Pharmaceutical composition comprising progestogens and/or estrogens and 5-methyl-(6s)-tetrahydrofolate

Abstract

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 medicament comprising:
 5-methyl-(6S)-tetrahydrofolate   one or more estrogens, selected from the group of ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol, estetrol and conjugated equine estrogens and/or progestogens,   optionally vitamin B 6  and/or vitamin B 2 ,   and pharmaceutically acceptable excipients/carriers in the absence of Vitamin B 12 .   
     
     
         2 . The medicament as claimed in  claim 1 , comprising
 at least one progestogen selected from the group of 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, 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 the compounds disclosed in WO 00/66570, especially tanaproget or   a crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid or   5-methyl-(6S)-tetrahydrofolate, drospirenone and ethinylestradiol.   
     
     
         3 . The medicament as claimed in  claim 1  comprising 5-methyl-(6S)-tetrahydrofolate, drospirenone and ethinylestradiol, comprising
 a daily dose of from 0.1 to 10 mg of 5-methyl-(6S)-tetrahydrofolate or   a daily dose of from 0.4 to 1 mg of 5-methyl-(6S)-tetrahydrofolate or   a daily dose of 451 μg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid or   a daily dose of from 0.5 to 5 mg of drospirenone or   a daily dose of 3 mg of drospirenone or   a daily dose of from 10 to 50 μg of ethinylestradiol or   a daily dose of from 10 to 30 μg of ethinylestradiol or   a daily dose of 20 μg of ethinylestradiol or   a daily dose of 30 μg of ethinylestradiol or
 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 or 
 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. 
   
     
     
         4 . A kit comprising
 at least 20 daily dose units comprising the medicament of  claim 1  and   at least one daily dose unit comprising 5-methyl-(6S)-tetrahydrofolate, and optionally vitamin B 6  and/or vitamin B 2 ,   where the number of all the dose units present in the kit is at least 28 and   the dose units are disposed so that first the dose units comprising the medicament, and subsequently the dose units comprising only 5-methyl-(6S)-tetrahydrofolate, are to be taken.   
     
     
         5 . The kit as claimed in  claim 4  comprising
 20-30 daily dose units comprising the medicament and   1-10 daily dose units comprising 5-methyl-(6S)-tetrahydrofolate or   21-26 daily dose units comprising the medicament and   2-7 daily dose units comprising 5-methyl-(6S)-tetrahydrofolate   where the number of all the dose units present in the kit is 28 or   21 daily dose units comprising the medicament and   7 daily dose units comprising 5-methyl-(6S)-tetrahydrofolate or   24 daily dose units comprising the medicament and   4 daily dose units comprising 5-methyl-(6S)-tetrahydrofolate or   451 μg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid in each daily dose unit.   
     
     
         6 . The use of
 5-methyl-(6S)-tetrahydrofolate   one or more estrogens, selected from the group of ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol, estetrol or conjugated equine estrogen and/or progestogens,   optionally vitamin B 6  and/or vitamin B 2 ,   and pharmaceutically acceptable excipients/carriers in the absence of Vitamin B 12 , for producing a medicament for reducing the risk of disorders caused by folate deficiency and congenital malformations caused by folate deficiency for at least 6-10 weeks after termination of previous long-term and continual intake of this medicament.   
     
     
         7 . The use as claimed in  claim 6 ,
 characterized in that the preceding long-term regular intake amounts to at least 30 weeks or   where the progestogen is selected from the group of 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, 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 the compounds disclosed in WO 00/66570, especially tanaproget or   characterized in that the preceding long-term regular intake amounts to at least 30 weeks for reducing the risk of neural tube defects or   characterized in that the preceding long-term regular intake amounts to at least 30 weeks for reducing the risk of cardiac defects, in particular ventricular valve defects or   characterized in that the preceding long-term regular intake amounts to at least 30 weeks for reducing the risk of malformations of the urinary tract (urogenital defects) or   characterized in that the preceding long-term regular intake amounts to at least 30 weeks for reducing the risk of cleft lip, jaw and palate or   characterized in that the preceding long-term regular intake amounts to at least 30 weeks for reducing the risk of spontaneous abortions or   characterized in that the preceding long-term regular intake amounts to at least 30 weeks for reducing the risk of malignant disorders, in particular carcinoma of the breast or colon or   characterized in that the preceding long-term regular intake amounts to at least 30 weeks for reducing the risk of cardiovascular disorders or   characterized in that the preceding intake of at least 5-methyl-(6S)-tetrahydrofolate takes place in a slow-release form.   
     
     
         8 . The use of 5-methyl-(6S)-tetrahydrofolate, drospirenone and ethinylestradiol or
 the use of 451 μg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, 3 mg of drospirenone and 20 μg of ethinylestradiol   characterized in that the preceding long-term regular intake amounts to at least 30 weeks for reducing the risk of neural tube defects as claimed in  claim 6 .   
     
     
         9 . The kit as claimed in  claim 4 , comprising
 21 daily dose units comprising a medicament comprising
 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 
 optionally vitamin B 6  and/or vitamin B 2 , 
 and pharmaceutically acceptable excipients/carriers in the absence of Vitamin B 12  and 
   7 daily dose units comprising 5-methyl-(6S)-tetrahydrofolate or   24 daily dose units comprising a medicament comprising
 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 
 optionally vitamin B 6  and/or vitamin B 2 , 
 and pharmaceutically acceptable excipients/carriers in the absence of Vitamin B 12  and 
   4 daily dose units comprising 5-methyl-(6S)-tetrahydrofolate or   21 daily dose units comprising a medicament comprising
 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 
 optionally vitamin B 6  and/or vitamin B 2 , 
 and pharmaceutically acceptable excipients/carriers in the absence of Vitamin B 12  and 
   7 daily dose units comprising 5-methyl-(6S)-tetrahydrofolate.   
     
     
         10 . A method for formulating the medicament as claimed in  claim 1 , characterized in that the 5-methyl-(6S)-tetrahydrofolate is absorbed only after the granulation or
 A method for formulating the medicament as claimed in  claim 1 , characterized in that the 5-methyl-(6S)-tetrahydrofolate is absorbed only after the granulation, characterized in that low-substituted hydroxypropylcellulose is used as binder.   
     
     
         11 . The kit as claimed in  claim 4 , comprising more than 28 daily dose units, where at least 28 daily dose units comprise the medicament, and where at least one daily dose unit comprises 5-methyl-(6S)-tetrahydrofolate, and where the dose units are disposed so that firstly the dose units comprising the medicament, and subsequently the dose units comprising only 5-methyl-(6S)-tetrahydrofolate, are to be taken. 
     
     
         12 . The kit as claimed in  claim 11 ,
 in which the number of dose units comprising the medicament is 28 plus 21, 22, 23, 24, 25, 26 or 27 or an integral multiple of 28 plus 21, 22, 23, 24, 25, 26 or 27, and where the number of daily dose units which comprise only 5-methyl-(6S)-tetrahydrofolate is 7, 6, 5, 4, 3, 2 or 1 or   in which the number of dose units comprising the medicament is 28 plus 21, 22, 23, 24, 25, 26 or 27 or an integral multiple of 28 plus 21, 22, 23, 24, 25, 26 or 27, and where the number of daily dose units which comprise only 5-methyl-(6S)-tetrahydrofolate is 7, 6, 5, 4, 3, 2 or 1, in which the multiple is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.   
     
     
         13 . A kit comprising more than 28 daily dose units, where at least 28 daily dose units comprise the medicament of  claim 1 , where at least one daily dose unit is a placebo or a blank pill day, and where the dose units are disposed so that first the dose units comprising the medicament are to be taken. 
     
     
         14 . The kit as claimed in  claim 13 ,
 in which the number of dose units comprising the medicament is 28 plus 21, 22, 23, 24, 25, 26 or 27 or an integral multiple of 28 plus 21, 22, 23, 24, 25, 26 or 27, and where the number of placebos or blank pill days is 7, 6, 5, 4, 3, 2 or 1 or   in which the number of dose units comprising the medicament is 28 plus 21, 22, 23, 24, 25, 26 or 27 or an integral multiple of 28 plus 21, 22, 23, 24, 25, 26 or 27, and where the number of placebos or blank pill days is 7, 6, 5, 4, 3, 2 or 1, in which the multiple is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.   
     
     
         15 . The kit as claimed in  claim 11 , in which the dose units comprise the medicament comprising
 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.   
     
     
         16 . The kit as claimed in  claim 13 , in which the dose units comprise the medicament comprising
 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.   
     
     
         17 . The kit as claimed in  claim 11 , in which the dose units comprise the medicament comprising
 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.   
     
     
         18 . The kit as claimed in  claim 11 , in which the dose units comprising the medicament comprising
 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.