HU208252B - Process for producing solution against parasites and comprising avermectin derivative - Google Patents

Description

The present invention relates to a process for the preparation of a veterinary solution for parenteral administration containing an active compound of formula (I) known as 25-cyclobexyl avermectin B1.

This compound is a member of the avermectin family disclosed in European Patent Publication No. 0214731. Avermectins are highly active antiparasitic agents that are particularly useful against gutworms, ectoparasites, arthropods and mites.

Parenteral, subcutaneous or intramuscular formulations are the most suitable forms of anti-parasitic compositions for treating animals. Water is usually the most convenient liquid for injection, but avermectins are very poorly water soluble, so simple aqueous solutions are too dilute to use.

Certain avermectins, as described in U.S. Patent No. 4,389,397, may be solubilized in water using a surfactant and a suitable co-solvent to form micellar solutions. However, these solutions do not contain enough active ingredient to be effective against both internal and external parasites of the animals.

European Patent Publication No. 146,414 discloses an avermectin cosolvent solution formulation for parenteral administration comprising a mixture of glycerol and propylene glycol or propylene glycol in a small amount of water. However, propylene glycol is known to be irritant upon subcutaneous or intramuscular injection. In addition, small amounts of water in the formulations may cause hydrolytic degradation of avermectin.

Formulations containing a water-miscible organic solvent for dissolving avermectin tend to precipitate undesired local avermectin at the site of injection. This causes imitation and swelling at the injection site, and the parasitic effect is reduced and varied.

A commercially available anti-co-solvent parasiticide containing the active ingredient "Ivomec Injection for Cattle", ivermectin (manufactured by Merck Sharp and Dohme Ltd.), which is only for subcutaneous use and is irritating at the injection site and causes swelling.

The injectable avermectin solution may also be prepared using a pharmaceutically acceptable oil. British Patent Publication No. 2166436 discloses peanut or cottonseed oil or ethyl oleic acid as a solvent for certain avermectins. However, peanut or cottonseed oil does not dissolve the active ingredient at a concentration of at least 10 g / l, which is usually required for veterinary medicines.

Veterinary formulations are often used or stored on farms where the temperature may drop to or below 4 ° C, and when avermectin is sufficiently soluble in oil at room temperature, it can precipitate under colder conditions and become unusable. The blend of pure oleic acid ethyl ester or predominantly oleic acid ethyl ester attacks the plastic and rubber elements of commonly used veterinary syringes and renders it unusable.

European Patent Application 285,561 mentions pure sesame oil as a possible solvent for another group of chemicals, milbemycins. When examining the viscosity and syringe applicability of sesame oil, it was found that the viscosity of pure sesame oil was too high when used in conventional veterinary syringes. Therefore, pure sesame oil cannot be used in practice as an injectable solvent.

SUMMARY OF THE INVENTION The present invention relates to the preparation of solutions for parenteral use against internal and external parasites comprising the active ingredient of formula (I), which are well suited for both subcutaneous and intramuscular administration to animals and are compatible with conventional injection devices.

SUMMARY OF THE INVENTION The present invention relates to solutions for the preparation of 25-cyclohexyl avermectin Β1 of the formula (I) containing from 50 to 95% by volume of sesame oil and from 5 to 50% by volume of ethyl ester of oleic acid.

The preferred solvent mixture comprises 75-90% by volume of sesame oil and 10-25% by volume of ethyl ester of oleic acid.

The composition suitable for subcutaneous or intramuscular injection contains 1-20 mg / ml, preferably 10 mg / ml avermectin.

The compositions of the present invention are single-phase solutions and are useful in the treatment of various diseases caused by endoparasites, in particular helminthiasis. These diseases are most often caused by parasitic worms known as nematodes and cause severe economic losses to pigs, sheep, horses, cattle, and livestock and poultry. The compositions include other animal infections such as Dirofilaria infecting dogs and various parasites infecting humans including gastrointestinal parasites such as Ancylostoma, Necator, Ascari, Strongyloides, Trichinella, Capillaria, Trichuris, Enterobius, and in blood or tissues. which are also active against Strongyloides and Trichinella, which cause infections outside the gut.

The compositions of the present invention are also useful in the treatment of ectoparasitic infections in mammals and birds, such as ticks, mites, lice, flies, dead insects, hip insects, and larvae of migratory bovine and equine mammals.

It has been found that the compositions of the present invention are more preferred than the similar prior art formulations described above, when the animals are injected subcutaneously or intramuscularly at the injection site, or not slightly.

They are removable, can be used with commonly used standard syringes, and have a permanent anti-parasitic effect.

A further advantage of the solution formulations of the present invention is that, due to the ester and unsaturated acid content of the solvent used, avermectin is protected against oxidation of the air during long storage.

The process according to the invention is carried out by dissolving 1020 g of the active ingredient in 1 liter of a mixture of 50-95% by volume of sesame oil and 550% by volume of ethyl ester of oleic acid, optionally with heating to facilitate dissolution, and after cooling, if desired. sterilization.

The following examples illustrate the compositions of the present invention in more detail.

In the experiments, oily preparations containing 25-cyclohexyl avermectin B1 were prepared and tested according to the following procedures.

Example 1

An injectable solution was prepared from the following ingredients:

The active ingredient of the formula I is 10 mg

Ethyl oleic ester 0.1 ml

To 1.0 ml with sesame oil.

The ethyl ester of oleic acid and sesame oil were mixed and the mixture was heated to 80 ° C under nitrogen purge. The active compound of formula (I) was added to the warm oil, kept warm until dissolved, and the solution was cooled rapidly and, if necessary, made up to 1 ml with sesame oil. The resulting solution was sterilized by membrane filtration and packaged aseptically.

Example 2

The injectable solution of Example 1 was prepared from the following ingredients:

The active ingredient of the formula I is 10 mg

Ethyl oleic ester 0.5 ml

To 1.0 ml with sesame oil.

Example 3

The injectable solution of Example 1 was prepared from the following ingredients:

The active ingredient of the formula I is 10 mg

Ethyl oleic ester 0.25 ml

To 1.0 ml with sesame oil.

Example 4

The activity of the active ingredient of formula (I) against ectoparasites is described by L. G. Cramer et al., Vet. Record, (1988), / 22, 611-612. was modified by the procedure described in the literature.

Two groups of bovine animals were dosed with 200 Rg / kg of the compound of formula (I) on day 0 by subcutaneous injection.

Group A received the active ingredient of Formula I in the form of an aqueous micellar formulation according to U.S. Patent 4,389,397. This formulation contains 2.5 mg of active ingredient of the formula I per milliliter, 120 mg of Tween 80 (e.g., polyoxyethylene / 20 EtO) sorbitan monooleate; Imperial Chemical Industries Ltd. 200 mg of glycerol and mg of benzyl alcohol and water in the remainder.

Group B was treated with the composition of Example 1.

The treated groups and one control animal for each treatment were inoculated with Boophilus microplus larvae on days 0, 2 and 4 and allowed to develop adult ticks.

21-32. day, adult, female ticks full of blood were collected; the average number of individuals collected per day is summarized in Table 1:

/. spreadsheet

Average daily amount of B. microplus female ticks collected

Sun Micellar preparation untreated control Example 1 untreated control 21 0 287 0 0 22 0 651 0 324 23 0 879 0 996 24 0 753 0 1507 25 16 554 0 663 26 76 267 0 852 27 85 48 0 329 28 36 10 8 35 29 28 5 15 19 30 16 0 3 1 31 0 0 3 1 32 0 0 1 0 Altogether 257 3454 30 4727

Treatment with the composition of Example 1 delayed the development of adult female ticks and had fewer ticks collected than in comparative studies.

Example 5

The tolerance of the bovine avermectin preparation was investigated with the injectable preparation of the animals into the eye membrane muscle, as described below.

During the impact assessment, animals are treated after treatment

On days 7 and 14, they were gently killed and the injection site was removed along with the surrounding tissue.

Pathological examination of the tissues was performed with the naked eye and damage at the injection site was determined using the following rating scale.

= normal, no visible damage

B = slight boil = strong boil = encrusted digestion <1.0 cm ³ = encrusted digestion> 1.0 <2.5 cm ³ = encrusted digestion> 2.5 cm ³ .

Damage on a scale of 0.1 and 2 is acceptable. A scale value greater than 2 indicates blocked destruction.

Formulations of Formula I according to Examples 1 and 2 were administered to cattle by intramuscular injection at a dose of 200 pg / kg.

A comparative study was conducted with the same co-solvent parasite formulation containing ivermectin (tradename: Ivomec for cattle) = Ivomec for cattle, using the same procedure and dose. The results of this study are summarized in Table 2.

Table 2

Comparison of intramuscular injection site tolerance scales

Treatment Sun The animals number Average scale value Example 1 7 5 0.4 14 10 0.0 Example 2 6 5 0.4 14 10 0.0 Ivomec 7 4 3.75 14 8 2.75

On the 7th day after treatment with the formulations containing the active ingredient (1) according to Examples 1 and 2, there were only a few minor lesions which disappeared completely on the 14th day. This means that these formulations are well tolerated by cattle. However, on the 7th day after intramuscular treatment with the Ivomec formulation, encapsulated autopsy was observed, which persisted on the 14th day. This means that this preparation is poorly tolerated by animals.

Claims (3)

CLAIMS 1. A process for the preparation of a veterinary solution containing 25-cyclohexyl avermectin B1 as an active ingredient, comprising 10-20 active ingredients in 50-95 volumes of sesame oil and 5-50 volumes; in 1 liter of a mixture of ethyl acetate and optionally by heating to facilitate dissolution, then sterilize the solution, if necessary after cooling, in a known manner. 2. A process according to claim 1 wherein the solvent mixture is 75 to 90 volumes of sesame oil and 10 to 25 volumes of oleic acid ethyl ester. 3. A process according to claim 1, wherein a solution containing 10 mg / ml of 25-cyclohexyl avermectin B1 is prepared.