TH90656B - Pharmaceutical compositions containing progestogen and/or estrogen and 5-methyl-(6S)-tetrahydrofolate. - Google Patents

Abstract

DC60 (28/09/52) This invention pertains to a pharmaceutical compound containing the progestogen, presumably dosspirinone, the estrogen, presumably ethinylestradiol, and 5-methyl-(6S)-tetrahydrofolate, which can be used as an oral contraceptive and, furthermore, prevents abnormalities caused by folate deficiency in consumers, particularly cardiovascular abnormalities and, after embryo fertilization, congenital functional abnormalities caused by folate deficiency, such as, for example, neural tube defects, ventricular defects, reproductive and excretory organ defects, and cleft lip, jaw and palate, without masking abnormalities of vitamin B12 deficiency, and at the same time, even in homozygous or heterozygous cases, the polymerization of methylenetetrahydrofolate reductase supports the non-degradable use of the folate component. 5-methyl-(6S)-tetrahydrofolate is bioavailable and therefore its biological action is to prevent congenital malformations caused by the aforementioned folate deficiency. Furthermore, the protective effect is prolonged even after discontinuation of contraception. This invention involves a pharmaceutical mixture containing a progestogen, preferably drospirenone; an estrogen, preferably ethinylestradiol; and 5-methyl-(6S)-tetrahydrofolate, which can be used as an oral contraceptive and also prevents malformations caused by folate deficiency in consumers, particularly cardiovascular abnormalities and, after embryo fertilization, congenital malformations. Congenital abnormalities caused by folate deficiency, such as, for example, neural tube defects, ventricular defects, reproductive and excretory organ defects, and cleft lip, jaw, and palate, without masking symptoms of vitamin B12 deficiency, and at the same time, even in homozygous or heterozygous cases, polymerization of methylenetetrahydrofolate reductase supports the non-degradable utilization of the folate component 5-methyl-(6S)-tetrahydrofolate by the body and thus the biological activity of such substance to prevent the aforementioned congenital abnormalities caused by folate deficiency. In addition, the protective effect persists even after cessation of contraception.

Claims (50)

Revised 23/02/2021. Claims 1. Method for formulation of a therapeutic substance comprising one or more estrogen and progesterone combinations, may include vitamin B6 and/or vitamin B2, and pharmaceutically acceptable drug fillers/carriers without vitamin B12, granulation of the mixture, and immediate addition of calcium salt of 5-methyl-(6S)-tetrahydrofolate after granulation. 2. Method for formulation of a drug under Claims 1 in which one or more estrogen is selected from a group consisting of ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrine, estriol, estretrol, and conjugated equinestrogen. 3. Method for formulation of a drug under Claims 1 or Claims 2 in which one or more progesterones are selected from a group consisting of Levonorgentrel, norgestimate, norethisterone, didrogesterone, dosspirinone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (=Etonogestrel), 17-Deacetylnorgestimate, 19-Norprogesterone, Acetoxypregnenolone, Allylestrinol, Amjestone, Chlormadinone, Cyproterone, Demegestone, Desogestrel, Dienogest, Dihydrogenesterone, Dimethisterone, Ethisterone, Ethinodiol Diacetate, Fluorogestone Acetate, Gastrione, Gestodine, Jestrinone, Hydroxymethylprogesterone, Hydroxyprogesterone, Linestrenol (Linoestrinol), Nesirogestone, Medoxyprogesterone, Megestrel, Melengestrel, Nomegestrel, Norethrindrone (Norethisterone), Norythinodrel, norgestrel, d-norgestrel, dl-norgestrel, norgestrienone, normethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-ine-3-one, thibolone, trimigestone, algestone-acetophenide, nestorone, promegestone, 17-hydroxyprogesterone ester, 19-nor-17hydroxyprogesterone, 17alpha-ethinyltestosterone, 17alpha-ethinyl-19-nortesnosterone, d-17beta-acetoxy-13beta-ethyl-17alpha-ethinilgon-4-N-3-oneoxym and Tanaproget ---------- Revised 28/03/2016 1. Method for formulation of a drug comprising: - a daily dose of 0.4 to 1 mg of 5-methyl-(6S)-tetrahydrofolate - one or more estrogen and/or progestogen and - one or more pharmaceutically acceptable drug filler/carrier without vitamin B12 in which 5-methyl-(6S)-tetrahydrofolate is absorbed only after granulation. 2. Method for formulation of a drug according to claim 1 in which one or more estrogen or More than one progestogen is selected from a group consisting of ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrain, estriol, estretrol, and conjugated equinestrogen. 3. Method for drug formulation according to claim 1 or claim 2 in which one or more progestogens are selected from a group consisting of... Levonorgestrel, norgestimate, norethisterone, dihydrogenesterone, dosspirinone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (= etonogestrel), 17-deacetylnorgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrinol, amjestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogenesterone, dimethisterone, ethisterone, ethinodiol diacetate, fluorogenestone acetate, gastrinon, gestodyne, gestrinone, hydroxymethylprogesterone. Hydroxyprogesterone, linestrenol (linoestrinol), nesirogestone, medoxyprogesterone, megestrol, melengestrol, nomegestrol, norythrindrone (norethisterone), norythinoderol, norgestrol, d-norgestrol, dI-norgestrol, norgestrienone, normethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-ine-3-one, thibolone, trimegestone, algestone-acetophenide, nestorone, promegestone, 17-hydroxyprogesterone ester. 19-nor-17hydroxyprogesterone, 17alpha-ethinyltestosterone, 17alpha-ethinyl-19-nortestosterone, d-17beta-acetoxy-13beta-ethyl-17alpha-ethinilgon-4-N-3-onoxime, and Tanaproget. 4. A method for formulating any drug under claims 1 through 3, in which the drug contains a crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid. 5. A method for formulating a drug under claim 1, in which the drug contains 5-methyl-(6S)-tetrahydrofolate, dosspirinone, and ethinylestradiol. 6. A method for formulating a drug under claim 5, in which the drug contains a crystalline calcium salt of 7. Method for compounding a drug formulation under claim 5 or claim 6, in which the drug contains a daily dose of 3 mg or more of dosspirinone. 8. Method for compounding a drug formulation under any one of claims 5 to 7, in which the drug contains a daily dose of 10 to 50 µg of ethinyl estradiol. 9. Method for compounding a drug formulation under any one of claims 5 to 7, in which the drug contains a daily dose of 10 to 30 µg of ethinyl estradiol. 10. Method for compounding a drug formulation under any one of claims 5 to 7, in which the drug contains a daily dose of 20 µg of ethinyl estradiol. 11. Method for compounding a drug formulation under any one of claims 5 to 7, in which the drug contains a daily dose of 20 µg of ethinyl estradiol. 7. Any one of the following, in which the drug is composed of: - a daily dose of 30 µg of ethinylestradiol; 12. Method for compounding the drug under claim 5, in which the drug is composed of: - a daily dose of 451 µg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, - a daily dose of 3 mg of dosspirinone, and - a daily dose of 20 µg of ethinylestradiol; 13. Method for compounding the drug under claim 5, in which the drug is composed of: - a daily dose of 451 µg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, - daily dose of 3 mg of dosspirinone and - daily dose of 30 µg of ethinylestradiol. 14. Drugs formulated by any of the methods specified in claims 1 through 13. --------------------------------------------------- 1. Therapeutic agents consisting of: - 5-methyl-(6S)-tetrahydrofolate, - one or more estrogen and/or progestogen, - possibly optional vitamin B6 and/or vitamin B2, - and pharmaceutically acceptable fillers/carriers. 2. Therapeutic agents as claimed in Patent 1, which contain at least one estrogen selected from the group of ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrain, estriol, estretrol and conjugated equinestrogen. 3. Therapeutic agents as claimed in Patent 1, which include at least one progestogen selected from a group of... Levonorgestrel, norgestimate, norethisterone, dihydrogenesterone, dosspirinone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (= etonogestrel), 17-deacetylnorgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrinol, amjestone, chlormadinone, cyproterone, demegestone, desogestrel, diednogest, dihydrogenesterone, dimethisterone, ethisterone, ethinodiol diacetate, fluorogenstone acetate, gastrinon, gestodyne, gestrinone, hydroxymethylprogesterone. Hydroxyprogesterone, linestrenol (= linoestrinol), mezerogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norythrindrone (= norethisterone), norythinoderol, norgestrel (including d-norgestrel and dl-norgestrel), norgestrienon, normethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-ine-3-one, thibolone, trimegestone, algestone acetophenide, nestorone, promegestone, 17-hydroxyprogesterone ester. 19-nor-17hydroxyprogesterone, 17alpha-ethinyltestosterone, 17alpha-ethinyl-19-nortestosterone, d-17beta-acetoxy-13beta-ethyl-17alpha-ethinylgon-4-n-3-onoxym, especially thanaproget. 4. Therapeutic substance as claimed in claim 1, which consists of a crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid. 5. Therapeutic agents as claimed in claim 1, which include 5-methyl-(6S)-tetrahydrofolate, dosspirinone and ethinylestradiol. 6. Therapeutic substance as claimed in claim 5, consisting of a dose of 0.1 to 10 mg of 5-methyl-(6S)-tetrahydrofolate per unit dose. 7. Therapeutic substance as claimed in claim 5, consisting of a dose of 0.4 to 1 mg of 5-methyl-(6S)-tetrahydrofolate per unit dose. 8. Therapeutic substance as claimed in claim 5, consisting of a dose of 451 μg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid per unit dose. 9. Therapeutic substance as claimed in claim 5, consisting of a dose of 0.5 to 5 mg of dosspirinone per unit dose. 10. Therapeutic agents as claimed in claim 5, which include a dosage of 3 mg or more of dosspirinone per unit dose. 11. Therapeutic substance as claimed in claim 5, consisting of a dose of 10 to 50 mug of ethinylestradiol per unit dose. 12. Therapeutic substance as claimed in claim 5, consisting of a dose of 10 to 30 mug of ethinylestradiol per unit dose. 13. Therapeutic substance as claimed in claim 5, consisting of a dose of 20 mug of ethinylestradiol per unit dose. 14. Therapeutic substance as claimed in claim 5, consisting of a dose of 30 mug of ethinylestradiol per unit dose. 15. Therapeutic agents as claimed in claim 5, which include: - a dose of 451 μg of calcium salt of 5-methyl-(6S)-tetrahydrofolic acid per unit dose, - a dose of 3 mg of dosspirinone per unit dose, and - a dose of 20 μg of ethinylestradiol per unit dose. 16. Therapeutic agents as claimed in claim 5, which include: - a dose of 451 μg of calcium salt of 5-methyl-(6S)-tetrahydrofolic acid per unit dose, - a dose of 3 mg of dosspirinone per unit dose and - a dose of 30 μg of ethinylestradiol per unit dose. 17. A drug kit consisting of - at least 20 drug units containing the therapeutic substance as entitled under any of the preceding claims, and - at least one drug unit containing 5-methyl-(6S)-tetrahydrofolate, and may optionally contain vitamin B6 and/or vitamin B2, - in which the total number of drug units contained in the kit is at least 28 units, and - the drug units are divided so that the first drug unit contains the therapeutic substance as entitled under any of the preceding claims, and then only the drug unit containing 5-methyl-(6S)-tetrahydrofolate is administered. 18. A drug kit as entitled in claim 17, consisting of - 20-30 drug units containing any one of the therapeutic agents entitled in claims 1 through 16, and - 1-10 drug units containing 5-methyl-(6S)-tetrahydrofolate. 19. A drug kit as entitled in Claim 17, consisting of - 21-26 drug units containing any one of the therapeutic agents entitled in Claim 1 through 16, and - 2-7 drug units containing 5-methyl-(6S)-tetrahydrofolate - where the total number of drug units in the kit is 28. 20. A drug kit as entitled in claim 17, comprising - 21 drug units containing any one of the therapeutic agents entitled in claims 1 through 16 and - 7 drug units containing 5-methyl-(6S)-tetrahydrofolate. 21. A drug kit as entitled in claim 17, consisting of - 24 drug units containing any one of the therapeutic agents entitled in claims 1 through 16, and - 4 drug units containing 5-methyl-(6S)-tetrahydrofolate. 22. A drug kit as entitled in claim 17, consisting of 451 μg of the calcium salt of 5-methyl-(6S)-tetrahydrofolic acid per unit dose. 23. Use of - 5-methyl-(6S)-tetrahydrofolate - one or more estrogen and/or progestogen, - may be optional with vitamin B6 and/or vitamin B2 - and pharmaceutically acceptable drug additives/carriers for the production of therapeutic agents to reduce the risk of folate deficiency-related disorders and congenital folate deficiency-related dysfunctions for at least 6–10 weeks following discontinuation of therapeutic agents for a long and continuous period. 24. Use as entitled in claim 23, which is characterized by a consistent dose received over a prior period of at least 30 weeks. 25. Use as provided for in claim 23 or 24, whereby estrogen is selected from the group of ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrain, estriol, estetrol, or conjugated quinestrogen. 26. Use as provided for in claims 23 or 24, whereby progestogens are selected from the group of levonorgestrel, norgestimate, norethisterone, dihydrogenesterone, dosspirinone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (= etonogestrel), 17-deacetylnorgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrinol, amjestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogenesterone, dimethisterone, ethisterone, ethinodiol diacetate, fluorogenstone acetate, gastrione, gestodine, Gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, linestrinol (= linoestrinol), mesirogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norythrindrone (= norethisterone), norythinoderol, norgestrel (including d-norgestrel and dl-norgestrel), norgestrienon, normethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-ine-3-one, thibolone, trimegestone, algestone acetophenide, nestorone, promegestone. 17-hydroxyprogesterone ester, 19-nor-17hydroxyprogesterone, 17alpha-ethinyltestosterone, 17alpha-ethinyl-19-nortestosterone, d-17beta-acetoxy-13beta-ethyl-17alpha-ethinylgon-4-n-3-onoxym, specifically Thanaproget. 27. Use as claimed in claim 25 or 26 for the reduction of risk of neural tube defects. 28. Use as entitled under claim 25 or 26 for the reduction of risk of cardiac defects, particularly ventricular defects. 29. Use as claimed under claim 25 or 26 for the reduction of risk of urinary tract dysfunction (reproductive and excretory organ dysfunction). 30. Use as entitled under claim 25 or 26 for the reduction of risk of cleft lip, jaw, and palate. 31. Use as claimed under claim 25 or 26 for reducing the risk of natural miscarriage. 32. Use as claimed under claim 25 or 26 for the reduction of the risk of serious abnormalities, particularly breast or colon carcinomas. 33. Use as entitled under claim 25 or 26 for reducing the risk of cardiovascular abnormalities. 34. Use of 5-methyl-(6S)-tetrahydrofolate, dosspirenone and ethinylestradiol as provided in any one of the rights under Clauses 27 through 33. 35. Use of 451 μg of calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, 3 mg of dosspirinone, and 20 μg of ethinylestradiol as provided for in any one of claims 27 through 33. 36. Use of 451 μg of calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, 3 mg of dosspirinone, and 30 μg of ethinylestradiol as entitled in any one of claims 27 through 33. 37. Use as provided for in claims 23 or 24, which is characterized by the prior acquisition of at least 5-methyl-(6S)-tetrahydrofolate in a slow-release form. 38. A drug kit as entitled in claim 17, comprising - 21 drug units containing the therapeutic substance entitled in claim 15 and - 7 drug units containing 5-methyl-(6S)-tetrahydrofolate. 39. A drug kit as entitled in claim 17, comprising - 24 drug units containing the therapeutic substance entitled in claim 15 and - 4 drug units containing 5-methyl-(6S)-tetrahydrofolate. 40. A drug kit as entitled in claim 17, comprising - 21 drug units containing the therapeutic substance entitled in claim 16 and - 7 drug units containing 5-methyl-(6S)-tetrahydrofolate. 41. Any method for the preparation of therapeutic compounds in any of the patents 1 through 16, which is characterized by the fact that 5-methyl-(6S)-tetrahydrofolate is adsorbed only after granulation. 42. The method as claimed in claim 41, which is characterized by the use of low-substitute hydroxypropyl cellulose as a binder. 43. A drug set entitled under claim 17, consisting of more than 28 drug units, in which at least 28 drug units contain any one of therapeutic agents entitled under claims 1 through 16, and in which at least one drug unit contains 5-methyl-(6S)-tetrahydrofolate, and in which the unit is divided so that the first drug unit contains any one of therapeutic agents entitled under claims 1 through 16 and the subsequent drug units contain only 5-methyl-(6S)-tetrahydrofolate, shall be received. 44. A drug set as entitled under claim 43, in which the number of drug units containing any one of the therapeutic agents entitled under claims 1 through 16 is 28 plus 21, 22, 23, 24, 25, 26 or 27, or an integer of 28 plus 21, 22, 23, 24, 25, 26 or 27, and in which the number of days of drug units containing only 5-methyl-(6S)-tetrahydrofolate is 7, 6, 5, 4, 3, 2 or 1. 45. A set of medicines as entitled in claim 44, which is multiplied by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. 46. A drug set consisting of more than 28 drug units, of which at least 28 drug units contain therapeutic substances as claimed in any of Requisitions 1 through 16, of which at least one unit of a drug unit is a placebo day or an empty pill, and of which the drug units are divided so that the first drug unit contains therapeutic substances as claimed in any of Requisitions 1 through 16. 47. A drug set as entitled in Claim 46, where the number of drug units comprising any of the drug units entitled in Claim 1 through 16 is 28 plus 21, 22, 23, 24, 25, 26 or 27 or an integer multiple of 28 plus 21, 22, 23, 24, 25, 26 or 27, and where the number of days of placebo or drug-free pills is 7, 6, 5, 4, 3, 2 or 1. 48. A set of medicines as entitled in claim 47, which is multiplied by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. 49. A pharmaceutical kit as entitled under any of Claims 43 through 48, in which a pharmaceutical unit is composed of a therapeutic substance as entitled under Claim 15. 50. A drug kit as entitled under any of Claims 43 through 48, in which a drug unit is composed of a therapeutic substance that is also a therapeutic substance as entitled under Claim 16.