 13% w/v of praziquantel.

6. An anthelmintic composition as claimed in claim 3, wherein the formulation contains levamisole hydrochloride from 1 to 10% w/v.

7. An anthelmintic composition as claimed in claim 5, wherein the formulation contains from 0.05 to 1% w/v of ivermectin or moxidectin or doramectin.

8. An anthelmintic composition as claimed in claim 5, wherein the formulation contains from 1-15% w/v of a benzimidazole chosen from the group comprising mebendazole, fenbendazole, oxfendazole, albendazole, cambendazole, parbendazole, oxibcndazole, flubendazole and cyclobendazole.

9. An anthelmintic composition substantially as herein described with reference to any one of the Examples.

10. A method for treating helminthiasis in animals with a composition as claimed hi any one of claims 1 to 9.

11.

12.

13.

14. 11. 12. 13. 14. A method as claimed in claim 10 wherein the composition is administered to sheep to prevent or control moniezia. A method as claimed in claim 11 wherein the composition is administered as a drench having an effective amount of praziquantel in the range of 2 to 7.5 mg/kg of body weight. A method as claimed in claim 10 substantially as herein described with reference to any one of the trials. Use of praziquantel together with at least one other anthelmintic in the manufacture of a composition for treating helminthiasis in animals.