BG61064B1 - Medicamentous form for the deparasitation of animals - Google Patents

Abstract

The agent is used for decontamination of farm and domestic animals in cestodoses, trematodoses and nematodes, and in mite infestation with mites. It covers a wide range of external and internal parasites and is tolerable at 10x the therapeutic dose. The agent is a combination of praziquantel and avermectins.

Description

The invention relates to a medicament for decontamination of farm and domestic animals in cestodoses, trematodoses, nematodes, invasion by insects and mites.

G BACKGROUND OF THE INVENTION

The compound 2- (cyclohexylcarbonyl) 1,2,3,6, -7,11b-hexahydro-4H-pyrazino [2,1-alpha] isoquinolin-4-one, is known [MERCK INDEX, 11th Edition, Merck & Co, Inc. , Rahway, NJ, USA, 1989] with the generic name praziquantel, (PC). It is used in veterinary medicine as an antiparasitic agent with anti-Stodot and partially antitremot action. However, the substance is not effective against nematodes as well as ectoparasites, [ROBERSON, E.L. - Anticestodal and Antitrematodal Drugs, in: Veterinary Pharmacology and Therapeutics, 6th Ed., By N.A. Booth and L.E. McDonald, Iowa State University Press, Ames, Iowa, 50010, USA, 1988, 928-949].

Avermectins, (ABM), are known to be broad-spectrum anti-parasitic antibiotics produced by streptomycetes, [MERCK INDEX, 11th

Edition, Merck & Co, Inc., Rahway, NJ, USA, 1989], of which the highest anti-parasite activity is the fraction B antibiotics | (B _1A and B _1B ), [CAMPBELL,

W.C., Ivermectin and Abamectin, Springer-Verlag, New York, 1989]. Avermectins ca endectocides - act on internal and external parasites: anthelmintic anti-nematode and anti-ectoparasite - insecticidal and acaricidal on parasitic animal ticks and pastures and blood sucking insects. Ivermectins (22,23 dihydroavermectins) are hydrogenated products of avermectins and have similar biological activity, [CAMPBELL, W.C., Ivermectin and Abamectin, SpringerVerlag, New York, 1989]. From hereinafter, avermectins will be understood to mean natural avermectins, semi-synthetic ivermectins and technical products containing avermectins or ivermectins. The disadvantage of avermectins is that they do not show anti-stodot and antitremot activity.

The action of anthelmintic substances is as follows:

- the drug must reach and pass the contact areas of the parasites (for the nematodes - the cuticle and through their digestive canal - the intestinal epithelium, and for the cestodes - the tegument) and enter them;

the drug must cause serious damage to the internal structure and function of the parasites.

There are also known a number of combination decontamination preparations in which the active substances mentioned separately are present as components, [WALKER, G. (comp.

by) - Compendium Data Sheets for Veterinary Preparations, 1992/93, Datapharm Publ. Ltd.,

London, 1992]:

praziquantel + pyrantel pamoate - with antistatic, antitremod and antinematod activity - against three classes of internal parasites;

- praziquantel + pyrantel embonate + febantel - with anti-stodot, antitrematod and antinematod activity - against three classes of internal parasites;

- ivermectin + pyrantel - with anti-nematode and anti-ectoparasite activity against one class of internal and two classes of external parasites.

A general disadvantage of known combinations may be that they do not cover the entire spectrum of internal and external parasites, and in animals very often the invasion is complex.

It is an object of the present invention to provide a highly effective animal disinfectant to cover a wide range of external and internal parasites.

SUMMARY OF THE INVENTION

The present invention is an animal decontamination drug comprising 2- (cyclohexylcarbonyl) -1,2,3,6,7,11b-hexahydro-4Hpyrazino [2,1-alpha] isoquinolin-4-one and avermectins equated to biological activity of fraction B, in quantitative proportions, as follows from 10: 1 to 50: 1.

The combination of the active ingredients praziquantel and avermectins is suitable for the preparation of pharmaceutical compositions and preparations. The finished dosage form may contain the active substances mixed with the usual excipients as shown in the exemplary embodiments. The agent of the invention may be administered orally or in some cases parenterally.

The advantages of the agent according to the invention are:

- enhancing the effect of avermectins through praziquantel on nematodes and praziquantel via avermectins on cestodes;

- broadening the spectrum of antiparasitic influence, compared to existing combinations, to include helminthoses - cestodoses, nematodoses, trematodoses (three classes of internal parasites) and arachnoentomoses - acarooses and insectoses (two classes of external parasites);

tolerance even at 10 times the therapeutic dose.

DESCRIPTION OF THE ANNEXED TABLES, TABLUMS AND

FIGURES

Tabulogram 1

Damage to model parasites of praziquantel, (PC), avermectins, (AVM) and a combination of praziquantel and avermectins (PK + AVM) - in vitro studies

Figure 1

Electron microscopic images of Ascaris suum after PC and AVM self-administration

Figure 2

Electron microscopic photographs of Ascaris suum after combined administration of

PC + AVM

Figure 3

Electron microscopic images of Toxocara canis after self-administration of PC and AVM

Figure 4

Electron microscopic images of Toxocara canis after combined administration of PC + AVM

Figure 5

Electron microscopic images of Moniezia expansa after self-administration of PC and AVM with

Figure 6

Electron microscopic images of Moniezia expansa after combined administration of PC + AVM

Non-limiting embodiments of the invention.

Example 1

Solid dosage formulation in%

Praiquantel11.35

Abamectin (Avermectin B ₁ Avermectin B _1A > 80%

Avermectin B | _at <20%), 1.13

Milk sugar50,70

Wheat starch33,82

Polyvinylpyrrolidone 25,000 (Colidon K ₂₅ ) 3,00

Granulation is carried out in a vortex dryer. The granulate thus obtained can be used as a premix or after suitable treatment with gliding, lubricating and disintegrating aids may be subjected to tableting or capsule filling.

Example 2

Solid dosage formulation in%

Praiquantel11,65

Bulmectin (a technical product equated to biological activity of 0,416% avermectin Bj) 15,76

Milk sugar34,21

Wheat starch29.98

Polyvinylpyrrolidone 25,000 (Collidon K ₂₅ ) 2.33

Sugar6.07

The technological treatment was carried out in the same manner as in Example No 1.

Example 3

Solid dosage formulation in%

Praiquantel11,27

Ivermectin (22,23-dihydroavermectin B j 22,23-dihydroavermectin B _1A > 80%

22,23-dihydroavermectin B _JB <20%) 0.23

Milk sugar51,68

Wheat starch33,82

Polyvinylpyrrolidone 25,000 (Colidon K ₂₅ ) 3,00

The technological treatment was carried out in the same manner as in Example No 1.

Example 4

Studies were performed with model nematodes and cestodes, incubated in vitro in nutrient fluid and addition of PC and AVM, alone and in combination PC + ABM for 4 h. The results are shown in Table 1.

X 1 1 F. 1 IF X 1 β About X X F. X In * X ah S X SE-J « In A Well No x g S Ц о X to O. A Well s to X S E < - ^a I> X E h a Well l w 3 e. S F ( x hell and F. > i " m x a e X in* E * Oh R HO “Oh Mr Rücker A w d ® + f and a s S « X X R 2 F> h n w bm XCU XX m Fr. «« And X Oh S Oh echo i x S χ «X A F. χ α No A X B * a _ is X «X X h S XI X R U X Yu X x E and □ η P4 k to X m < F. Well Φ X Μ η would x x a S Mr Rücker in » r x a «fh night I X S A ΪΦ X ο X JK4 Fr. x e ί i c o> <c υ l and > 4 L X b and bm > X to η pl The dream aoyayy ch E U C Li A X X X El N. and W s is yoyu>, and ufi dream A or l 11 f S FAL e 3 w _ HOYOHL SS X «3 ⁴⁰ J. X xn _and x and m X5 X Fr. with * 1 1 & « 1 and η Yu < 4 4 4 4 4 + + co 03 + 4 + 4 4 4 4 + F 4 4 4 4 Al ►h 1 4 + 4 4 4 1 4P to n me Q 4 + + X e 4 4 4 1 4 4 1 co 4 + 4 4 4 4 4 4 4 sch 9) + 4 4 4 4 4 4 4 4 4 1 1 <h M 1 4 + + + 4 4 4 sch § 4 4 4 4 4 44 4 4 1 1 hh ¹ ι nk 4 + 1 1 4 1 1 4 4 1 1 ΜΊ « 4 4 4 4 4 4 4 4 + 4 4 4 1 + 1 + 4 4 + 4 sch JS 4 4 4 4 and £ 4 4 m X δ _ 4 4 1 1 4 1 4 4 4 + 1 σι η < S 4 4 1 1 1 1 1 4 4 1 1 And * X 1 ι ае ф < F. X Well At X b X 5x and X R a to 2 F. I am X is> 3 and bh 5 Mr Rücker ₽ » A Qi a X E X B. x from k & x Mr Rücker Oh 4 FF X X fki ▻ oh X X U Well > » ФЮ Ф X χ x m CF h B. «If> 3 Q CQ F X O X 3 «<0 AHA fe χ x lol 9 x 2 X X <0 K 4 X ί β k l «X A X X I B * m & X <0 D ti A To 1 « x appear Μ A & I X D a X A r> X X η> and <K E O ς> ф л > <and X No K η I I S and « About PYGO Yes if Mon S Ο O c F I X X R A X K >> i a Μ and? f «»> <a Fr. 3 in a η JS x and x a ahhhh χ x & g < In «Yu □ There I ^am «Yu f Μ \ O> ιϋΐθ X l a 3 δ « O 0 a 1 1 1 and χ TO X S ' OHA O I X Fr. hh <h co

LEGEND: -------------------------------- (+ j - single (incident) injuries; (++) - encounters be damaged;

(+++) - Mass (very common) disabilities

I I III

Electron microscopic examinations of parasites treated in vitro with the aforementioned have revealed disturbances in the structures, to some extent explaining the compatibility and enhanced antiparasitic activity of the PK + ABM combination.

PC known to be inactive as an anti-nematode agent, [ROBERSON, E.L. - Anticestodal and Antitrematodal Drugs, in: Veterinary Pharmacology and Therapeutics, 6th Ed., By N.A. Booth and L.E. McDonald, Iowa State University Press, Ames, Iowa, 50010, USA, 1988, 928-949], in fact, is not completely indifferent to the nematodes examined. It, self-administered, affects the integrity of the cuticle and the transverse wall, (Table 1, Table 1, Figures 1 and 3), although it does not cause the death of the parasites.

AVMs, on their own effect, lead to serious changes in the structure of the cuticle and intestinal epithelium of the two nematodes (Table 1, Figs. 1 and 3).

The most severe are the damage of the two model parasites of the combination AVM + PK - in the cuticle (peeling, pocketing, tearing), in the intestinal epithelium (formation of vesicular structures' among the microvilli, formation of myelin structures, vacuolation and necrosis), Tochosaga canis with lesions in the hypodermis and the basement membrane, and in Ascaris suum with more necrotic changes (Table 1, Table 1, Figs 2 and 4). The greater damage to the structure of the nematodes studied under the influence of PC + AVM could be explained by the influence of PC, which creates an entrance door for easier penetration of AVM into the body of the parasites and, accordingly, its stronger effect.

Experiments with the cestode Moniezia expansa produced similar, in terms of AVM, effects. AVMs that are known to have no anti-stodic action, [ROBERSON, E.L. - Anticestodal and Antitrematodal Drugs, in: Veterinary Pharmacology and Therapeutics, 6th Ed., By N.A. Booth and L.E. McDonald, Iowa State University Press, Ames, Iowa, 50010, USA, 1988, 928-949], in electron microscopic studies also did not appear indifferent to cestodes. They cause minor damage in the monesium tegument - in the microvilli, in the basal and in the muscular layer (erosion, even small necrotic areas), (Table 1, Table 1, Figure 5). PC lesions are significantly greater (Table 1, Table 1, Figure 5). The most significant were the disturbances in the structure of the cestode of the combination PC + AVM. They are dominated by a decrease in the number of microvilli, erosion, necrosis in the basal layer, and also a reduction in chromatin and damage to the nucleus of the tegument cells (Table 1, Table 1, Figure 6). The explanation of the more severe and widespread lesions in the structure of the cestodes by the PC + AVM combination should be sought in the additional influence of the AVM, which facilitates the penetration of the PC into the body of the cestodes and increases their lesions.

Herd of grams. 1

Damage to model parasites of praziquantel / PK /, avermectins / AVM / and a combination of praziquantel + avermectins / PK + AVM / - INVESTIGATIONS

FIG. 1

Electron Microscopic PICTURES of Ascaris suum AFTER SELF-APPLICATION OF PC AND AVM

AVM

FIG. 2

Electron microscopic images of Ascaris suum after combined administration of PC + AVM

E ': Λ

FIG. 3

Electron microscopic images of tohosa cants after continuous application of PC and AVM self-

PC

AVM and

Electron microscopic photographs of

Toxocara canis SL6D COMFig. 4 binary application of PC and AVM

II

Moniezia expansa trail

FIG. 5

Electron microscopic self-application images of PC and AVM

AVM &

FIG. 6

Electron microscopic photographs

Moniesia expanse after combined administration of PC + AVM

Claims (3)

An animal disinfectant medicament comprising 2- (cyclohexylcarbonyl) 1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1 alpha] isoquinolin-4-one and avermectins , equated by the biological activity of fraction Bj, in quantitative ratios as follows from 10: 1 to 50: 1. Medicament according to claim 1, characterized in that the semi-synthetic ivermectins are used as avermectins. Medicament according to claim 1, characterized in that as avermectins a technical product containing avermectins equated by biological activity with fraction B _{p is used}