Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/18—Feminine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to a pharmaceutical composition for contraception and to reduce the risk of congenital malformations, which in a daily dose 0 - 2.0 mg 17 ⁇ -cyanomethyl-17- ⁇ -hydroxyestra-4,9-diene-3on (dienogest) and 0.015 mg 17 ⁇ - Ethinylestradiol (ethinylestradiol) and (6S) -5-methyl-tetrahydrofolate ((6S) -5-MTHF) or
• the invention relates to a kit which contains 21 daily dosage units of the aforementioned active ingredient combination and 7 daily dosage units with (6S) -5-MTHF.
• the invention also relates to a tablet, preferably a film-coated tablet, with the aforementioned active ingredient combination.
• dienogest is proportional, (6S) -5-MTHF not or proportionately or contained as total content and in the film coating, the other part of dienogest, (6S) -5-MTHF not or proportionately or as total content and ethinylestradiol as the total content. 5 State of the art
• Oral contraceptive agents consisting of a progestagen component and an estrogen component first appeared on the market in the early 1960s.
• WO 98/004269 discloses u. a. oral administration of a combination of 250 ⁇ g - 4 mg dienogest and 10 ⁇ g - 20 ⁇ g ethinylestradiol for contraception. To achieve the substantial reduction in the total contraceptive steroid administered per cycle while maintaining good cycle control, the low dose gestagen / estrogen combination is administered for 23 to 25 days of a 28-day menstrual cycle.
• the patent does not disclose any results and data demonstrating that the inventive idea is also successful and what type of release of the steroids is sought.
• Folic acid also pteroyl-mono-glutamic acid, N- (4 - (((2-amino-1,4-dihydro-4-oxo-6-pteridinyl) methyl) amino) benzoyl) glutamic acid (empirical formula: C 19 H 19 N 7 ) O 6 ), called folinic acid, is a heat- and light-sensitive, water-soluble vitamin from the vitamin B complex (vitamin B 9 ). It is known that folates predominantly exist in the diet as pteroyl polyglutamate. These are hydrolyzed after ingestion first in the mucosa cells to pteroyl monoglutamates, then mainly absorbed in the intestine by active transport.
• the predominantly unmethylated folates are converted into methylated folates and bound to the cells mainly as 5-methyltetrahydrofolate (5-MTHF) bound to albumin and ⁇ -macroglobulin, where they are taken up, demethylated and converted into the polyglutamate form.
• 5-MTHF 5-methyltetrahydrofolate
• Demethylation involves the amino acid homocysteine and an enzyme that requires vitamin B 12 as a coenzyme.
• a concentration above 10 ⁇ mol / l is considered critical and from 12 ⁇ mol / l there is need for action.
• enzyme defects can also cause an increase in the homocysteine concentration.
• the connection between increased homocysteine concentrations in the blood and vascular diseases, for example, as a risk factor for cardiovascular diseases has been discussed for some time. It is also discussed whether folic acid / folate can protect against malignant diseases because of its importance for DNA methylation and DNA strand stability.
• congenital malformations such as congenital heart defects, congenital malformations of the urinary tract, acute lymphoblastic leukemia, cleft lip and palate or malformations of the central nervous system, such as neural tube effects (spina bifida or Anencephaly).
• WO 2003/070255 discloses an oral contraceptive, or a kit for oral, hormonal contraception, which contains estrogens and / or gestogens, tetrahydrofolates and mandatory vitamin B 12 or optionally vitamin B 6 .
• WO 2005/1 15349 discloses a dosage form for hormonal contraception with hormone-containing daily units and hormone-free daily units, wherein the hormone-containing daily units contain up to 200 ⁇ folic acid and the hormone-free daily units greater than 200 ⁇ g folic acid.
• Patent EP 0 898 965 claims the use of 5-methyl- (6S) -tetrahydrofolic acid or its pharmaceutically acceptable salts for the prevention of neural tube defects.
• EP 1 044 975 discloses crystalline salts of 5-methyl- (6R 1 S) -, - (6S) -and- (6R) -tetrahydrofolic acid and use as a food supplement ingredient.
• the object of the invention is to disclose a pharmaceutical composition based on dienogest and ethinylestradiol whose steroidal dosage is reduced and which simultaneously reduces the risk of congenital malformations after the onset of pregnancy.
• a pharmaceutical composition for contraception and for reducing the risk of congenital malformations containing in a daily dose of 2.0 mg of ma- cyanomethyl-17-.beta.-hydroxyestra-4,9-dien-3-one (dienogest) and 0.015 mg 17 ⁇ -ethinylestradiol (ethinylestradiol) and (6S) -5-methyltetrahydrofolate ((6S) -5-MTHF) or 1 .5 mg dienogest and 0.015 mg ethinylestradiol and (6S) -5-methyl-tetrahydrofolate ((6S) -5 -MTHF) together with one or more pharmaceutically acceptable excipients / carriers.
• (6S) -5-MTHF or (6S) -5-methyltetrahydrofolic acid may also be referred to as 5-methyl- (6S) -tetrahydrofolate or 5-methyl- (6S) -tetrahydrofolic acid.
• (6S) -5-MTHF the free acid form and pharmaceutically acceptable salts and modifications of (6S) -5-methyltetrahydrofolic acid (N- [4 - [[(2-amino-1, 4,5, 6,7,8-hexahydro-4-oxo-5-methyl- (6S) -pteridinyl) methyl] amino] benzoyl] -L-glutamic acid).
• Pharmaceutically acceptable salts should be pharmacologically as well as pharmaceutically acceptable. Such pharmacologically and pharmaceutically ver Suitable salts may be alkali or alkaline earth metal salts, preferably sodium, potassium, magnesium or calcium salts.
• the calcium salt of (6S) -5-methyltetrahydrofolic acid (metafolin) can be used in various suitable crystalline forms.
• the crystalline calcium salt of (6S) -5-methyltetrahydrofolic acid (metafolin) is used according to the invention as (6S) -5-MTHF.
• the calcium salt of (6S) -5-methyltetrahydrofolic acid (metafolin) is used in a dosage of 0.4 to 1 mg, preferably 451 ⁇ g.
• the aforementioned calcium salt can be used as a racemate in a dosage of 100 to 800 ⁇ g or used in a microencapsulated form.
• (6S) -5-MTHF also (6R) -5-methyl tetra-hydrofolate be used in approximately double the dosage.
• the object is also achieved according to the invention with a tablet, preferably a film-coated tablet, with the aforementioned active ingredient combination.
• dienogest is proportional, (6S) -5-MTHF not or proportionally or as total content and in the film coating the other part of dienogest, (6S) -5-MTHF not or proportionately or as total content and ethinylestradiol contained as a total content ie the film-coated tablet has one
• the proportion of dienogest and the proportion of (6S) -5-MTHF are at least 10%, preferably 30% or optionally the total content of (6S) -5-MTHF almost completely retarded after greater than 30 minutes dissolved out of the tablet core, as with the dissociation lutionstest using water at 37 0 C as dissolution medium and 50 determines U / min as stirring speed. The determination is made according to Ph.Eur. using a rotary basket apparatus using 1000 ml of water.
• the content of dienogest as well as the total content of ethinylestradiol as well as the total content of (6S) -5-MTHF from the film coating are at least 75% dissolved out in a maximum of 45 minutes, preferably 70% in 30 minutes, as with the dissolution test below Use of water with 37 0 C as the dissolution medium and 50 U / min determined as the stirring speed. It is also conceivable that in the second phase, together with the proportion of dienogest, a proportion of ethinyl estradiol is released from the total content of ethinyl estradiol, preferably released from the tablet core.
• the object is also achieved by a kit comprising 21 daily dosage units of 2.0 or 1.5 mg of dienogest and in each case 0.015 mg of 17 ⁇ -ethinylestradiol and (6S) -5-MTHF, preferably 451 ⁇ g of the calcium salt of the 5-methyl- (6S) -tetrahydrofolic acid (metafolin) in each daily unit dose or and containing 7 daily dosage units with (6S) -5-MTHF alone without steroid combination, preferably 451 ⁇ g metafolin in each daily unit dose.
• the task can also be solved by a kit,
• (6S) -5-MTHF which comprises 22 to 24 daily dosage units of 2.0 or 1.5 mg of dienogest and 0.015 mg each of 17 ⁇ -ethinylestradiol and (6S) -5-MTHF and 4 to 6 daily dosage units with (6S) -5-MTHF alone without steroid combination, preferably as (6S) -5-MTHF contains 451 ⁇ g of the calcium salt of 5-methyl- (6S) -tetrahydrofolic acid (metafolin) in each daily unit dose or
• the object is also achieved according to the invention by the use of the indicated active ingredient combination of 2.0 mg or 1 .5 mg dienogest and 0.015 mg ethinylestradiol and (6S) -5-MTHF together with one or more pharmaceutically acceptable excipients / carriers for the preparation of a pharmaceutical composition - to reduce the risk of congenital deficiency-induced congenital malformations in pregnancy.
• Ethinylestradiol can also ethinylestradiol beta-cyclodextrin complex can be used.
• ethinylestradiol-beta-cyclodextrin complex (1: 2) is maximum or about ten times the amount used.
• Example 1 Tablets having the following composition are prepared:
• Ethinylestradiol may also be an ethinylestradiol-beta-cyclodextrin complex.
• ethinylestradiol-beta-cyclodextrin complex (1: 2) is maximum or about ten times the amount used. All substances are suitably mixed and granulated. The metafolin is taken up after completion of the granulation process, remixing, tableting and, if appropriate, filming.
• Healthy young women of child-bearing age are bled 8 weeks apart and the erythrocyte folate level is checked with a validated microbiological, immunological or instrumental (eg HPLC, LC-MS / MS) method or a suitable combination of these methods.
• a validated microbiological, immunological or instrumental eg HPLC, LC-MS / MS

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Gynecology & Obstetrics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Steroid Compounds (AREA)

Priority Applications (1)

Applications Claiming Priority (4)

Publications (1)

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• 2007
  • 2007-05-05 WO PCT/EP2007/003982 patent/WO2008003363A1/de active Application Filing
  • 2007-05-05 DE DE112007001600T patent/DE112007001600A5/de not_active Withdrawn
  • 2007-05-05 JP JP2009516918A patent/JP2009542588A/ja active Pending
  • 2007-05-05 MX MX2009000256A patent/MX2009000256A/es not_active Application Discontinuation
  • 2007-05-05 EP EP07724906A patent/EP2037935A1/de not_active Withdrawn
  • 2007-05-05 KR KR1020097002387A patent/KR20090029824A/ko not_active Application Discontinuation
  • 2007-05-05 BR BRPI0713999-3A patent/BRPI0713999A2/pt not_active Application Discontinuation
  • 2007-05-05 CA CA002665788A patent/CA2665788A1/en not_active Abandoned
  • 2007-05-05 RU RU2009102443/15A patent/RU2009102443A/ru not_active Application Discontinuation
  • 2007-07-03 US US11/773,037 patent/US20080268048A1/en not_active Abandoned
  • 2007-07-04 UY UY30461A patent/UY30461A1/es not_active Application Discontinuation
  • 2007-07-05 CL CL2007001961A patent/CL2007001961A1/es unknown
  • 2007-07-05 PE PE2007000865A patent/PE20080400A1/es not_active Application Discontinuation
  • 2007-07-06 TW TW096124769A patent/TW200810764A/zh unknown
  • 2007-07-06 AR ARP070103017A patent/AR061959A1/es not_active Application Discontinuation
• 2008
  • 2008-12-24 IL IL196154A patent/IL196154A0/en unknown

Non-Patent Citations (1)

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