HU217811B - Process for producing gellike antiparasitical veterinary preparation containing methyl-5(6)-benzoyl-2-benzimidazole carbamate - Google Patents

Abstract

The subject of the invention is a process for the production of a water-based, gel-form antiparasitic preparation containing methyl-5,6-benzoyl-2-imidazole-carbamate as an active ingredient, which is characterized by mixing the active ingredient with a wetting agent, a surfactant, water and, where applicable, other excipients, and then the resulting suspension it is mixed with a gel-like substance prepared from a gel-forming agent and additional auxiliary substances. ŕ

Description

The present invention relates to a novel gel formulation containing an antiparasitic methyl 5,6-benzoyl-2-benzimidazole carbamate in the form of a gel.

Methyl 5,6-benzoyl-2-benzimidazole carbamate (hereafter mebendazole) is a known compound (The Merck Index, Merck and Co., Ind., Rahway, N.J., USA, 904.0, 1989).

The composition according to the invention can be used in any animal in need, but the development has been aimed primarily at the convenience of use in domestic animals, including so-called "pets".

In our description, the term "favorite animal" is used primarily to mean dog and cat.

Mebendazole is a broad spectrum anthelminthic drug. It has a pronounced wormicidal effect through selective and irreversible inhibition of glucose uptake by worms.

It virtually kills parasitic nematodes in dogs and cats in single doses and Ancylostoma and Uncinaria species in repeated doses.

It is equally effective in cases of nematodes in poultry, pigs, ruminants and horses.

80-90% of the administered mebendazole is excreted within 3 days, mostly in faeces and unchanged faeces in dogs and rats, and 30-50% in pigs in urine, mostly in decarboxylated form.

Its favorable therapeutic index and low toxicity make it suitable for use in food, even for the treatment of larger stocks.

It affects not only adult worms but also young forms at different stages of development.

Dogs and cats are known to be infected by various parasites, but the extent and dangers of this infection are largely unknown to the majority of the population. Animal parasitic infestation occurs not only in animals kept in poor conditions but also under the best hygiene conditions.

For three reasons, it is important to protect your favorite animals from infection.

1. All types of worms, to a lesser or greater extent, cause damage to the body of the animal and may also cause the animal to die.

2. The larvae in the environment may infect other food producing livestock, which will result in reduced production and confiscation of the infected parts at the slaughterhouse as they are partially or totally unfit for consumption.

3. Parasites include those that can infect humans and cause serious damage to the human body, and sometimes cause death.

Various studies show that about 20-25% of dogs and 45-50% of cats are infected with a worm. Most animals become infected with each other's intestines or by eating contaminated food, but the infection is caused by fleas, lice, earth, water, etc. can also be distributed.

Almost all puppies are considered to be infected at birth, as they are transmitted from the mother through the womb, often even when the animal does not show signs of parasitic infection.

A highly infected animal can sometimes have 100 to 200 tapeworms, producing hundreds of millions of eggs a day. These eggs continue to infect the animal's excrement.

Because of the above, it is important to regularly dispose of the animals.

Keeping dogs and cats free from worms can only be achieved by providing boat hygiene conditions and regularly treating the animals with an effective anthelmintic.

Several formulations of different active ingredients are known for this purpose, for example: Telmin and Vermox tablets also containing Mebendazole active ingredient, Lopatol tablets (Nitroscanat), Drontal Plus tablets (Febantel + Priaziquantel) and Banminth paste (Pirantel pamoate), Droncit tablets (Prazinquantel).

Many of these formulations do not have the appropriate spectrum of action or are formulated as tablets that are difficult to use in animals.

According to DE 3 423 649, mebendazole embedded in a liposome after multiple lyophilization is formulated for intravenous administration, that is to say, it is not concerned with the preparation of oral formulations, whereas in FR 2 461 495 a prolonged release tablet for ruminants is provided. Formulations are described. Hungarian Patent Publication No. 198 025 discloses the preparation of benzimidazole derivatives having amorphous anthelmintic activity and further requires the formulation of the active ingredient into a standard (animal) pharmaceutical preparation.

In animals, the administration of drugs is a general problem, especially for poor-tasting, water-insoluble active ingredients such as mebendazole. Incorporation of the drug into the diet is inappropriate because the animals detect a low dose of the bad taste active ingredient and thus do not, or only partially, consume the drug-containing diet, thus making it difficult to control the dosage administered. That is, in the case of a bad taste active ingredient, only proper dosing can be ensured by direct feeding. For this purpose, the conventional tablet formulation is inappropriate because of the animal's lack of response, which makes it difficult to administer and bites the animal, and the animal usually spits the tablet into the mouth. Liquid administration is also inappropriate because the animal will not be swallowed by the animal, and some of the liquid will drain out of the mouth (in the case of a water-insoluble active substance, a problem with the liquid formulation is inherently problematic).

It has been suggested that oral dosage forms that are not customary for pharmacists in oral pharmacies may provide a solution to the problem,

EN 217 811 konz if the gel is of such consistency that it adheres to the palate and tongue of the animal so that it cannot be spit out, ie it is forced to swallow, but it is still so fluid that it can be injected using pump or syringe dispensers animal's mouth. Obviously, the problem arose that adhesion could be enhanced by increasing the strength of the gel and pump dosing by increasing the fluidity of the gel, i.e. the two properties required opposite rheological properties.

It is an object of the present invention to provide an antiparasitic agent, preferably a gel formulation containing mebendazole, which is convenient and safe for use in animals, especially pets.

The composition of the composition should be rheological, viscous in such a way that it is fluid under pressure to allow uniform delivery through the narrow dosing opening while at the same time retaining its original structure once the pressure has ceased and not leaking out during storage.

It should be noted that oral dosage forms of the active ingredient in the form of a gel are not known at all in the veterinary field (nor are such formulations known in the human art).

The present invention therefore relates to a process for the preparation of an antiparasitic agent, characterized in that the mebendazole is formulated in a gel form in admixture with excipients and / or carriers conventionally used in veterinary medicine.

Preferably, the composition is an aqueous base comprising a gelling agent such as acrylic acid polymerizates (e.g. Carbopol), a hydrophobic reducing humectant such as polyhydric alcohols (e.g. propylene glycol, glycerol, etc.), a surfactant such as polyethylene glycol derivative (e.g. polysorbates, etc.). as an excipient, a flavoring agent such as a ham or salami flavor, a preservative, a coloring agent, and the like. contain.

Particularly noteworthy is the fact that mebendazole has been able to formulate a water-based gel of appropriate consistency, since mebendazole is substantially insoluble in water, so that it is not obvious to those skilled in the art that it can be formulated in an aqueous, stable, gel form.

Many unexpected problems have been encountered in the development of the gel formulation of the present invention. In our experiments, it has been found that it is only at a certain pH and dosage order that a suitable formulation can be prepared.

At the beginning of the experiment, one of ordinary skill in the art first attempted to obtain a composition of appropriate consistency, i.e., by adding the active ingredient to the wetting agent, surfactant and gelling agent with vigorous stirring, and then distributing the active ingredient uniformly. However, an apparatus failed to produce a gel of sufficient consistency, since the gel with a sufficiently high viscosity for adhesion did not evenly distribute the active ingredient in any dosing sequence or in any of the phases.

After lengthy experimentation, it has been found that the gel of the desired consistency can only be obtained by premixing the active ingredient in a separate solution with the specially selected surfactant (ionic surfactants failed to achieve the desired effect) and then adding the resulting dispersion separately. prepared gel-like base. With this dosing sequence, the subsequent rubbing is effective, producing the desired stable, heterodisperse gel consistency system with relatively high viscosity.

A further advantage of the water-based gel form is that the flavors commonly used in the food industry can be easily added to the gel. Particularly advantageous was the ham-flavored aroma, which was able to suppress the unpleasant taste of mebendazole, so that the flavored gel could be safely administered to the animals when mixed with food. Thus, large animals, which may be dangerous to humans, can be safely dosed with an agent which would otherwise cause defenses, such as mebendazole.

The present invention thus relates to a process for the preparation of the above composition comprising admixing the active ingredient with a wetting agent, surfactant, water and optionally other excipients, and then mixing the resulting suspension with a gel-like material prepared from a gelling agent and further excipients. If desired, the active ingredient is distributed evenly throughout the mixture.

In a preferred embodiment of the process of the invention, an aqueous solution containing an organic acid, preferably citric acid, is first prepared and the Carbopol 934 gelling agent is added to this acid solution with vigorous stirring. Stirring is continued until Carbopol 934 is completely dissolved.

To the resulting aqueous gel is added an alkali metal hydroxide, preferably sodium hydroxide in the form of a 40% aqueous solution. The role of the alkali metal hydroxide is twofold, on the one hand adjusting the pH of the aqueous solution to the desired value (pH 5-6) and on the other hand forming a buffer with citric acid. Subsequently, a flavoring agent, preferably fuming or other authorized food flavoring, is added to the aqueous gel.

If desired, the aqueous gel is stained with a food coloring.

In parallel with the preparation of the aqueous gel described above, potassium sorbate is dissolved in distilled water, propylene glycol and polysorbate 80 are added, and the intended amount of antiparasitic agent, preferably mebendazole, is suspended. Alternatively, the active ingredient may be added to a mixture of propylene glycol and polysorbate 80, followed by the addition of water and a potassium sorbate preservative.

HU 217 811 Β

The suspension is passed through a colloidal mill and added to the aqueous solution with constant stirring. During pH control, the composition is made up to volume with distilled water and, after repeated mixing, is filled into a container fitted with a metering pump.

Dosage

For single treatment: 20-60 mg / kg (body weight), practically 50 mg / kg / day, administered orally as a single oral administration to animals.

For cure-based treatment: 2x50 mg / animal per 2 kg bodyweight per day for 3-5 days. Above 2 kg 2 x 100 mg / animal daily for 3-5 days. Whereas in large animals (over 30 kg) 2 x 200 mg / animal daily for 3-5 days.

The process of the present invention is illustrated by the following example, without limiting our claims.

Example mebendazole 5.00 g NaOH 0.15 g citric acid 0.10 g potassium sorbate 0.10 g carbopol 934 0.50 g (1.0 g) polysorbate 80 1.50 g propylene glycol 2.00 g flavoring (smoked marshmallow flavor) (1) 0.30 g distilled water (1) manufactured by: Döhler-Szilas Kft. ad 100 g

Solution I Dissolve 0.1 g of citric acid in g of distilled water and add 0.5 g (1.0 g) of carbopol 934 to the solution. After swelling, add 0.15 g of NaOH dissolved in 5.0 g of distilled water, and the resulting gel is stained, if desired, with an approved food coloring agent and then, with constant agitation, 0.3 g of fumarate or other authorized food. We add flavor to it.

II. Dissolve 1.5 g of polysorbate 80 in 1 g of propylene glycol and mix with the intended amounts (5 g and 25 g) of mebendazole and add 0.1 g of potassium sorbate in 15 g of distilled water.

The suspension is passed through a colloidal mill and added to solution I with constant stirring. After pH control (pH 5-6), the composition is made up to 100 g with distilled water, mixed again, and filled into a container fitted with a metering pump.

The typical rheological properties of the formulations were determined using a Haake RV 100 rotary viscometer equipped with SVDIN probe at 25 ° C. The results are given in the following table:

mebendazole Speed shear dynamic The amount (· S) viscosity (crowd%) (MPa) 5 50 1665 5 500 398 25 50 2390 25 500 390

PATENT CLAIMS

Claims (4)

PATENT CLAIMS CLAIMS 1. A process for the preparation of an aqueous, gel-based, antiparasitic composition comprising methyl 5,6-benzoyl-2-benzimidazole carbamate as an active ingredient, comprising mixing the active ingredient with a humectant, a surfactant, water and optionally other excipients, and the resulting suspension is admixed with a gel-like material prepared from a gelling agent and additional excipients. 2. The process of claim 1 wherein the gelling agent is an acrylic acid polymer. Process according to any one of claims 1 or 2, characterized in that the wetting agent is propylene glycol and the surfactant is polysorbate. 4. A process according to any one of claims 1 to 3, characterized in that a flavoring agent and / or a preservative are used as excipients.