HU206621B - Process for producing veterinary compositions containing lyotrope liquide christalline benzimidazol derivative - Google Patents

Abstract

Veterinary anthelmintic compositions comprise 20-40 % by weight of a compound of the general formula I, having a particle size below 100 mu m: <IMAGE> - wherein X is -O-, -S-, -CO-, -SO-, -SO2- or a valence bond, R is a group of the general formula -NH-COOR<2> wherein R<2> is (1-4 alkyl, or a 4-thiazolyl group, R<1> is hydrogen, C1-4 alkyl, or phenyl, and 5-15 % by weight of surfactant having at least 8 carbon atoms, 10-40 % by weight of a water immiscible organic liquid (e.g. liquid paraffin) and 20-60 % by weight of excipient material (e.g. sucrose).

Description

The present invention relates to a process for the preparation of grafting lyotropic liquid crystalline compositions for the treatment of often widespread helminthoses in farm animals.

Benzimidazole derivatives such as 5 (6) propylthio-2-benzimidazolylmethylcarbamate (albendazole) are widely used in the treatment of helminthoses.

The disadvantages of the known formulations are that the colloidal system is easily disrupted in the thinner suspension due to the settling of the suspended active ingredients and the high viscosity in the case of denser cream-like products makes it difficult to dispense properly.

It is an object of the present invention to provide formulations which have a low viscosity value and yet have sufficient stability to provide a therapeutic effect that is more favorable than that of the known formulations.

According to the present invention, graftable lyotropic liquid crystalline compositions for use in the veterinary field are prepared by formulating 5-15% by weight of the surfactant (s) containing at least 8 carbon atoms, 10-40% by weight of a water-immiscible solvent and 20-60% by weight of the composition. a solution or suspension containing by weight 2020% by weight of a compound of formula I in a particle size below 100 µm, where

X is -S-,

R is -NH-COOR ² ,

R ¹ is C 1 -C 4 alkyl,

R ² is C 1 -C 4 alkyl, and if desired, an additional additive is added to the resulting composition.

Surfactants are known to form lyotropic liquid crystalline systems with solvents in amounts of 37-80% by weight. (Flüssig-Crystalline Eigenschaften von Tensiden, R. Heusch Proc. VII. Interm. Congr. On Surfactants, Moscow 1978, pp. 911-9404; J. of Pharm. Sci. Vol. 78, No. 8, p. 683 -687.). These systems have a high viscosity (50,000 mPa.s). Such high viscosity systems are not applicable in practice. Thus, the lyotropic liquid crystal system has not yet been applied to the active compounds of the present invention.

In the lyotropic liquid crystalline composition of the present invention, the liquid crystalline order is formed by interaction with the dispersed solid surface, and the liquid crystalline order can be provided with 5-15% surfactant. The liquid crystal systems of the present invention have a viscosity of 70-11 mPa.s. and are thus suitable for practical use.

The surfactants in the compositions of the invention are ionic (anionic and cationic) and / or nonionic and / or amphoteric surfactants, salts of carboxylic acids such as fatty acid soaps, sulfates such as alkyl sulfates, preferably sodium dodecyl sulfate, salts of sulfonic acids, e.g. benzenesulfonates, phosphates such as alkylphosphates and their salts, esters of ethoxylated fatty alcohols with inorganic acids (preferably sulfuric acid, phosphoric acid) and their salts, ammonium salts such as cetyltrimethylammonium quaternaryl, e.g. salts of alkylpyridinium salts, alkylamines or alkylamides adducts with ethylene oxide, such as oxyethylated coconut fatty acid amides, fatty acid esters of non-ionic polyhydric alcohols, e.g. ethylene oxide adducts, alkyl phenol polyethylene oxide adducts, preferably alkyl phenol poly (glycol ether), alkyl amines or alkyl amides with ethylene oxide, poly (propylene glycols) ethylene oxide adducts, alkyl (polyethylene) ether) -o-phosphoric acid triesters may be used as amphoteric salts, preferably betaine or phosphoric acid derivatives with choline.

Aliphatic and / or aromatic solvents, such as mineral oils and low molecular weight ketones, mono- or polyhydric alcohols and esters, vegetable and animal oils, saturated or unsaturated and above C ₆ unsaturated carboxylic acids may be used as solvents and co-solvents.

Excipients which may be used are those commonly used in veterinary medicine.

Most preferred surfactants in the compositions of the present invention are fatty acid soaps, fatty acid polyethylene glycol esters, fatty acid esters of polyhydric alcohols, high aliphatic alcohols, or mixtures thereof, with paraffin oil as a solvent, and sucrose as excipient. The liquid crystal structure of the compositions of the present invention was confirmed by polarization microscopy (using a crossed polarizer and analyzer using plaster red plate).

The present invention is illustrated by the following examples:

1. A suspension having the following composition is prepared:

5 (6) -propylthio-2-benzimidazolylmethylcarbamates (albendazole) crowd% the) b) (average particle size: less than 10 pm) 33.3 33.3 saccharose 11.86 11.86 nipagin 0.1 - Ethanol (solvent for nipagin) 0.45 - Polyoxyethylene Sorbitan Monostearate (Tween 60) 7.5 7.5 paraffin 13.5 13.5 Emulsogenic M (fatty alcohol polyethylene glycol ether) 1.5 1.5 propylene glycol 5.0 4.0 Aerosil 300 - 0.1 benzyl alcohol - - y 1.0 distilled water 26.79 27.24

HU 206 621 Β

The preparation procedure is described in la. composition.

The aqueous solution of sucrose, Tween 60, propylene glycol, ethanol solution of nipagin and paraffin oil solution of Emulsogen-M were weighed and albendazole was added.

The resulting mixture was thoroughly mixed and then type T-45. Ultra Turraxol with 45 K head max. and stirred at high speed for 2.5 to 3.5 minutes (homogenized with high shear mixer). The paste, which has become warm and thickened during cooling, is cooled and stirred several times. The paste obtained is filled into a disposable plastic syringe. The composition, when examined using a polarization microscope using a gypsum red plate, exhibits an ordered structure characteristic of a liquid crystal.

The two efficacy studies were conducted in a herd of equine animals where the composition of the herd, its age distribution, and its current gestational condition predetermined comparative formulations.

In the first study, the effects of the compositions on Strongylus were investigated (Table 1). The animals were divided into five groups.

Group I consisted of 35 horses, including annual foals and working horses. These were treated with 10mg / kg of Vermitana Paste A.U.V., [formulation 1a),

AII. Group 3 included pregnant mares, suckling foals, suckling foals, yearling foals and working horses, number 38. (Table 1 shows only 37 individuals at day -7 and +7, as the faeces collected for examination are transported They were treated with a conventionally prepared (non-liquid crystalline) structure of Vermitan Paste AUV 10 mg / kg body weight.

The ΙΠ. group consisted of 12 horses. This included annual foals as well as working horses and treated with the prescribed dose of Rintal Plus Paste (30 mg / kg / kg).

The IV. Group 17 animals were treated with Systamex Paste 18.5% at a standard dose of 5.0 mg / kg. This group had a mixed mare, an empty mare and a suckling foal.

Group V, which included 5 animals, had untreated controls. Pregnant mares, suckling foals, suckling foals, mating females and work platforms were mixed by age group and use.

In the second study, the efficacy of the formulations against Parascaris equorum was investigated. (Table 2). Agents used:

I. a Vermitan paste according to the invention,

II. the traditional non-liquid crystal Vermitan paste,

HL Rintol plus-paste,

ARC. Systamex paste,

V. 5 infected horses were used as untreated controls.

Table 2 shows the number of subjects and treatment success.

(There were 24 animals in group H, but 1 of the day -7 and +7 day samples were unsuitable for faecal examination.)

The flocks were not exposed to antiparasitic treatment, vaccination or immunosuppressive effects on resistance or medication the day before the start of the experiment. no other treatment was given.

Horses were included in the above categorization on the basis of a preliminary qualitative coprology and clinical examination (day -7). The efficacy of each formulation was determined by comparing the results of the coprology tests. Test materials were collected on the day of treatment (day 0) and then on days 7, 14, 21 and 28 after treatment. Based on the individual identification of the animals (neck or saddle padding), the test results could be evaluated individually. The identification of suckling foals was made possible by the fact that they were in unique boxes with their mother during the experiment.

Qualitative coprological analyzes were carried out by flotation with the internationally accepted saturated NaCl solution, and quantitative McMaster's method was used for quantitative analysis (Nemeséri L., Holló F .: Veterinary Parasitological Diagnosis, Agricultural Publisher, Bp. 1972,469).

The Ε. E. definition and method of calculation:

ZJxtenz Effectiveness: Effectiveness of the product on the incidence (frequency) of infections

C -T

EE (%) = ^pp x 100 S where C _p is the percentage of infected animals in the control group

_Tp :% of infected animals in the treated group

When evaluating the studies, control values within the groups were considered as pre-treatment results.

The untreated group merely served to confirm that the infection did not resolve spontaneously.

Preliminary exploratory studies revealed that Strongylus and Parascaris parasite species were present in the surveyed equine herd. The results of the tests are shown in Tables 1 and 2.

Composition of the comparator:

Rintal Plus Paste: 8.87% active ingredient febantel (manufactured by Bayer)

Sistamex Paste: Active substance 18.5% oxfendazole (manufactured by Coopers Anim. Hercz. Ltd)

Vermitan Paste (Conventional): 33.3% albendazole active ingredient

HU 206 621 Β

Table 1

Comparative Efficacy Study in Strongylus Horses

Sample- reception time * (Sun) Vermitan Paste A. U.V. 10 mg / kg body weight according to the invention Vermitan Paste A. U.V. 10 mg / kg body weight conventional Rintal plus-paste (Bayer) 30 mg / kg body weight Systamex Pasta 18.5% 5 mg / kg body weight untreated control vizsg./ fit. fit. % Ε. E. vizsg./ fit. fit. % EE. vizsg./ fit. fit. % Ε. E. vizsg./ fit. fit. % EE. vizsg./ fit. fit. % -7. 35/30 86 37/37 100 12/12 100 17/17 100 5/5 100 0th 35/32 91 38/38 100 12/12 100 17/17 100 5/5 100 7th 35/4 11 87 37/11 30 70 12/5 42 58 17/8 47 53 5/5 100 14 35/2 6 93 38/11 29 71 12/4 33 67 17/9 53 47 5/5 100 21st 35/1 3 97 38/5 13 87 12/3 25 75 17/5 29 71 5/5 100 28th 35/2 6 93 38/11 29 71 12/3 25 75 17/8 47 53 5/5 100

* relative to treatment

Table 2

Comparative efficacy study in horses Parascaris

Sampling time * (Sun) Vermitan Paste A. U.V. 10 mg / kg according to the invention Vermitan Paste A. U.V. 10 mg / kg body weight conventional Systamex Pasta 18.5% (Wellcome) 5 mg / kg body weight untreated control vizsg./ Hone. fit. % EE. vizsg./ fit. fit. % Ε. E. exam / fit. Hone. % Ε. E. vizsg./ fit. Hone. % -7. 21/8 38 23/19 83 5/5 100 5/5 100 0th 21/10 47 24/18 75 5/5 100 5/5 100 7th 21/2 10 76 23/11 5 94 5/2 40 60 5/5 100 14th 21/0 0 100 24/1 4 95 5/3 60 40 5/5 100 21st 21/0 0 100 24/0 0 100 5/3 60 40 5/5 100 28th 21/0 0 100 24/1 4 95 5/2 40 60 5/5 100

* relative to treatment

Claims (3)

A process for the preparation of a compound of formula I for use in veterinary medicine, wherein X is -S-, R 1 is -ΝΗ-COOR ² , R ¹ is C 1 -C 4 alkyl, ^R2 preparing graft lyotropic liquid crystalline compositions containing from 1 to 4 carbon atom alkyl group, characterized in that 5-15 wt%, relative to surfactant (s) having at least eight carbon atoms in the composition, 10-40 wt% of water-immiscible solvent, and a solution or suspension containing from 20 to 60% by weight of other excipients with 20 to 40% by weight of a compound of formula (I) below a particle size of 100 µm Wherein X, R, R ¹ and R ² are inoculated within the scope of the invention and, if desired, additional additives are added to the resulting composition. 2. The process of claim 1 wherein the surfactant is a fatty alcohol polyethylene glycol ether. 3. A process according to claim 1 wherein the solvent is paraffin oil and the excipient is sucrose.