Pharmaceutical composition containing a tetrahydrofolic acid
View Patent ↗The present invention relates to solid pharmaceutical compositions, in particular to oral contraceptives, comprising a progestogen, such as drospirenone; an estrogen, such as ethinylestradiol; a tetrahydrofolic acid or a pharmaceutically acceptable salt thereof, such as calcium 5-methyl-(6S)-tetrahydrofolate; and at least one pharmaceutical acceptable excipient or carrier. The compositions of the invention provide good stability of the tetrahydrofolic acid upon storage while still ensuring a fast and reliable release of the estrogen and the progestogen present in the composition.
1. A tablet core comprising a solid pharmaceutical composition comprising,
particles comprising 3 mg of micronized drospirenone, 0.02 or 0.03 mg of ethinyl estradiol, 25-36 wt % (based on tablet core total weight) of microcrystalline cellulose, 52-63 wt % (based on tablet core total weight) of lactose monohydrate, and 0.42-0.49 mg of an alkaline earth metal salt of 5-methyl-(6S)-tetrahydrofolic acid,
wherein the in vitro dissolutions of drospirenone and the salt of 5-methyl-(6S)-tetrahydrofolic acid individually are such that at least 85% of each is dissolved from the composition within 30 minutes, as determined by the USP XXIX Paddle Method II using water (for drospirenone) and a 0.03% ascorbic acid aqueous solution (adjusted to pH 3.5 with 0.05 M phosphate buffer (for the salt of 5-methyl-(6S)-tetrahydrofolic acid) at 37° C. as the dissolution media and 50 rpm as the stirring rate, and
wherein the stability of the salt of 5-methyl-(6S)-tetrahydrofolic acid is such that at least 90% of said amount thereof is present in the composition after storage in a closed container for 12 months at 25° C. and 60% relative humidity.
2. The tablet according to claim 1 , wherein the ethinyl estradiol is in the form of an estrogen-β-cyclodextrin complex.
3. The tablet according to claim 1 , wherein the ethinyl estradiol is micronized.
4. The tablet according to claim 1 , wherein the estrogen-β-cyclodextrin complex is micronized.
5. The tablet according to claim 1 , wherein the salt of 5-methyl-(6S)-tetrahydrofolic acid is the calcium salt.
6. The tablet according to claim 5 , wherein the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid is in crystalline form.
7. The tablet according to claim 6 , wherein the crystalline form is the Type I crystalline form.
8. The tablet according to claim 1 , wherein the composition does not contain vitamin B12.
9. The tablet according to claim 1 , wherein the composition contains less than 2% polyvinylpyrrolidone (PVP) by weight of the composition.
10. The tablet according to claim 1 , wherein the tablet is coated.
11. The tablet according to claim 10 , wherein the tablet is film-coated.