Pharmaceutical composition comprising pimobendan
The invention relates to novel solid formulations comprising as pharmaceutically active compound pimobendan and to processes for producing such solid formulations. The invention furthermore relates to a method for manufacturing a medicament for the prevention and/or treatment of congestive heart failure, wherein the solid formulations according to the invention are used.
1. A solid formulation comprising a homogenous dispersion of:
pimobendan or a pharmaceutically acceptable salt thereof provided in an amount of 0.5 mg to 20 mg;
a polyvalent acid selected from the group consisting of citric acid, tartaric acid, an anhydride thereof and mixtures thereof, wherein the polyvalent acid is present in an amount of 2.5 percent to 10 percent by weight of said solid formulation, and wherein the solid formulation includes a weight ratio of 1:10 to 1:40 of pimobendan to polyvalent acid; and
a flavor acceptable to small animals, wherein the flavor is present in an amount of 5 to 30 percent by weight of said solid formulation.
2. The solid formulation of claim 1 , further comprising carriers or excipients, where the carriers or excipients are selected from the group consisting of diluents, disintegrants, carriers, binders, flow regulators, lubricants, solvents and mixtures thereof.
3. The solid formulation of claim 2 , further comprising starch and lactose.
4. The solid formulation of claim 3 , wherein the starch is selected from the group consisting of native starch, gelatinized starch, partly gelatinized starch, starch powder, starch granules, chemically modified starch, swellable physically modified starch and mixtures thereof.
5. The solid formulation of claim 4 , wherein the starch is corn starch.
6. The solid formulation of claim 3 , wherein the lactose consists of coarse particles greater than 200 μm in size.
7. The solid formulation of claim 1 , comprising 1.25 mg, 2.5 mg, 5 mg, or 10 mg of pimobendan.
8. The solid formulation of claim 1 , wherein the weight of the whole solid formulation is in the range of 250 to 3000 mg.
9. The solid formulation of claim 1 , wherein the solid formulation is a tablet or a granule.
10. The solid formulation of claim 1 , wherein the solid formulation comprises 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and lactose, corn starch, croscarmellose-sodium, 50 mg/g citric acid, artificial beef flavor, polyvidone, colloidal anhydrous silica and magnesium stearate.
11. A solid formulation comprising a homogenous dispersion of:
pimobendan or a pharmaceutically acceptable salt thereof provided in an amount of 0.5 mg to 20 mg;
a polyvalent acid selected from the group consisting of citric acid, tartaric acid, an anhydride thereof and mixtures thereof, wherein the polyvalent acid is present in an amount of 2.5 percent to 10 percent by weight of said solid formulation, and wherein the solid formulation includes a weight ratio of 1:10 to 1:40 of pimobendan to polyvalent acid;
starch in an amount of 25 to 50 percent by weight of said solid formulation;
lactose in an amount of 25 to 50 percent by weight of said solid formulation; and
a flavor acceptable to small animals, wherein the flavor is present in an amount of 5 to 30 percent by weight of said solid formulation.
12. The solid formulation of claim 11 , comprising 1.25 mg, 2.5 mg, 5 mg or 10 mg of pimobendan.
13. The solid formulation of claim 11 , characterized in that the solid formulation is a tablet or a granule.
14. The solid formulation of claim 1 , wherein the solid formulation exhibits a dissolution profile, utilizing a paddle dissolution method at a rotation speed 75 RPM and a buffer pH of 4.0, in which a majority of the solid formulation has dissolved at 30 minutes.
15. The solid formulation of claim 11 , wherein the solid formulation exhibits a dissolution profile, utilizing a paddle dissolution method at a rotation speed 75 RPM and a buffer pH of 4.0, in which a majority of the solid formulation has dissolved at 30 minutes.
16. The solid formulation of claim 1 , wherein the content uniformity of the pimobendan or the pharmaceutically acceptable salt thereof is 94.8 percent or greater.
17. The solid formulation of claim 11 , wherein the content uniformity of the pimobendan or the pharmaceutically acceptable salt thereof is 94.8 percent or greater.
18. The solid formulation of claim 1 , wherein the flavor is homogenously dispersed within the solid formulation.
19. The solid formulation of claim 1 , wherein the solid formulation is obtained by an aqueous manufacturing process.
20. The solid formulation of claim 1 , wherein the solid formulation is obtained by an aqueous fluid-bed granulation process.
21. The solid formulation of claim 1 , wherein the solid formulation is obtained by a fluid-bed granulation process, the fluid-bed granulation process comprising the following steps:
a) spraying an aqueous solution of pimobendan and a binder onto a solid support comprising at least one excipient, a flavor and citric acid anhydrous to form a mixture;
b) drying the mixture of a);
c) sieving and de-agglomerating the mixture of b);
d) adding a flow regulator to the mixture of c);
e) adding a lubricant to the mixture of d); and
f) blending the mixture of e) for uniformity of granules to obtain final granules.
22. The solid formulation of claim 21 , wherein the fluid-bed granulation
process further comprises:
g) compressing the final granules of f) to tablets.
23. The solid formulation of claim 16 , wherein the content uniformity is blend uniformity.
24. The solid formulation of claim 16 , wherein the content uniformity of the pimobendan or the pharmaceutically acceptable salt thereof is at least 98.0 percent.