SK180190A3 - Solution based on 25-cyclohexyl-avermectin b1 and preparation method thereof - Google Patents

Abstract

Disclosed is a 25-cyclohexyl-avermectine B1 solution of the general formula (I) in the diluent composed of 50 to 95 % content of the sesame oil, with the proviso that the rest comprises ethyl oleate. This solution contains advantageously 1 to 30 mg/ml of 25-cyclohexyl-avermctine B1 in the diluent containing 50 to 95 % content of the sesame oil and the rest comprises ethyl oleate. The solution is effective against the vermin, well toleranced by animals and could be fed by the standard injection equipment.

Description

ROZTORyŽ & CYCLOHEXYL * avermectin

B1 AND THE WAY OF IT

PREPARATION

Technical field

The invention relates to the preparation of a compound of the formula (I) of formula (I) for parenteral administration.

BACKGROUND OF THE INVENTION

This compound belongs to the group of avermectins described in European Patent Application 0214731, which exhibit excellent antiparasitic properties. These compounds are particularly effective as anpfelmintics, ectoparasiticides, insecticides and acaricides.

Antiparasitic agents are best administered to animals in the form of parenteral, subcutaneous or intramuscular preparations. Water is generally a suitable liquid for injection. In the present case, however, avermectins are poorly water soluble and simple aqueous solutions are too dilute. The aqueous solubility of some avermectins can be increased by the addition of surfactants and suitable organic solvents to form a micelle solution, as described in U.S. Patent 4,389,397. However, even these formulations do not guarantee sufficient doses of the active agent to completely remove both internal and external animal parasites.

European Patent Application 146414 discloses mixed solutions of avermectins in the form of mixtures of glycerin format and propylene glycol or propylene glycol containing a small amount of water. These compositions are suitable for parenteral use. However, propylene glycol is known to cause irritation following subcutaneous or intramuscular injections. In addition, small amounts of water in these formulations may cause hydrolytic degradation of avermectin.

Such formulations containing organic water-miscible solvents tend to form undesirable local clots of avermectin at the injection site. These precipitates may cause irritation and swelling at the injection site and insufficient and unbalanced antiparasitic effect.

The commercially available antiparasitic preparation Ivomec in injections for cattle, a formulation containing mixed solvents and avermectin, known as ivermectin, is only suitable for subcutaneous administration and may cause irritation and swelling at the injection site.

An alternative procedure for preparing an injectable solution of avermectin is to dissolve avennectin in a pharmaceutically acceptable oil. The use of peanut oil and cottonseed oil as well as ethyl oleate as solvents for some avermectins is described in British patent 166436. However, peanut oil and cottonseed oil do not provide a solution of the compound of formula G) at a concentration of at least 1% by weight. product. Veterinary preparations are generally used and stored on farms at low temperatures, for example around 4 ° C and although avermectin is sufficiently soluble at normal temperatures, at low temperatures it tends to precipitate as a supersaturated solution and is therefore unusable. Pure ethyl oleate and oil blends containing a large proportion of ethyl oleate are corrosive to some of the plastic or rubber parts of commonly used veterinary syringes to such an extent that their use is impermissible.

European Patent Application 285561 discloses pure sesame oil as a possible solvent for various classes of compounds referred to as milbemycins. Comparative studies of viscosity and injectability have shown that pure sesame oil has too high a viscosity to be used as a solvent for injectables for commonly used veterinary syringes. For this reason, pure sesame oil cannot be used as an injectable solvent for practical field conditions.

SUMMARY OF THE INVENTION

The present invention provides a parenteral preparation of a compound of formula (I), effective against both internal and external parasites, which is tolerated by animals by both subcutaneous and intremuscular administration and which is compatible with conventional injection equipment.

According to the invention, the formulation is a solution of 25-cyclohexylavermectin B1, a compound of formula (I), in a solvent of 50 to 95% by volume of sesame oil and the remainder of the ethyl acetate.

The solvent mixture is preferably comprised of 75 to 90% sesame oil and the remainder ethyl acetate.

The avermectin content for subcutaneous or intramuscular injection is preferably in the range of 1 to 30 mg / ml, most often about 10 mg / ml. The compositions of the invention are monophasic solutions suitable for the treatment of diseases caused by endoparasites, such as helminthiasis, which is most commonly caused by a group of parasitic worms, referred to as nematodes, and which cause significant economic losses in pigs, sheep, horses and cattle and domestic animals. animals and poultry. The compounds are also effective against other nematodes that attack different species of animals, such as Dirofilaria in dogs and against various other parasites that can attack humans, including gastrointestinal parasites such as Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichurisia , Enterobius and parasites found in the blood and other tissues and organs such as filigree worms and the extraintestinal stages of Strongyloides and Trichinella.

The compositions of the invention are further suitable for the treatment of ectoparasitic infections, including anthropodic ectoparasites of animals and birds, such as ticks, mites, lice, fleas, stinging insects and migrating winged larvae that attack cattle and horses.

It has surprisingly been found that the formulations of the invention exhibit superior properties over known formulations, in particular in that they cause little or no irritation at the injection site when administered by subcutaneous or intramuscular injection in animals, are suitable for use in commonly used standard syringes and provide a more balanced antiparasitic effect.

A further advantage of the compounds of the invention is that the formulation carrier contains unsaturated acid esters that prevent the oxidation of avermectin by air oxygen during long storage.

The solutions of the invention can be prepared by simply dissolving the compound of formula (G) in a mixture of sesame oil and ethyl oleate by conventional sterilization and packaging.

The compositions of the invention will be further described by way of example.

DETAILED DESCRIPTION OF THE INVENTION

Solutions of 25-cyclohexyl-avermectin B1 in oil formulations were prepared and tested by the following methods.

Example 1

The following ingredients were used to prepare an injectable solution containing 10 mg of compound I in 1 ml of a nominal mixture of 90/10 sesame oil and ethyl oleate:

Compound i ethyl oleate mg

0.1 ml sesame oil up to 1.0 ml

Ethyl oleate and sesame oil are mixed and heated to 80 ° C under nitrogen purge. Subsequently, the compound of formula I is added to the hot oils until complete dissolution and the resulting solution is cooled rapidly and the volume is made up to 1 ml with sesame oil as necessary. This final solution is sterilized by membrane filtration and packaged antiseptic.

Example 2

Using the procedure of Example 1, the following ingredients are used to prepare an injectable solution containing 10 mg of a compound of formula I in 1 ml of a nominal mixture of 50/50 sesame oil and ethyl oleate:

Compound I ethyl oleate mg

0.5 ml sesame oil to 1.0 ml

Example 3

Using the procedure of Example 1, the following ingredients are used to prepare an injectable solution containing 10 mg of a compound of formula I in 1 ml of a nominal mixture of 75/25 sesame oil and ethyl oleate:

Compound I ethyl oleate sesame oil to ml

0.25 ml

1.0 ml

Example 4

The activity of the compound of formula I against ectoparasites was determined by a modified procedure described by L. G. Cramer et al., V Vet Record, 122,611-612.

Compound I was administered to two groups of cows by subcutaneous injection at a dose of 20 µg / kg per day. Group A receives Compound I in an aqueous micelle solution formulation of North American Patent 4389397 containing 2.5 mg of Compound I, 120 mg of Tween 80 (Registered Trademark), 200 mg of glycerol fonmal, about 10 mg of benzyl alcohol and the remainder of the formulation up to 1 ml water. Group B was administered Compound I in the formulation of Example I. Treated groups, together with the control group for each test, were inoculated with Boophilus microplus larvae on days 0, 2, and 4, and the tick was allowed to develop into adulthood. Hicked female ticks were collected between days 21 and 32 and the average daily values recorded in Table I.

Table I

Mean daily number of B. microplus ticks Day Preparations based on micelle solutions Untreated control Preparations according to Example 1 untreated control 21 0 287 0 0 22 0 651 0 324 23 0 879 0 996 24 0 753 0 1 507 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 Pretty: 257 3 454 30 4 727

Treatment with the formulation of Example 1 slowed the development of adult female ticks and resulted in fewer ticks.

Example 5

Tolerance to avermectin preparations was determined after injection into bovine semimembrane muscle. Animals were gently sacrificed 7 and 14 days after injection and injection site and surrounding tissue removed. Tissues were examined by pathological procedures and tissue damage at the injection site evaluated according to the following system:

= normal, without visible damage

-1 = light scar = severe scar = necrotic residues <1.0 cm ³ = necrotic residues> 1.0 <2.5 cm ³ = necrotic residues> 2.5 cm ³

Values of 0, 1 and 2 are acceptable. Values higher than 2 represent necrotic residues. Compound I in the preparations of Examples 1 and 2 was administered to bovine animals by intramuscular injection at a dose of 200 µg / kg. The injection site reaction was compared to that of formulations based on mixed solutions of antiparasitic agents, ivermectin (trademark; Ivomec for cattle), which were administered at the same dose and in the same manner.

Table 2

Comparison of injection site reaction following intramuscular injection

treatment Day Number of animals Average values agent 7 5 0.4 according to pr. 1 14 10 0.0 agent 7 5 0.4 according to pr. 2 14 10 0.0 Ivomec 7 4 3.75 14 8 2.75

Compound I in the formulations of Examples 1 and 2 was better tolerated and resulted in only minor tissue damage 7 days after injection, which healed completely 14 days after injection. In contrast, Ivomec, given as an intramuscular injection, was poorly tolerated and necrotic tissue was still visible 14 days after injection.

Claims (8)

A solution based on 25-cyclohexyl-avermectin B1, characterized in that it contains 25-cyclohexyl-avermectin B1 in a solvent of 50 to 95% by volume of sesame oil, the remainder being ethyl oleate. 25-Cyclohexyl-avermectin B1-based solution according to claim 1, characterized in that the solvent is 75% to 90% by volume of sesame oil, the remainder being ethyl oleate. 25-Cyclohexyl-avermectin B1-based solution according to claim 1 or 2, characterized in that it contains 1 to 30 mg / ml of 25-cyclohexyl-avermectin B1. The 25-cyclohexyl-avermectin B1-based solution of claim 3, comprising about 10 mg / ml of 25-cyclohexyl-avermectin B1. 25-Cyclohexyl-avermectin B1-based solution according to any one of claims 1 to 4, characterized in that it is in the form of subcutaneous or intramuscular injection for animals. 25-Cyclohexyl-avermectin B1-based solution according to any one of claims 1 to 4, characterized in that and. that said solution is an antiparasitic solution. 7. A process for the preparation of a solution based on 25-cyclohexyl-avermectin B1, characterized in that 25-cyclohexyl-avermectin B1 is dissolved in a solvent of 50 to 95% by volume of sesame oil, the remainder being ethyl oleate. V76293H-03.0L2000 Process according to claim 7, characterized in that 25cyclohexyl avermectin B1 is dissolved in a solvent of 75 to 0% by volume of sesame oil, the remainder being ethyl oleate.