Pharmaceutical composition comprising progestogens and/or estrogens and 5-methyl-(6S)-tetrahydrofolate
View Patent ↗The present invention relates to a pharmaceutical composition which comprises progestogens, preferably drospirenone, estrogens, preferably ethinylestradiol and 5-methyl-(6S)-tetrahydrofolate, can be employed as oral contraceptive and moreover prevents disorders caused by folate deficiency in the consumers, in particular cardiovascular disorders and, after conception of the embryo, congenital malformations caused by folate deficiency such as, for example, neural tube defects, ventricular valve defects, urogenital defects, and cleft lip, jaw and palate, without masking the symptoms of vitamin B 12 deficiency, and at the same time even in the case of homozygous or heterozygous polymorphism of methylenetetrahydrofolate reductase facilitates unimpaired utilizability of the folate component 5-methyl-(6S)-tetrahydrofolate by the body and thus its biological activity for preventing the abovementioned congenital malformations caused by folate deficiency. In addition, a prolonged protective effect is maintained after discontinuation of the contraceptive.
1. A process for preparing a medicament comprising 5-methyl-(6S)-tetrahydrofolate, one or more estrogens and/or progestogens, optionally vitamin B 6 and/or vitamin B 2 , and a pharmaceutically acceptable carrier, the process comprising
granulating the one or more estrogens and/or progestogens, optionally vitamin Bo and/or vitamin B 2 , and the pharmaceutically acceptable carrier, such that granules are formed,
thereafter absorbing the 5-methyl-(6S)-tetrahydrofolate onto and/or into said granules, wherein the absorption of the 5-methyl-(6S)-tetrahydrofolate onto and/or into said granules is performed by dry admixture.
2. The process of claim 1 wherein said medicament comprises dienogest and no estrogen.
3. The process of claim 1 wherein said medicament comprises estrogen and progestogen.
4. The process of claim 1 wherein said medicament comprises progestogen and no estrogen.
5. The process of claim 1 wherein said medicament comprises a crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid.
6. The process of claim 1 wherein said medicament comprises a daily dose of 451 μg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid.
7. The process of claim 1 wherein said medicament comprises an amount of dienogest as a daily dose of 2-3 mg.
8. The process of claim 6 wherein said medicament comprises a daily dose of 451 μg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid.
9. The process of claim 1 wherein said medicament comprises dienogest and a pharmaceutically acceptable estradiol salt.
10. The process of claim 1 wherein said medicament comprises estrogen and no progestogen.
11. The process of claim 1 wherein the medicament is free of folic acid.
12. The process of claim 10 wherein the medicament is free of folic acid.
13. The process of claim 1 wherein the granulation of the one or more estrogens and/or progestogens, optionally vitamin B 6 and/or vitamin B 2 , and the pharmaceutically acceptable carrier is performed in the presence of a binder, and wherein the formed granules further contain said binder.
14. The process of claim 13 wherein the binder is starch.
15. A process for preparing a medicament comprising 5-methyl-(6S)-tetrahydrofolate, at least one estrogen which is ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol, estetrol or conjugated equine estrogens, and/or at least one progestogen, and a pharmaceutically acceptable carrier, the process comprising
granulating the at least one estrogen which is ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol, estetrol or conjugated equine estrogens, and/or at least one progestogen, and the pharmaceutically acceptable carrier, such that granules are formed,
thereafter absorbing the 5-methyl-(6S)-tetrahydrofolate onto and/or into said granules, wherein the absorption of the 5-methyl-(6S)-tetrahydrofolate onto and/or into said granules is performed by dry admixture.
16. The process of claim 15 wherein the granulation of the at least one estrogen which is ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol, estetrol or conjugated equine estrogens, and/or at least one progestogen, and the pharmaceutically acceptable carrier is performed in the presence of a binder, and wherein the formed granules further contain said binder.
17. The process of claim 16 wherein the binder is starch.
18. The process of claim 15 , wherein said at least one progestogen is levonorgestrel, norgestimate, norethisterone, dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (=etonogestrel), 17-deacetylnorgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, amgestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate, gastrinone, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol (=lynoestrenol), mecirogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone (=norethisterone), norethynodrel, norgestrel (including d-norgestrel and dl-norgestrel), norgestrienone, normethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one, tibolone, trimegestone, algestone-acetophenide, nestorone, promegestone, a 17-hydroxyprogesterone esters, 19-nor-17hydroxyprogesterone, 17alpha-ethynyltestosterone, 17alpha-ethynyl-19-nortestosterone, d-17beta-acetoxy-13beta-ethyl-17alpha-ethynylgon-4-en-3-one oxime or tanaproget.
19. The process of claim 15 wherein said medicament comprises a crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid.
20. The process of claim 18 wherein said medicament comprises a crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid.
21. The process of claim 18 wherein said medicament comprises a crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, drospirenone and ethinylestradiol.
22. The process of claim 18 wherein said medicament comprises d- or dl-norgestrel.
23. The process of claim 21 wherein said medicament comprises a daily dose of from 0.1 to 10 mg of said calcium salt, a daily dose of from 0.5 to 5 mg of drospirenone and a daily dose of from 10 to 50 μg of ethinylestradiol.
24. The process of claim 21 wherein said medicament comprises a daily dose of from 0.1 to 10 mg of said calcium salt, a daily dose of from 0.5 to 5 mg of drospirenone and a daily dose of from 10 to 30 μg of ethinylestradiol.
25. The process of claim 21 wherein said medicament comprises a daily dose of from 0.4 to 1 mg of said calcium salt, a daily dose of 3 mg of drospirenone and a daily dose of from 10 to 30 μg of ethinylestradiol.
26. The process of claim 21 wherein said medicament comprises a daily dose of from 0.1 to 10 mg of said calcium salt, a daily dose of 3 mg of drospirenone and a daily dose of from 10 to 30 μg of ethinylestradiol.
27. The process of claim 21 wherein said medicament comprises a daily dose of from 0.4 to 1 mg of said calcium salt, a daily dose of from 0.5 to 5 mg of drospirenone and a daily dose of from 10 to 30 μg of ethinylestradiol.
28. The process of claim 21 wherein said medicament comprises a daily dose of 451 μg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, a daily dose of 3 mg of drospirenone and a daily dose of 20 μg of ethinylestradiol.
29. The process of claim 21 wherein said medicament comprises a daily dose of 451 μg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, a daily dose of 3 mg of drospirenone and a daily dose of 30 μg of ethinylestradiol.