Granulates of hexahydropyrazine derivatives which can be...

Details Granulates of hexahydropyrazine derivatives which can be... Granulates of hexahydropyrazine derivatives which can be...

1999-01-13

2003-01-07

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S484000, C424S485000

Reexamination Certificate

active

06503536

ABSTRACT:

The present invention relates to the preparation of orally administrable granules of hexahydropyrazine derivatives and also to granules which are prepared by this process.
Hexahydropyrazine derivatives, such as, for example, praziquantel and epsiprantel, are known (see U.S. Pat. No. 4,001,411, EP-A 134,984). Because of the bitter taste of the active compounds, a simple oral administration to taste-sensitive animals, such as, for example, cats, is not easily possible. Likewise, it is not possible to convert the active compounds by customary methods of taste masking, such as salt formation with embonic acid or binding to ion exchangers, into orally administrable compositions. Experience has shown that even by taste masking with flavors or using encapsulated formulations, it is not possible to obtain compositions of these active compounds which can be administered orally to cats.
It is known that hexahydropyrazine derivatives, such as, for example, praziquantel, can be separated into their enantiomers by column chromatography using chiral packing materials, such as, for example, cellulose triacetate (see Lim Beegim, Ching, Chibun, Industrial & Engineering Chemnistry Research, Vol 35, 1996, 169-175; Lim Beegim, Ching, Chibun, Separations Technology, Vol 5, 1995, 213-228; Blaschke G, Journal of Liquid Chromatoraphy, Vol 9/2-3, 1986, 341-368). This separation is effected owing to the different weak interaction between the column packing and the enantiomers of the active compound. There are no indications that it is possible in this manner to obtain active compound/carrier complexes which have a neutral taste.
It has now been found that orally administrable formulations of hexahydropyrazine derivatives are obtained by mixing the active compound in the presence of suitable solvents with hydrophobic carriers, if appropriate in the presence of auxiliaries, and converting the resulting mixture, if appropriate, into other ready-to-use forms.
By the process according to the invention, hexahydropyrazine-derivative-containing granules are obtained which can be administered orally without problems even to animals which normally refuse hexahydropyrazine-derivative-containing formulations because of their bitter taste.
To prepare the granules according to the invention, it is sufficient to mix active compound and solvent separately or an active compound solution with the hydrophobic carrier to give granules which contain the active compound. Furthermore, it was surprising that the granules prepared in this manner are accepted orally without hesitation even by taste-sensitive animals.
The granules comprise the components:
hydrophobic carrier 80 to 99.9% by weight,
hexahydropyrazine derivatives 0.1 to 20% by weight,
if appropriate further auxiliaries.
Hexahydropyrazine derivatives are known from U.S. Pat. No. 4,001,411, EP-A 13498, EP-A 185 012. The structural formulae and the individual compounds which are mentioned therein are expressly incorporated herein by reference.
Particular mention may be made of:
praziquantel (2-cyclohexylcarbonyl)-1,3,3,6,7-11b-hexahydro-4H-pyrazino[2,1-a]-isoquinolin-4-one and
epsiprantel 2-(cyclohexylcarbonyl)-2,3,6,7,8,12b-hexahydro-pyrazino[2,1-a]benzazepin-3(1H)-one.
Hydrophobic carriers which may be mentioned are: cellulose esters, such as cellulose triacetate, cellulose 2,5-acetate, cellulose propionate, cellulose butyrate, hydrophobicized silica gels, such as, for example, the reveresed phase phases RP2(-dimethyl), RP4(-butyl), RP8(-octyl), RP18(-ocetadecyl), RP-phenyl, RP-nitrile, which are used in column chromatography, talc, bentionite and dimethyldioctylammonium bentionite (bentionite 34).
Preference is given to cellulose acetate.
Further anthelminthically active compounds may be added to the granules according to the invention, for use at an application rate per kg of 0.1 to 20 mg, preferably of 1 to 10 mg, particularly preferably of approximately 5 mg.
Such active compounds which may be mentioned are phenylguanidines, such as febantel or netobimin; benzimidazoles, such as fenbendazole, albendazole, oxibendazole, oxfendazole, mebendazole, tricabendazole, mebendazole, fenbendazole, parbendazole, luxabendazole; tetrahydropyrimidines, such as pyrantel, morantel, oxantel; ivermectines and avermectines such as ivermectin, abamectin, moxidectin, doramectin; milbemycines; levamisole, tetramisole; cyclic depsipeptides such as PF 1022.
To prepare the granules according to the invention, other auxiliaries such as preservatives, antioxidants, photostabilizers, colorants, absorption-promoting substances, disintegration-promoting substances, binders or lubricants and stabilizers may be added.
Suitable preservatives are, for example, benzyl alcohol, benzoic acid, p-hydroxybenzoic acid, propionic acid and its derivatives and salts and also sorbic acid and its derivatives and salts.
Suitable antioxidants are, for example, albumins; amino acids, ascorbic acid, its salts and derivatives; butylhydroxyanisole; butylhydroxytoluene; derivatized hydroquinones.
Suitable photostabilizers are, for example, derivatives of aromatics, compounds with a suitable absorption wavelength.
Suitable colorants are, for example, pigments, such as, for example, iron pigments, water-soluble colorants or colorants soluble in organic solvents.
Suitable bioabsorption-promoting substances are, for example, fatty acid, fatty acid esters and mixtures thereof, fatty alcohols, lecithin, bile acid salts.
Suitable stabilizers are, for example, sodium sulphite, EDTA and its salts.
Suitable lubricants are, for example, magnesium stearate, stearic acid, talc, bentonites; suitable disintegration-promoting substances are, for example, starch or cross-linked polyvinylpyrrolidone, suitable binders are, for example, starch, gelatin or linear polyvinylpyrrolidone and also dry binders such as microcrystalline cellulose.
The process according to the invention is carried out by mixing the active compounds and carriers in the presence of solvents. The order in which the components are added is not crucial. The solvents used are usually evaporated again during the preparation of the granules.
Thus, the carrier and auxiliary components can be charged initially in a conventional mixer and mixed. To this mixture, active compound is added in the form of its solution, and mixed.
Suitable solvents for the active compounds are, for example:
Mono- or polyhydric alcohols, such as methanol, propylene glycol, ethanol, isopropyl alcohol, ketones, such as acetone, aromatic and non-aromatic hydrocarbons, such as toluene, xylene, ligroin, ethyl acetate, water THF, methylene chloride, dioxane.
The concentration of the active compound (salt) solution is from 0.5 to 50%; preferably 10 to 40%.
The individual components can be mixed in any type of mixer. For example, high intensity mixers having chopping devices are particularly suitable for preparing a homogeneous mixture. The solutions employed or water are added to the dry mixture in any order, including alternately, continuously or batchwise, by tipping, pouring, spraying or atomizing.
The moist mixture is processed further and, for example, grated, dried, then, for example, sieved or micronized.
Likewise, granulation using the fluidized-bed process is a suitable method of preparation. For this purpose for example the solutions are sprayed onto the moving mixture using one or more nozzles and, if desired, dried in the process.
If particularly small particles are required, micronizing may be an option (for example by using an air impact, bead or trituration mill).
The granules prepared according to the invention can be admixed with other carriers, in foodstuff applications these can be for example single feeds or mixtures thereof. Such formulations can be extruded or pelletized in powder form, dry or moist. They can also be applied dry on food pellets. The addition of a binder may be useful. Suitable binders are, for example, vegetable, animal or synthetic oils, fats, fatty acids, fatty alcohols, waxes, gelatin. The granules prepared according to the process of the

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