Solid oral pharmaceutical compositions for isoxazoline compounds
A solid oral pharmaceutical composition for delivery of a pharmaceutically acceptable active ingredient to an animal where the composition comprises an isoxazoline compound, a solvent and an excipient, a process for the manufacture of such solid oral pharmaceutical composition and a method of controlling a parasite infection administering such solid oral pharmaceutical composition.
1. A soft chewable veterinary pharmaceutical composition comprising an isoxazoline compound of Formula (I)
Formula (I),
wherein
R 1 =halogen, CF 3 , OCF 3 , CN,
n=integer from 0 to 3,
R 2 =C 1 -C 3 -haloalkyl,
T=5- or 6-membered ring, which is optionally substituted by one or more radicals Y,
Y=methyl, halomethyl, halogen, CN, NO 2 , NH 2 —C═S, or two adjacent radicals Y form together a chain, especially a three or four membered chain;
Q=X—NR 3 R 4 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;
X=CH 2 , CH(CH 3 ), CH(CN), CO, CS,
R 3 =hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,
wherein Z A =hydrogen, halogen, cyano, halomethyl;
R 4 =hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl;
Or R 3 and R 4 together form a substituent selected from the group consisting of:
or a salt or solvate thereof, a macrocyclic lactone selected from the group of ivermectin, milbemycin, and moxidectin, a solid carrier and a solvent wherein the solvent is 2.0-35.0% w/w of the composition with solubility for the isoxazoline compound and wherein the solid carrier is microcrystalline cellulose.
2. The soft chewable veterinary pharmaceutical composition of claim 1 further comprising pamoic acid or a pharmaceutically acceptable salt thereof.
3. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the isoxazoline compound is fluralaner.
4. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the composition comprises an additional pharmaceutically active compound.
5. A method of preparing the composition of claim 1 comprising dissolving the isoxazoline compound in the solvent and then adsorbing the resulting solution on to the solid carrier excipient.
6. The method of claim 5 , where the solvent is 2-pyrrolidone or dimethyl acetamide.
7. The method of claim 6 , where the solvent is 2-pyrrolidone.
8. The method of claim 6 , where the solvent is dimethyl acetamide.
9. A method of controlling parasite infestation in an animal comprising administering to the animal a therapeutically effective amount of the composition of claim 1 .
10. A soft chewable veterinary pharmaceutical composition comprising an isoxazoline compound of Formula (I)
Formula (I),
wherein
R 1 =halogen, CF 3 , OCF 3 , CN,
n=integer from 0 to 3,
R 2 =C 1 -C 3 -haloalkyl,
T=5- or 6-membered ring, which is optionally substituted by one or more radicals Y,
Y=methyl, halomethyl, halogen, CN, NO 2 , NH 2 —C═S, or two adjacent radicals Y form together a chain, especially a three or four membered chain;
Q=X—NR 3 R 4 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;
X=CH 2 , CH(CH 3 ), CH(CN), CO, CS,
R 3 =hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,
wherein Z A =hydrogen, halogen, cyano, halomethyl;
R 4 =hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl;
Or R 3 and R 4 together form a substituent selected from the group consisting of:
or a salt or solvate thereof, a macrocyclic lactone selected from the group of ivermectin, milbemycin, and moxidectin, a solid carrier and a solvent wherein the solvent is 2.0-35.0% w/w of the composition with solubility for the isoxazoline compound and wherein the solvent is 2-pyrrolidone.
11. The soft chewable veterinary pharmaceutical composition of claim 10 wherein the solid carrier is microcrystalline cellulose.
12. The soft chewable veterinary pharmaceutical composition of claim 10 further comprising pamoic acid or a pharmaceutically acceptable salt thereof.
13. The soft chewable veterinary pharmaceutical composition of claim 10 wherein the isoxazoline compound is fluralaner.
14. A method of controlling parasite infestation in an animal comprising administering to the animal a therapeutically effective amount of the composition of claim 10 .