EP2194978A1 - Use of gestagens in combination with (6s)-5-methyltetrahydrofolate for the therapy of endometriosis with simultaneous reduction of therapy side effects and the reduction of the risk of congenital malformations in case of pregnancy - Google Patents

Use of gestagens in combination with (6s)-5-methyltetrahydrofolate for the therapy of endometriosis with simultaneous reduction of therapy side effects and the reduction of the risk of congenital malformations in case of pregnancy

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Publication number
EP2194978A1
EP2194978A1 EP08785200A EP08785200A EP2194978A1 EP 2194978 A1 EP2194978 A1 EP 2194978A1 EP 08785200 A EP08785200 A EP 08785200A EP 08785200 A EP08785200 A EP 08785200A EP 2194978 A1 EP2194978 A1 EP 2194978A1
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EP
European Patent Office
Prior art keywords
methyltetrahydrofolate
risk
therapy
pregnancy
daily dose
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Withdrawn
Application number
EP08785200A
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German (de)
French (fr)
Inventor
Christian Seitz
Annemarie Wasserfall
Konstanze Diefenbach
Kristina King
Holger Zimmermann
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Bayer Pharma AG
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Bayer Schering Pharma AG
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Application filed by Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Priority to EP08785200A priority Critical patent/EP2194978A1/en
Publication of EP2194978A1 publication Critical patent/EP2194978A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • 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
    • 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
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • 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
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens

Definitions

  • progestins in combination with (6S) -5-methyltetrahydrofolate for the treatment of endometriosis with concomitant reduction of therapy side effects as well as the reduction of the risk of congenital malformations at onset of pregnancy
  • the invention relates to the use of progestogens in combination with (6S) -5-methyltetrahydrofolate, wherein the daily dose of the gestagen corresponds at most to twice the Ovulationshemmdosis, for the preparation of pharmaceutical preparations for the treatment of endometriosis with simultaneous reduction of therapy side effects, such as the negative Influence on bone density / bone metabolism and risk of osteoporosis, as well as, if pregnancy occurs, the risk of congenital malformations, such as neural tube defects, cleft lip and palate, and pregnancy complications such as placental detachment and prematurity ,
  • the invention is suitable for long-term use. State of the art
  • Endometriosis is a chronic, gynecological disease that occurs primarily in 5-20% of women of childbearing age.
  • endometriosis is defined as the presence of endometrial or endometrial-like tissue outside the uterine cavity.
  • Typical symptoms of endometriosis are dysmenorrhea, dyspareunia and pain in bowel movements.
  • Endometriosis patients often complain of pelvic pain. Abdominal pain, which occurs in the second half of the cycle, followed by a painful menstrual period and subsequent freedom from symptoms until the middle of the following cycle is often thought to endometriosis, but permanent pain is not uncommon. However, about 30-40% of those suffering from endometriosis have no complaints. The disease is then only discovered by chance in conjunction with other diagnostic measures. In about 50-60%, the diagnosis "disease of endometriosis" as a random diagnosis in the clarification of sterility.
  • US 6,569,845 discloses the treatment of angiogenic diseases with dienogest in a daily dose of 0.5 to 10 mg.
  • exemplified pharmaceutical compositions which could also be widely used for the treatment of endometriosis, have a dienogest content of 400 mg to 2 g.
  • Osteoporosis is shown in the literature as irreversible bone loss with increased bone fragility. More than 5 million people in Germany suffer from osteoporosis. Women are affected more often than men. Osteoporosis is a painless, creeping process that not only reduces the amount of bone, but also changes the bone's 'architecture' to such an extent that it can no longer withstand normal stress. A common osteoporotic episode is the femoral neck fracture or extremely painful vertebral body fractures. Despite treatment, the risk of further fractures is very high. The main medication for osteoporosis is the combination of calcium with vitamin D. The first choice for osteoporosis therapy is the bisphosphonates alendronate and risedronate and the selective estrogen receptor modulator raloxifene.
  • BR ⁇ LL, H. et al explains in "Consensus statement: Therapy of postmenopausal osteoporosis, J. Min. 1/2007, 45-48, that as termination reasons of a therapy with oral bisphosphonates, the side effects come first.
  • Side effects of the indicated bisphosphonates include abdominal pain, flu-like syndrome, constipation, peripheral edema, tinnitus, and bronchitis.
  • Another disadvantage is that because of the risk of mucosal inflammation bisphosphonates are strictly according to prescription; In the morning sober while standing with a large glass of water. After taking it you should not lie down for at least half an hour.
  • the disadvantages of raloxifene are described in the literature with possible hot flashes, calf cramps and edema.
  • Estrogen-containing preparations are used in hormone replacement therapy to maintain bone mass. Estrogen-containing therapy is also associated with certain risks. It should be used to prevent uterine cancer only in women with intact uterus.
  • endometriosis is associated with subfertility and is often diagnosed during the evaluation of an unfulfilled desire to have a baby. A therapeutic goal in endometriosis is therefore often to increase the likelihood of pregnancy.
  • congenital malformations such as congenital heart defects, congenital malformations of the urinary tract, acute lymphoblastic leukemia, cleft lip and palate, or central nervous system malformations such as neural tube effects (spina bifida or anencephaly). being able to lead.
  • the German Society for Nutrition therefore recommends 400 ⁇ g folic acid as a daily dose, 600 ⁇ g for pregnant women and 600 ⁇ g for nursing mothers. This is a global statement. Lack of vitamin B 12 and folate deficiency show identical changes in the blood picture. By folate / folic acid folate deficiency can be compensated, but the lack of vitamin B 12 is not indicated. There is thus the danger of a masked vitamin B 12 deficiency.
  • 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: Ci 9 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 ).
  • folates predominantly exist in the diet as pteroyl polyglutamates. 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 are mainly bound to the cells as 5-methyltetrahydrofolate (5-MTHF) bound to albumin and ⁇ -macroglobulin transported, taken there, 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. Furthermore, it is known that losses can occur in the folate content of food by the preparation (cooking) and storage. It is also known that intense UV radiation striking the human skin reduces folic acid in the body. Fair-skinned people are particularly affected. Inadequate supply of folate and / or vitamin B 12 is the
  • homocysteine in the blood rise The concentration of homocysteine in the blood can therefore be used as an indicator of the folate content.
  • hyperhomocysteinemia is reported by Malinow, MR et al, Homocyst (e) ine, diet, and cardiovascular disease, Statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 99, 178-182, 1999, defined by the following concentration in plasma: 16 - 30 ⁇ mol / L (moderate); 31-100 ⁇ mol / L (medium); > 100 ⁇ mol / l (heavy). A concentration above 10 ⁇ mol / l is considered critical and from 12 ⁇ mol / l there is need for action.
  • 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. Presentation of the invention
  • the object of the invention is to find a way to protect endometriosis patients from osteoporosis risk, to reduce endometriosis and to achieve the goal of endometriosis reduction, namely the onset of pregnancy, without realizing side effects.
  • progestogens in combination with (6S) -5-methyl-tetrahydrofolate (metafolin), wherein the daily dose of the gestagen corresponds at most twice and at least the Ovulationshemmdosis, together or separately with one or more pharmaceutically acceptable excipients / carriers for the manufacture of pharmaceutical preparations.
  • the daily dose of the gestagens may be up to twice the Ovulationshemmdosis.
  • the daily dose of dienogest is 1 mg up to a maximum of 2 mg.
  • Cyproterone acetate or chlormadinone acetate are used according to the invention in a daily dosage up to twice the Ovulationshemmdosis.
  • the ovulation inhibition dose of cyproterone acetate is 1 mg, that of chlormadinone acetate 1 .7 mg.
  • the object is also preferred according to the invention by the use of 0.1 to 10 mg (6S) -5-methyltetrahydrofolate as the daily dosage unit 0.4 to 1 mg of (6S) -5-methyltetrahydrofolate, more preferably 451 ⁇ g
  • the use according to the invention also realizes the production of pharmaceutical preparations with continuous administration of the dosage form for a period of at least 169 days or 25 weeks to several years, preferably more than 2 years, and is therefore surprisingly suitable for long-term application.
  • Tablets, capsules, dragees, wafers, transdermal therapy systems, ampoules, suppositories, gels, ointments, implants, vaginal rings or nasal sprays can be used for the use according to the invention.
  • the daily gestagen dose delivered by the non-oral forms of the pharmaceutical preparation is equivalent to one to two times the Ovulationshemmdosis amount daily in the oral Forms or maximally equivalent to the efficacy of 2 mg dienogest.
  • the object is achieved by a method for producing a pharmaceutical preparation for endometriosis therapy with simultaneous reduction of therapy side effects, such as the negative impact on bone density / bone metabolism and osteoporosis risk, and, if a pregnancy occurs, the reduction the risk of congenital malformations and pregnancy complications such as neural tube defects, cleft lip and palate, placental detachment and prematurity, containing a combination of progestins with (6S) -5-
  • Methyltetrahydrofolate and, together or separately, one or more pharmaceutically acceptable excipients / carriers, wherein the daily dose of progestin corresponds to at least the ovulation inhibitory dose to a maximum of twice the ovulation inhibitory dose.
  • Further embodiments of the pharmaceutical preparation produced by the method according to the invention correspond to claims 1 1, 1 2, 1 3, 14, 15, 16, 17 and 18. Exemplary embodiments Example 1
  • Example 2 All substances are suitably mixed, tabletted and optionally film-coated.
  • Example 2 All substances are suitably mixed, tabletted and optionally film-coated.
  • Tablets having the following composition are prepared: dienogest, micronized 2,000 mg min, 99% ⁇ 20 ⁇ m, 100% ⁇ 30 ⁇ m lactose monohydrate 62,800 mg microcrystalline cellulose 18,000 mg
  • Dienogest is used micronized with a mean particle size of 20 microns and mixed with lactose monohydrate, microcrystalline cellulose and potato starch.
  • the povidone K 25 is sprayed during granulation. After drying and mixing of talc, crospovidone and magnesium stearate, the mixture of the substances is pressed into tablets with a diameter of 7 mm and a mass of 135 mg.

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Abstract

Antiandrogenic gestagens in a daily dosage unit, corresponding to no more than two times the dosage required to suppress ovulation, are used in combination with (6S)-5-methyltetrahydrofolate for the production of pharmaceutical preparations for the therapy of endometrioses with simultaneous reduction of therapy side effects, such as the negative impact on bone density/bone metabolism and the risk for osteoporosis, and in the event of pregnancy, the reduction of the risk on congenital malformations, such as neural tube defects, cheilognathopalatoschisis and complications during pregnancy, such as the detachment of the placenta and premature birth. The invention is suitable for long-term use.

Description

Verwendung von Gestagenen in Kombination mit (6S)-5-Methyltetra- hydrofolat zur Therapie der Endometriose mit gleichzeitiger Verminderung von Therapie-Nebenwirkungen sowie der Verminderung des Risikos angeborener Fehlbildungen bei Eintritt einer Gravidität Use of progestins in combination with (6S) -5-methyltetrahydrofolate for the treatment of endometriosis with concomitant reduction of therapy side effects as well as the reduction of the risk of congenital malformations at onset of pregnancy
Technisches GebietTechnical area
Die Erfindung betrifft die Verwendung von Gestagenen in Kombination mit (6S)-5-Methyltetrahydrofolat, wobei die tägliche Dosis des Gestagens maximal dem Zweifachen der Ovulationshemmdosis entspricht, zur Herstellung pharmazeutischer Präparate zur Therapie der Endometriose mit gleichzeitiger Verminderung von Therapie-Nebenwirkungen, wie dem negativen Ein- fluss auf die Knochendichte/den Knochenstoffwechsel und auf das Osteopo- rose-Risikio, sowie, bei Eintritt einer Gravidität, der Verminderung des Risi- kos angeborener Fehlbildungen, wie Neuralrohrdefekten, Lippen-Kiefer- Gaumenspalten, und Schwangerschaftskomplikationen, wie Plazentaablösung und Frühgeburtlichkeit. Die Erfindung ist zur Langzeitanwendung geeignet. Stand der TechnikThe invention relates to the use of progestogens in combination with (6S) -5-methyltetrahydrofolate, wherein the daily dose of the gestagen corresponds at most to twice the Ovulationshemmdosis, for the preparation of pharmaceutical preparations for the treatment of endometriosis with simultaneous reduction of therapy side effects, such as the negative Influence on bone density / bone metabolism and risk of osteoporosis, as well as, if pregnancy occurs, the risk of congenital malformations, such as neural tube defects, cleft lip and palate, and pregnancy complications such as placental detachment and prematurity , The invention is suitable for long-term use. State of the art
Die Endometriose ist eine chronische, gynäkologische Erkrankung, die primär bei 5-20% der Frauen im gebärfähigen Alter vorkommt. In der Fachliteratur wird die Endometriose definiert als das Vorkommen von Endometrium oder endometriumähnlichem Gewebe außerhalb des Cavum uteri. Typische Beschwerdebilder der Endometrioseerkrankung sind die Dysmenorrhoe, Dyspareunie und Schmerzen beim Stuhlgang. Endometriose-Patientinnen klagen häufig über Schmerzen im Beckenbereich. Unterleibsschmerzen, die in der 2. Zyklushälfte auftreten, gefolgt von einer schmerzhaften Regelblutung und anschließender Beschwerdefreiheit bis Mitte des folgenden Zyklus lassen häufig an eine Endometrioseerkrankung denken, aber auch dauerhafte Schmerzen sind nicht selten. Allerdings haben ca. 30- 40 % der an Endo- metriose Erkrankten keine Beschwerden. Die Erkrankung wird dann nur zufällig im Zusammenhang mit anderen diagnostischen Maßnahmen festgestellt. In ca. 50-60% wird die Diagnose „Erkrankung an Endometriose" als zufällige Diagnose bei der Abklärung einer Sterilität gestellt.Endometriosis is a chronic, gynecological disease that occurs primarily in 5-20% of women of childbearing age. In the literature, endometriosis is defined as the presence of endometrial or endometrial-like tissue outside the uterine cavity. Typical symptoms of endometriosis are dysmenorrhea, dyspareunia and pain in bowel movements. Endometriosis patients often complain of pelvic pain. Abdominal pain, which occurs in the second half of the cycle, followed by a painful menstrual period and subsequent freedom from symptoms until the middle of the following cycle is often thought to endometriosis, but permanent pain is not uncommon. However, about 30-40% of those suffering from endometriosis have no complaints. The disease is then only discovered by chance in conjunction with other diagnostic measures. In about 50-60%, the diagnosis "disease of endometriosis" as a random diagnosis in the clarification of sterility.
Aus der Fach- und Patentliteratur ist bekannt, Endometriose medikamen- tös mit Danazol, einem Derivat von 17α-Ethinyltestosteron, GnRH-Agonisten, Gestagen/Estrogen-Kombinationen oder Gestagen-Monopräparaten zu behandeln.It is known from the technical and patent literature that endometriosis is medicinally-associated with danazol, a derivative of 17α-ethynyltestosterone, GnRH agonists, To treat progestogen / estrogen combinations or progestogen monopreparations.
US 6,569,845 offenbart die Behandlung von angiogenen Erkrankungen mit Dienogest in einer täglichen Dosis von 0,5 bis 10 mg. Entsprechende, als Beispiele ausgewiesene pharmazeutische Zusammensetzungen, die man weitläufig auch zur Behandlung von Endometriose einsetzen könnte, besitzen einen Dienogest-Gehalt von 400 mg bis 2 g.US 6,569,845 discloses the treatment of angiogenic diseases with dienogest in a daily dose of 0.5 to 10 mg. Corresponding, exemplified pharmaceutical compositions, which could also be widely used for the treatment of endometriosis, have a dienogest content of 400 mg to 2 g.
Moore, C. et a/. , The treatment of endometriosis, Drugs of Today 1999, 35 (Suppl C): 41 -52 untersuchten in klinischen Studien die Wirksamkeit von Dienogest bei der Behandlung von Endometriose vergleichsweise zum Behandlungsregime mit Danazol oder GnRH-Agonisten. Den Endometriose Betroffenen wurden 24 Wochen 2 mg Dienogest pro Tag verabreicht. Das Ergebnis der Behandlung ist vergleichbar mit dem Ergebnis einer Behandlung mit Danazol oder GnRH-Agonisten. Bis zu 90 % der Betroffenen berichteten über irreguläre Blutungen, jedoch keine berichtete über unerträgliche Blutungen. Die Wirksamkeit der Standardbehandlung mit Danazol wird durch signifikante androgene Effekte geschmälert, während GnRH-Agonisten mit „meno- pausalen Symptomen" in Zusammenhang stehen.Moore, C. et a /. , The treatment of endometriosis, Drugs of Today 1999, 35 (Suppl C): 41-52 investigated in clinical trials the efficacy of dienogest in the treatment of endometriosis compared to the treatment regimen of danazol or GnRH agonists. Endometriosis patients were given 2 mg dienogest per day for 24 weeks. The result of treatment is similar to the result of treatment with danazol or GnRH agonists. Up to 90% of those affected reported irregular bleeding, but no reports of intolerable bleeding. The efficacy of standard treatment with danazol is diminished by significant androgenic effects, while GnRH agonists are associated with "menopausal symptoms".
Schweppe, K. -W, Stellenwert der Gestagene, Zentralbl Gynakol 2003, 125: 276-280 erklärt, dass bei kontinuierlicher oraler Gestagenbehandlung (beispielsweise mit Medroxyprogesteronacetat, Dienogest, Dydrogesteron, Lynestrenol in einer täglichen Dosierung von 5 mg bis 20 mg, als niedrig dosiert bezeichnet und eingestuft als wirksames Behandlungsprinzip bei Endometriose bedingten Symptomen) niedrige Estrogenspiegel zu verzeichnen sind. Es resultieren häufig Schmier- und Zwischenblutungen. Dies zwingt zur Dosiserhöhung und/oder Estrogenzugabe. Rezidivraten liegen langfristig über 50 %.Schweppe, K.W, Proportion of gestagens, Zentralbl Gynakol 2003, 125: 276-280 states that in continuous oral gestagen treatment (for example, with medroxyprogesterone acetate, dienogest, dydrogesterone, lynestrenol in a daily dosage of 5 mg to 20 mg, as low dosed and classified as effective treatment principle in endometriosis-related symptoms) low estrogen levels are recorded. This often results in lubrication and bleeding. This forces the dose increase and / or estrogen addition. Recurrence rates are above 50% in the long term.
Eine Sicherheitsinformation von 2005 zu einem Medroxyprogesteronace- tat-Produkt zeigt auf, dass Gestagen-Monopräparate besonders bei Langzeit- behandlung negative Wirkung auf die Knochendichte ausüben können.2005 safety information on a medroxyprogesterone acetate product shows that progesterone monospecifics can have a negative effect on bone density, especially in long-term treatment.
In Kombination mit Estrogenen dagegen üben einige Gestagene einen positiven Einfluss auf den Knochenstoffwechsel aus.In combination with estrogens, some progestagens exert a positive influence on bone metabolism.
Eine weitere Sicherheitsinformation, NDA 21 -584, FDA 22.03.2005, zu depo-subQ provera 104™ (Medroxyprogesteronacetat i.m. - 104 mg/0.65 ml), verweist darauf, dass Frauen, welche dieses Präparat verwenden, einen Kno- chenmineraldichteverlust erleiden, der sich mit der Dauer der Verwendung des Präparates vergrößert und nicht mehr komplett reversibel ist.Further safety information, NDA 21-584, FDA 22.03.2005, on depo-subQ provera 104 ™ (medroxyprogesterone acetate - 104 mg / 0.65 ml), indicates that women who use this preparation Chen chenmineraldichteverlust suffer, which increases with the duration of use of the preparation and is no longer completely reversible.
Knauthe, R und Habenicht U. F. , Levonorgestrel has benefical effects, Exp Clin Endocrinol diabetes 106 (1998) Suppl 1 : 37 zeigen bereits 1998 auf, dass dabei die partielle androgene Wirkung eines Gestagens (Levonorgestrel) und nicht die gestagene Aktivität ausschlaggebend ist für diesen positiven Einfluss auf den Knochenstoffwechsel.Knauthe, R and Habenicht UF, Levonorgestrel has benefical effects, Expocin Endocrinol diabetes 106 (1998) Suppl 1: 37 show as early as 1998 that the partial androgenic effect of a gestagen (levonorgestrel) and not the gestagenic activity is crucial for this positive Influence on bone metabolism.
Auch Kühl, H. , Klimakterium, Postmenopause und Hormonsubstitution, 3. Aufl. , Bremen. UN I-MED, 2006, 1 17 betont, dass bestimmte Gestagene über ihre androgene Partialwirkung wirksam werden. Ferner erklärt Kühl, dass Androgene die positive Wirkung der Estrogene auf die Knochendichte erheblich verstärken.Also, cooling, H., climacteric, postmenopause and hormone substitution, 3rd ed., Bremen. UN I-MED, 2006, 1 17 emphasizes that certain progestagens take effect via their androgenic partial action. Furthermore, Kühl states that androgens significantly enhance the positive effects of estrogens on bone density.
Die Osteoporose wird In der Fachliteratur als nicht-rückgängig zu machender Knochenabbau mit erhöhter Knochenbrüchigkeit aufgezeigt. Mehr als 5 Millionen Menschen in Deutschland leiden an Osteoporose. Frauen sind häufiger betroffen als Männer. Die Osteoporose ist ein schmerzloser, schleichender Vorgang, bei dem nicht nur die Menge der Knochensubstanz abnimmt, sondern auch die .Architektur' des Knochens so verändert wird, dass dieser den normalen Belastungen nicht mehr standhält. Eine häufige Osteo- porosefolge ist die Schenkelhalsfraktur oder die äußerst schmerzhaften Wirbelkörperbrüche. Trotz Behandlung ist das Risiko weiterer Knochenbrüche sehr hoch. Die Basismedikation bei Osteoporose ist die Kombination von Kalzium mit Vitamin D. mittel der ersten Wahl für eine Osteoporose-Therapie sind die Bisphosphonate Alendronat und Risedronat sowie der selektive Estrogen-Rezeptor-modulator Raloxifen.Osteoporosis is shown in the literature as irreversible bone loss with increased bone fragility. More than 5 million people in Germany suffer from osteoporosis. Women are affected more often than men. Osteoporosis is a painless, creeping process that not only reduces the amount of bone, but also changes the bone's 'architecture' to such an extent that it can no longer withstand normal stress. A common osteoporotic episode is the femoral neck fracture or extremely painful vertebral body fractures. Despite treatment, the risk of further fractures is very high. The main medication for osteoporosis is the combination of calcium with vitamin D. The first choice for osteoporosis therapy is the bisphosphonates alendronate and risedronate and the selective estrogen receptor modulator raloxifene.
BRÖLL, H. et al erklärt in „ Konsensus-Statement: Therapie der postme- nopausalen Osteoporose, J.Miner.Stoffwechs. 1/2007, 45-48, dass als Abbruchgründe einer Therapie mit oralen Bisphosphonaten, die Nebenwirkungen an erster Stelle stehen. Zu den Nebenwirkungen der bezeichneten Bisphosphonate gehören Bauchschmerzen, grippeähnliches Syndrom, Verstopfung, peripheres Ödem, Tinnitus und Bronchitis. Nachteilig erweist sich ebenfalls, dass wegen der Gefahr von Schleimhautentzündungen Bisphosphonate streng nach Vorschrift einzunehmen sind; Morgens nüchtern im Stehen mit einem großen Glas Wasser . Nach Einnahme sollte man sich mindestens eine halbe Stunde nicht hinlegen. Die Nachteile von Raloxifen sind in der Literatur mit möglichen Hitzewallungen, Wadenkrämpfe und Ödeme beschrieben.BRÖLL, H. et al explains in "Consensus statement: Therapy of postmenopausal osteoporosis, J. Min. 1/2007, 45-48, that as termination reasons of a therapy with oral bisphosphonates, the side effects come first. Side effects of the indicated bisphosphonates include abdominal pain, flu-like syndrome, constipation, peripheral edema, tinnitus, and bronchitis. Another disadvantage is that because of the risk of mucosal inflammation bisphosphonates are strictly according to prescription; In the morning sober while standing with a large glass of water. After taking it you should not lie down for at least half an hour. The disadvantages of raloxifene are described in the literature with possible hot flashes, calf cramps and edema.
Estrogenhaltige Präparate werden in der Hormonersatztherapie zum Erhalt der Knochenmasse angewendet. Eine estrogen-haltige Therapie ist eben- falls mit gewissen Risiken verbunden. Sie sollte zur Vermeidung von Gebärmutterschleimhautkrebs nur bei Frauen mit intakter Gebärmutter angewendet werden.Estrogen-containing preparations are used in hormone replacement therapy to maintain bone mass. Estrogen-containing therapy is also associated with certain risks. It should be used to prevent uterine cancer only in women with intact uterus.
Es ist auch bekannt, dass Endometriose mit Subfertilität assoziiert ist und häufig während der Abklärung eines unerfüllten Kinderwunsches diag- nostiziert wird. Ein Therapieziel bei Endometriose ist daher häufig auch, die Wahrscheinlichkeit für eine Schwangerschaft zu erhöhen.It is also known that endometriosis is associated with subfertility and is often diagnosed during the evaluation of an unfulfilled desire to have a baby. A therapeutic goal in endometriosis is therefore often to increase the likelihood of pregnancy.
Ferner ist bekannt, dass ein unzureichender Folatstatus in der Schwangerschaft zu angeborenen Fehlbildungen, wie beispielsweise angeborene Herzfehler, angeborene Fehlbildungen der Harnwege, eine akute lymphoblastische Leukämie, Lippen-, Kiefer- und Gaumenspalten oder Fehlbildungen des Zentralnervensystems, wie Neuralrohrdeffekte (Spina bifida oder Anencephalie) führen können.In addition, insufficient folate status in pregnancy is known to cause congenital malformations, such as congenital heart defects, congenital malformations of the urinary tract, acute lymphoblastic leukemia, cleft lip and palate, or central nervous system malformations such as neural tube effects (spina bifida or anencephaly). being able to lead.
Die Deutsche Gesellschaft für Ernährung e.V. empfiehlt deshalb als Tagesdosis grundsätzlich 400 μg Folsäure, für Schwangere 600 μg und für stillende Mütter 600 μg. Dies ist eine globale Aussage. Mangel an Vitamin B12 und Folatmangel weisen im Blutbild identische Veränderungen auf. Durch Verabreichung von Folat/Folsäure kann der Folatmangel kompensiert werden, jedoch der Mangel an Vitamin B12 wird nicht angezeigt. Es ist damit die Gefahr eines maskierten Vitamin-B12-Mangels gegeben. Folsäure, auch Pteroyl-mono-glutaminsäure, N-(4-(((2-Amino-1 ,4- dihydro-4-oxo-6-pteridinyl)methyl)-amino)benzoyl)glutaminsäure (Summenformel: Ci9H19N7)O6), Folinsäure genannt, ist ein hitze- und lichtempfindliches, wasserlösliches Vitamin aus dem Vitamin-B-Komplex (Vitamin B9).The German Society for Nutrition therefore recommends 400 μg folic acid as a daily dose, 600 μg for pregnant women and 600 μg for nursing mothers. This is a global statement. Lack of vitamin B 12 and folate deficiency show identical changes in the blood picture. By folate / folic acid folate deficiency can be compensated, but the lack of vitamin B 12 is not indicated. There is thus the danger of a masked vitamin B 12 deficiency. 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: Ci 9 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 ).
Es ist bekannt, dass in der Nahrung Folate überwiegend als Pteroylpo- lyglutamate vorliegen. Diese werden nach Nahrungsaufnahme zunächst in den Mukosazellen zu Pteroylmonoglutamaten hydrolisiert, dann im Darm durch aktiven Transport hauptsächlich resorbiert.It is known that folates predominantly exist in the diet as pteroyl polyglutamates. These are hydrolyzed after ingestion first in the mucosa cells to pteroyl monoglutamates, then mainly absorbed in the intestine by active transport.
In der Leber werden die überwiegend nicht-methylierten Folate in me- thylierte Folate umgewandelt und hauptsächlich als 5-Methyltetrahydrofolat (5-MTHF) an Albumin und α-Makroglobulin gebunden an die Zellen weiter transportiert, dort aufgenommen, demethyliert und in die Polyglutamatform umgewandelt.In the liver, the predominantly unmethylated folates are converted into methylated folates and are mainly bound to the cells as 5-methyltetrahydrofolate (5-MTHF) bound to albumin and α-macroglobulin transported, taken there, demethylated and converted into the polyglutamate form.
An der Demethylierung sind die Aminosäure Homocystein sowie ein Enzym, welches Vitamin B12 als Coenzym benötigt, beteiligt. Ferner ist bekannt, dass Verluste am Folatgehalt von Lebensmitteln durch die Zubereitung (Kochen) sowie die Lagerung entstehen können. Weiterhin ist bekannt, dass auf die menschliche Haut treffende intensive UV- Strahlung die Folsäure im Körper reduziert. Hellhäutige Menschen sind dabei besonders betroffen. Bei unzureichender Versorgung mit Folat und/oder Vitamin B12 wird derDemethylation involves the amino acid homocysteine and an enzyme that requires vitamin B 12 as a coenzyme. Furthermore, it is known that losses can occur in the folate content of food by the preparation (cooking) and storage. It is also known that intense UV radiation striking the human skin reduces folic acid in the body. Fair-skinned people are particularly affected. Inadequate supply of folate and / or vitamin B 12 is the
Homocysteinstoffwechsel behindert, als Folge kann die Konzentration vonHomocysteine metabolism hinders, as a result, the concentration of
Homocystein im Blut ansteigen. Die Konzentration an Homocystein im Blut kann demnach als ein Indikator für den Folatgehalt herangezogen werden.Homocysteine in the blood rise. The concentration of homocysteine in the blood can therefore be used as an indicator of the folate content.
Der Zustand der Hyperhomocysteinämie wird nach Malinow, MR et al, Homocyst(e)ine, diet, and cardiovascular disease, Statement for healthcare Professionals from the Nutrition Committee, American Heart Association. Circulation 99, 178-182, 1999, durch folgende Konzentration im Plasma definiert: 16 - 30μmol/l (moderat); 31 - 100μmol/l (mittel); > 100μmol/l (schwer). Eine Konzentration über 10μmol/l wird als kritisch angesehen und ab 12μmol/l besteht Handlungsbedarf.The condition of hyperhomocysteinemia is reported by Malinow, MR et al, Homocyst (e) ine, diet, and cardiovascular disease, Statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 99, 178-182, 1999, defined by the following concentration in plasma: 16 - 30 μmol / L (moderate); 31-100 μmol / L (medium); > 100 μmol / l (heavy). A concentration above 10μmol / l is considered critical and from 12μmol / l there is need for action.
Neben dem Mangel an Folat und dem Vitamin B12 können aber auch Enzymdefekte den Anstieg der Homocysteinkonzentration bewirken. Der Zusammenhang zwischen erhöhten Homocysteinkonzentrationen im Blut und Gefäßerkrankungen, beispielsweise auch als Risikofaktor für Herz- Kreislauf-Erkrankungen wird seit einiger Zeit diskutiert.In addition to the lack of folate and the vitamin B 12 but also enzyme defects can cause the increase in homocysteine. 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.
Ebenso wird diskutiert, ob Folsäure/Folat wegen seiner Bedeutung für die DNA-Methylierung und die DNA-Strangstabilität vor malignen Erkrankungen schützen kann.It is also discussed whether folic acid / folate can protect against malignant diseases because of its importance for DNA methylation and DNA strand stability.
Die Patentschrift EP 0 898 965 beansprucht die Verwendung von 5- Methyl-(6S)-tetrahydrofolsäure oder deren pharmazeutisch verträgliche Salze zur Vorbeugung von Neuralrohrdefekten.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.
Die Patentschrift EP 1 044 975 offenbart kristalline Salze der 5-Methyl- (6R1S)-, -(6S)-und-(6R)-tetrahydrofolsäure und der Verwendung als Bestandteil Nahrungsmittelergänzungsstoff. Darstellung der ErfindungEP 1 044 975 discloses crystalline salts of 5-methyl- (6R 1 S) -, - (6S) -and- (6R) -tetrahydrofolic acid and use as a food supplement ingredient. Presentation of the invention
Aufgabe der Erfindung ist es, eine Möglichkeit zu finden , Endometriose- Patientinnen vor einem Osteoporoserisiko zu schützen, die Endometriose zu vermindern und das Erreichen eines Zieles der Endometrioseverminderung , nämlich den Eintritt einer Schwangerschaft, ohne Nebenwirkungen zu realisieren.The object of the invention is to find a way to protect endometriosis patients from osteoporosis risk, to reduce endometriosis and to achieve the goal of endometriosis reduction, namely the onset of pregnancy, without realizing side effects.
Es wurde nun gefunden, dass die Aufgabe erfindungsgemäß gelöst wird durch die Verwendung von Gestagenen in Kombination mit (6S)-5-Methyl- tetrahydrofolat (Metafolin), wobei die tägliche Dosis des Gestagens maximal dem Zweifachen und mindestens der Ovulationshemmdosis entspricht, gemeinsam oder getrennt mit einem oder mehreren pharmazeutisch annehmbaren Hilfsstoffen/Trägern zur Herstellung pharmazeutischer Präparate.It has now been found that the object is achieved according to the invention by the use of progestogens in combination with (6S) -5-methyl-tetrahydrofolate (metafolin), wherein the daily dose of the gestagen corresponds at most twice and at least the Ovulationshemmdosis, together or separately with one or more pharmaceutically acceptable excipients / carriers for the manufacture of pharmaceutical preparations.
Es wurde gefunden , dass neben der Minderung der Endometriose überraschenderweise keine negative Beeinflussung des Knochenstoffwechsels er- folgt, so dass keine Abnahme/Verringerung der Knochendichte zu verzeichnen ist, kein Osteoporoserisiko besteht und dass das Risiko angeborener Fehlbildungen , wie Neuralrohrdeffekten und Lippen-Kiefer-Gaumenspalten, und Schwangerschaftskomplikationen , wie Plazentaablösung und Frühgeburt- lichkeit bei Eintritt einer Gravidität ebenfalls vermindert werden kann . Gleichwohl gelingt es mit der erfindungsgemäßen Verwendung des pharmazeutischen Präparates überraschenderweise, die von den konventionellen Arzneimitteln zur Behandlung der Endometriose bekannten Nebenwirkungen , z. B. Hitzewallungen , Änderung des Lipidprofils im erträglichen Maße zu halten. Erfindungsgemäß sind die verwendeten Gestagene mit antiandrogenerIt has been found that in addition to the reduction of endometriosis surprisingly no negative effect on the bone metabolism occurs, so that there is no decrease / decrease in bone density, no osteoporosis risk exists and that the risk of congenital malformations, such as neural tube and cleft lip and palate , and pregnancy complications, such as placental abruption and preterm delivery, can also be reduced if pregnancy occurs. Nevertheless, it is surprisingly possible with the inventive use of the pharmaceutical preparation, the known from the conventional medicines for the treatment of endometriosis side effects, eg. As hot flashes, change the lipid profile to a tolerable extent. According to the invention, the gestagens used are antiandrogenic
Wirksamkeit Dienogest, Cyproteronacetat oder Chlormadinonacetat. Die tägliche Dosis an den Gestagenen kann bis maximal das Zweifache der Ovulationshemmdosis betragen.Efficacy dienogest, cyproterone acetate or chlormadinone acetate. The daily dose of the gestagens may be up to twice the Ovulationshemmdosis.
Die tägliche Dosis an Dienogest beträgt 1 mg bis zu maximal 2 mg . Auch Cyproteronacetat oder Chlormadinonacetat werden erfindungsgemäß in einer täglichen Dosierung bis zum Zweifachen der Ovulationshemmdosis eingesetzt. Die Ovulationshemmdosis von Cyproteronacetat beträgt 1 mg , die von Chlormadinonacetat 1 .7 mg .The daily dose of dienogest is 1 mg up to a maximum of 2 mg. Cyproterone acetate or chlormadinone acetate are used according to the invention in a daily dosage up to twice the Ovulationshemmdosis. The ovulation inhibition dose of cyproterone acetate is 1 mg, that of chlormadinone acetate 1 .7 mg.
Auch wird die Aufgabe erfindungsgemäß durch die Verwendung von 0.1 bis 1 0 mg (6S)-5-Methyltetrahydrofolat als tägliche Dosiseinheit, bevorzugt 0.4 bis 1 mg (6S)-5-Methyltetrahydrofolat , besonders bevorzugt 451 μgThe object is also preferred according to the invention by the use of 0.1 to 10 mg (6S) -5-methyltetrahydrofolate as the daily dosage unit 0.4 to 1 mg of (6S) -5-methyltetrahydrofolate, more preferably 451 μg
(6S)-5-Methyltetrahydrofolat.(6S) -5-methyltetrahydrofolate.
Die erfindungsgemäße Verwendung realisiert auch die Herstellung pharmazeutischer Präparate mit einer kontinuierlichen Verabreichung der Do- sierungsform für die Dauer von mindestens 169 Tagen oder 25 Wochen bis mehreren Jahren, vorzugsweise mehr als 2 Jahren und ist daher überraschenderweise für die Langzeitapplikation geeignet.The use according to the invention also realizes the production of pharmaceutical preparations with continuous administration of the dosage form for a period of at least 169 days or 25 weeks to several years, preferably more than 2 years, and is therefore surprisingly suitable for long-term application.
Für die erfindungsgemäße Verwendung können Tabletten, Kapseln , Dragees, Wafer, Transdermalen-Therapie-Systemen, Ampullen, Suppositorien, Gelen, Salben, I mplantaten , Vaginalringen oder Nasenspray eingesetzt werden.Tablets, capsules, dragees, wafers, transdermal therapy systems, ampoules, suppositories, gels, ointments, implants, vaginal rings or nasal sprays can be used for the use according to the invention.
Dabei ist die von den nichtoralen Formen des pharmazeutischen Präparates, wie Transdermales-Therapie-System, Ampulle, Suppositorie, Gel, Salbe, Implantat, Vaginalring oder Nasenspray abgegebene tägliche Gestagen- dosis äquivalent zum Ein- bis Zweifachen der Ovulationshemmdosis betragende täglichen Dosiseinheit bei den oralen Formen bzw. maximal äquivalent zur Wirksamkeit von 2 mg Dienogest.Here, the daily gestagen dose delivered by the non-oral forms of the pharmaceutical preparation, such as transdermal therapy system, ampoule, suppository, gel, ointment, implant, vaginal ring or nasal spray is equivalent to one to two times the Ovulationshemmdosis amount daily in the oral Forms or maximally equivalent to the efficacy of 2 mg dienogest.
Weiterhin wird die Aufgabe durch ein Verfahren zur Herstellung eines pharmazeutischen Präparates zur Endometriose-Therapie mit gleichzeitiger Verminderung von Therapie-Nebenwirkungen, wie dem negativen Einfluss auf die Knochendichte/den Knochenstoffwechsel und auf das Osteoporose- Risikio, sowie, bei Eintritt einer Gravidität, der Verminderung des Risikos angeborener Fehlbildungen und Schwangerschaftskomplikationen wie Neuralrohrdefekten, Lippen-Kiefer-Gaumenspalten, Plazentaablösung und Frühge- burtlichkeit, enthaltend eine Kombination von Gestagenen mit (6S)-5-Furthermore, the object is achieved by a method for producing a pharmaceutical preparation for endometriosis therapy with simultaneous reduction of therapy side effects, such as the negative impact on bone density / bone metabolism and osteoporosis risk, and, if a pregnancy occurs, the reduction the risk of congenital malformations and pregnancy complications such as neural tube defects, cleft lip and palate, placental detachment and prematurity, containing a combination of progestins with (6S) -5-
Methyltetrahydrofolat und , gemeinsam oder getrennt, einen oder mehrere pharmazeutisch annehmbare Hilfsstoffe/Träger , wobei die tägliche Dosis des Gestagens mindestens der Ovulationshemmdosis bis maximal dem Zweifachen der Ovulationshemmdosis entspricht. Weitere Ausführungsformen des durch das erfindungsgemäße Verfahren hergestellte pharmazeutische Präparates entsprechen den Ansprüchen 1 1 , 1 2, 1 3, 14, 15, 16, 1 7 und 1 8. Ausführungsbeispiele Beispiel 1Methyltetrahydrofolate and, together or separately, one or more pharmaceutically acceptable excipients / carriers, wherein the daily dose of progestin corresponds to at least the ovulation inhibitory dose to a maximum of twice the ovulation inhibitory dose. Further embodiments of the pharmaceutical preparation produced by the method according to the invention correspond to claims 1 1, 1 2, 1 3, 14, 15, 16, 17 and 18. Exemplary embodiments Example 1
Es werden Tabletten mit folgender Zusammensetzung hergestellt: Kern:Tablets of the following composition are produced: Core:
Dienogest 2.000 mgDienogest 2,000 mg
Metafolin 0.451 mgMetafolin 0.451 mg
Laktose-Monohydrat 46.349 mgLactose monohydrate 46,349 mg
Microcrystalline Cellulose 24.800 mg Hydroxypropylcellulose 1.600 mgMicrocrystalline cellulose 24,800 mg Hydroxypropyl cellulose 1,600 mg
Croscarmellose 3.200 mgCroscarmellose 3,200 mg
Magnesiumstearat 1 .600 mgMagnesium stearate 1 .600 mg
Alle Substanzen werden in geeigneter Weise gemischt, tablettiert und gegebenenfalls befilmt. Beispiel 2All substances are suitably mixed, tabletted and optionally film-coated. Example 2
Es werden Tabletten mit folgender Zusammensetzung hergestellt: Dienogest, micronisiert 2.000 mg min, 99% ≤ 20 μm, 100 % < 30 μm Lactose-Monohydrat 62.800 mg Microkristalline Cellulose 18.000 mgTablets having the following composition are prepared: dienogest, micronized 2,000 mg min, 99% ≤ 20 μm, 100% <30 μm lactose monohydrate 62,800 mg microcrystalline cellulose 18,000 mg
Kartoffelstärke 36.000 mgPotato starch 36,000 mg
Povidon K 25 8.100 mgPovidone K 25 8,100 mg
Magnesiumstearat 1 .350 mgMagnesium Stearate 1 .350 mg
Talkum 4.050 mg Crospovidon 2.700 mgTalc 4,050 mg crospovidone 2,700 mg
Dienogest wird micronisiert mit einer mittleren Teilchengröße von 20 μm eingesetzt und mit Lactose-Monohydrat, Microkristalliner Cellulose und Kartoffelstärke vermischt. Das Povidon K 25 wird während der Granulierung eingesprüht. Nach Trocknen und Zumischen von Talkum, Crospovidon und Magnesiumstearat wird die Mischung aus den Substanzen zu Tabletten mit einem Durchmesser von 7 mm und einer Masse von 135 mg gepresst.Dienogest is used micronized with a mean particle size of 20 microns and mixed with lactose monohydrate, microcrystalline cellulose and potato starch. The povidone K 25 is sprayed during granulation. After drying and mixing of talc, crospovidone and magnesium stearate, the mixture of the substances is pressed into tablets with a diameter of 7 mm and a mass of 135 mg.
451 μg (6S)-5-Methyltetrahydrofolat werden separat mit einem oder mehreren pharmazeutisch annehmbaren Hilfsstoffen/Trägern nach bekannten Methoden verarbeitet und gleichzeitig mit der Dienogest-Formulierung verab- reicht. Beispiel 3451 μg of (6S) -5-methyltetrahydrofolate are separately processed with one or more pharmaceutically acceptable excipients / carriers by known methods and administered simultaneously with the dienogest formulation. Example 3
In einer klinischen Studie wurden 252 Frauen mit laparoskopisch diagnostizierter Endometriose über einen Zeitraum von 6 Monaten entweder mit dem GnRH-Agonisten Leuprorelin Acetat (LA) 3,75 mg s.c. alle 4 Wochen o- der mit 2mg/d oral des Gestagens Dienogest (DNG) behandelt. 128 Patientinnen wurden in die LH-Gruppe und 124 Patientinnen in die DNG-Gruppe randomisiert. Die Wirksamkeit der jeweiligen Therapie wurde u.a. mittels einer von der Patientin auszufüllenden Schmerzskale (Visual Analogue Scale, VAS) untersucht. Am Ende der Behandlung zeigte sich in beiden Vergleichs- gruppen eine ähnliche Reduktion der Schmerzen im Vergleich zum Studienbeginn (-47,5 mm für DNG; -46,0 mm für LA). Die statistische Analyse zeigte die Nicht-Unterlegenheit von DNG gegenüber LA. Gleichzeitig wurde in einer Subpopulation nachgewiesen, dass in der Dienogestgruppe kein Knochendichteabfall erfolgte wogegen in der LA-Gruppe die Knochendichte um 4 % abnahm. In a clinical study, 252 women with laparoscopically diagnosed endometriosis were treated with either the GnRH agonist Leuprorelin Acetate (LA) over a 6-month period with s.c. every 4 weeks or 2 mg / d orally of the progestin dienogest (DNG). 128 patients were randomized to the LH group and 124 patients to the DNG group. The effectiveness of the respective therapy was u.a. examined by means of a pain scale to be filled in by the patient (Visual Analogue Scale, VAS). At the end of treatment, a similar reduction in pain was observed in both control groups compared with baseline (-47.5 mm for DNG, -46.0 mm for LA). The statistical analysis demonstrated the non-inferiority of DNG to LA. At the same time, it was demonstrated in a subpopulation that no bone density decrease occurred in the dienogest group whereas in the LA group the bone density decreased by 4%.

Claims

Patentansprüche claims
1 . Verwendung von Gestagenen in Kombination mit (6S)-5-Methyltetra- hydrofolat, wobei die tägliche Dosis des Gestagens mindestens der Ovulati- onshemmdosis bis maximal dem Zweifachen der Ovulationshemmdosis ent- spricht, zur Herstellung pharmazeutischer Präparate zur Therapie der Endometriose mit gleichzeitiger Verminderung von Therapie-Nebenwirkungen, wie dem negativen Einfluss auf die Knochendichte/den Knochenstoffwechsel und dem Osteoporose-Risikio, sowie der Verminderung des Risikos angeborener Fehlbildungen und Schwangerschaftskomplikationen bei Eintritt einer Gravidi- tat.1 . Use of progestogens in combination with (6S) -5-methyltetrahydrofolate, wherein the daily dose of the progestogen corresponds at least to the ovulation inhibiting dose up to a maximum of twice the ovulation inhibiting dose, for the preparation of pharmaceutical preparations for the treatment of endometriosis with concomitant reduction of therapy Side effects, such as the negative influence on bone density / bone metabolism and risk of osteoporosis, as well as the reduction of the risk of congenital malformations and pregnancy complications at the onset of gravidat.
2. Verwendung von Gestagenen und (6S)-5-Methyltetrahydrofolat nach Anspruch 1 , wobei die angeborenen Fehlbildungen und Schwangerschaftskomplikationen bei Eintritt einer Gravidität Neuralrohrdefekte, Lippen-Kiefer- Gaumenspalten, Plazentaablösung und Frühgeburtlichkeit sind.2. The use of progestins and (6S) -5-methyltetrahydrofolate according to claim 1, wherein the congenital malformations and pregnancy complications at the onset of pregnancy are neural tube defects, cleft lip and palate, placenta detachment and prematurity.
3. Verwendung von Gestagenen und (6S)-5-Methyltetrahydrofolat nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass die Gestagenkomponente 17α-Cyanomethyl-17-ß-hydroxyestra-4,9-dien-3on (Dienogest), Cyproterona- cetat oder Chlormadinonacetat ist.3. Use of progestins and (6S) -5-Methyltetrahydrofolat according to claim 1 or 2, characterized in that the gestagen component 17α-cyanomethyl-17-β-hydroxyestra-4,9-diene-3on (dienogest), cyproterone cetate or Chlormadinone acetate is.
4. Verwendung von Gestagenen und (6S)-5-Methyltetrahydrofolat nach Anspruch 1 , 2 oder 3, dadurch gekennzeichnet, dass die tägliche Gestagendosis 1 bis 2 mg Dienogest oder eine äquivalente Menge an Cyproteronacetat oder Chlormadinonacetat beträgt.4. The use of progestins and (6S) -5-methyltetrahydrofolate according to claim 1, 2 or 3, characterized in that the daily gestagen dose is 1 to 2 mg dienogest or an equivalent amount of cyproterone acetate or chlormadinone acetate.
5. Verwendung von Gestagenen und (6S)-5-Methyltetrahydrofolat nach Anspruch 1 , 2, 3 oder 4, dadurch gekennzeichnet, dass die tägliche Dosis (6S)- 5-Methyl-tetrahydrofolat 0.1 bis 10 mg beträgt.5. Use of progestins and (6S) -5-methyltetrahydrofolate according to claim 1, 2, 3 or 4, characterized in that the daily dose of (6S) - 5-methyl-tetrahydrofolat is 0.1 to 10 mg.
6. Verwendung von Gestagenen und (6S)-5-Methyltetrahydrofolat nach Anspruch 1 , 2, 3, 4 oder 5, dadurch gekennzeichnet, dass die tägliche Dosis (6S)-5-Methyltetrahydrofolat 0.4 bis 1 mg beträgt. 6. Use of progestins and (6S) -5-methyltetrahydrofolate according to claim 1, 2, 3, 4 or 5, characterized in that the daily dose of (6S) -5-methyltetrahydrofolat is 0.4 to 1 mg.
7. Verwendung von Gestagenen und (6S)-5-Methyltetrahydrofolat nach Anspruch 1 , 2, 3, 4, 5 oder 6, dadurch gekennzeichnet, dass die tägliche Dosis des (6S)-5-Methyltetrahydrofolat 451 μg des Kalziumsalzes der (6S)-5- Methyltetrahydrofolsäure beträgt7. Use of gestagens and (6S) -5-methyltetrahydrofolate according to claim 1, 2, 3, 4, 5 or 6, characterized in that the daily dose of (6S) -5-methyltetrahydrofolate 451 μg of the calcium salt of (6S) 5-methyltetrahydrofolic acid
8. Verwendung von Gestagenen und (6S)-5-Methyltetrahydrofolat nach Anspruch 1 , 2, 3, 4, 5, 6 oder 7 zur Herstellung pharmazeutischer Präparate mit kontinuierlicher Verabreichung für die Dauer von mindestens 169 Tagen oder 25 Wochen bis mehreren Jahren, vorzugsweise mehr als 2 Jahren, zur Vermeidung von Nebenwirkungen, wie dem negativen Einfluss auf die Knochendichte/den Knochenstoffwechsel und das Osteoporose-Risikio, sowie der Verminderung des Risikos angeborener Fehlbildungen bei Eintritt einer Gravidität während oder nach der Endometriose-Therapie.8. Use of progestins and (6S) -5-Methyltetrahydrofolat according to claim 1, 2, 3, 4, 5, 6 or 7 for the manufacture of pharmaceutical preparations with continuous administration for a period of at least 169 days or 25 weeks to several years, preferably more than 2 years, to avoid side effects such as the negative impact on bone density / bone metabolism and the risk of osteoporosis, and to reduce the risk of congenital malformations in the event of pregnancy during or after endometriosis therapy.
9. Verwendung von Gestagenen und (6S)-5-Methyltetrahydrofolat nach Anspruch 1 , 2, 3, 4, 5, 6, 7 oder 8, dadurch gekennzeichnet, dass das pharmazeutische Präparat in Form von Tabletten, Kapseln, Dragees, Wafer, Transdermalen-Therapie-Systemen, Ampullen, Suppositorien, Gelen, Salben, Implantaten, Vaginalringen oder Nasenspray vorliegt.9. Use of progestins and (6S) -5-Methyltetrahydrofolat according to claim 1, 2, 3, 4, 5, 6, 7 or 8, characterized in that the pharmaceutical preparation in the form of tablets, capsules, dragees, wafers, transdermal Therapy systems, ampoules, suppositories, gels, ointments, implants, vaginal rings or nasal spray is present.
10. Verfahren zur Herstellung eines pharmazeutischen Präparates zur Endometriose-Therapie mit gleichzeitiger Verminderung von Therapie- Nebenwirkungen, wie dem negativen Einfluss auf die Knochendichte/den Knochenstoffwechsel und dem Osteoporose-Risiko, sowie der Verminderung des Risikos angeborener Fehlbildungen und Schwangerschaftskomplikationen bei Eintritt einer Gravidität, dadurch gekennzeichnet, dass eine Kombination von Gestagenen mit (6S)-5-Methyltetrahydrofolat verwendet wird, wobei die tägliche Dosis des Gestagens mindestens der Ovulationshemmdosis bis maximal dem Zweifachen der Ovulationshemmdosis entspricht.10. A process for the preparation of a pharmaceutical preparation for endometriosis therapy with concomitant reduction of therapy side effects, such as the negative impact on bone density / bone metabolism and the risk of osteoporosis, as well as the reduction of the risk of congenital malformations and pregnancy complications at the onset of pregnancy, characterized in that a combination of progestins with (6S) -5-methyltetrahydrofolate is used, wherein the daily dose of progestin corresponds to at least the Ovulationshemmdose up to a maximum of twice the Ovulationshemmdosis.
1 1 . Verfahren nach Anspruch 10, dadurch gekennzeichnet, dass die angeborenen Fehlbildungen und Schwangerschaftskomplikationen bei Eintritt einer Gravidität Neuralrohrdeffekte, Lippen-Kiefer-Gaumenspalten, Plazentaablösung und Frühgeburtlichkeit sind. 1 1. A method according to claim 10, characterized in that the congenital malformations and pregnancy complications at the onset of pregnancy are Neuralrohrdeffekte, cleft lip and palate, Plazentaablösung and premature birth.
12 . Verfahren nach Anspruch 10 oder 1 1 , dadurch gekennzeichnet, dass die Gestagenkomponente 17α-Cyanomethyl-17-ß-hydroxyestra-4,9-dien-3on (Dienogest), Cyproteronacetat oder Chlormadinonacetat ist.12. A method according to claim 10 or 1 1, characterized in that the gestagen component is 17α-cyanomethyl-17-β-hydroxyestra-4,9-diene-3-one (dienogest), cyproterone acetate or chlormadinone acetate.
13 . Verfahren nach Anspruch 10, 1 1 oder 12, dadurch gekennzeichnet, dass die tägliche Dosis 1 bis 2 mg Dienogest oder eine äquivalente Menge an13. A method according to claim 10, 11 or 12, characterized in that the daily dose is 1 to 2 mg dienogest or an equivalent amount of
Cyproteronacetat oder Chlormadinonacetat und (6S)-5-Methyltetrahydrofolat beträgt.Cyproterone acetate or chlormadinone acetate and (6S) -5-methyltetrahydrofolate.
14 . Verfahren nach Anspruch 10, 1 1 , 12 oder 13, dadurch gekennzeichnet, dass die tägliche Dosis 0.1 bis 10 mg (6S)-5-Methyltetrahydrofolat beträgt.14. The method of claim 10, 1 1, 12 or 13, characterized in that the daily dose is 0.1 to 10 mg (6S) -5-methyltetrahydrofolate.
15 . Verfahren nach Anspruch 10, 1 1 , 12, 13 oder 14, dadurch gekennzeichnet, dass die tägliche Dosis 0.4 bis 1 mg (6S)-5-Methyltetrahydrofolat beträgt.15. The method of claim 10, 1 1, 12, 13 or 14, characterized in that the daily dose is 0.4 to 1 mg (6S) -5-methyltetrahydrofolate.
16. Verfahren nach Anspruch 10, 1 1 , 12, 13, 14 oder 15, dadurch gekennzeichnet, dass die tägliche Dosis 451 μg des Kalziumsalzes der (6S)-5- Methyltetrahydrof Ölsäure beträgt.16. The method of claim 10, 1 1, 12, 13, 14 or 15, characterized in that the daily dose is 451 ug of the calcium salt of (6S) -5-methyltetrahydrof oleic acid.
17. Verfahren nach Anspruch 10, 1 1 , 12, 13, 14, 15 oder 16, mit einer kontinuierlichen Verabreichung für die Dauer von mindestens 169 Tagen oder 25 Wochen bis mehreren Jahren, vorzugsweise mehr als 2 Jahren.17. The method of claim 10, 11, 12, 13, 14, 15 or 16, with a continuous administration for a period of at least 169 days or 25 weeks to several years, preferably more than 2 years.
18. Verfahren nach Anspruch 10, 1 1 , 12, 13, 14, 15, 16 oder 17, dadurch gekennzeichnet, dass das pharmazeutische Präparat in Form von Tabletten, Kapseln, Dragees, Wa- fer, Transdermalen-Therapie-Systemen, Ampullen, Suppositorien, Gelen, Salben, Implantaten, Vaginalringen oder Nasenspray vorliegt. 18. The method of claim 10, 1 1, 12, 13, 14, 15, 16 or 17, characterized in that the pharmaceutical preparation in the form of tablets, capsules, dragees, wafers, transdermal therapy systems, ampoules, Suppositories, gels, ointments, implants, vaginal rings or nasal spray.
EP08785200A 2007-08-24 2008-07-30 Use of gestagens in combination with (6s)-5-methyltetrahydrofolate for the therapy of endometriosis with simultaneous reduction of therapy side effects and the reduction of the risk of congenital malformations in case of pregnancy Withdrawn EP2194978A1 (en)

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EP07016642A EP2027855A1 (en) 2007-08-24 2007-08-24 Use of gestagens in combination with (6S)5-methyl tetrahydro folate for endometriosis therapy with simultaneous reduction of the side effects of therapy and reduction in the risk of congenital deformities for with the onset of pregnancy
EP08785200A EP2194978A1 (en) 2007-08-24 2008-07-30 Use of gestagens in combination with (6s)-5-methyltetrahydrofolate for the therapy of endometriosis with simultaneous reduction of therapy side effects and the reduction of the risk of congenital malformations in case of pregnancy
PCT/EP2008/006253 WO2009027003A1 (en) 2007-08-24 2008-07-30 Use of gestagens in combination with (6s)-5-methyltetrahydrofolate for the therapy of endometriosis with simultaneous reduction of therapy side effects and the reduction of the risk of congenital malformations in case of pregnancy

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EP08785200A Withdrawn EP2194978A1 (en) 2007-08-24 2008-07-30 Use of gestagens in combination with (6s)-5-methyltetrahydrofolate for the therapy of endometriosis with simultaneous reduction of therapy side effects and the reduction of the risk of congenital malformations in case of pregnancy

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WO1999033856A1 (en) 1997-12-26 1999-07-08 Mochida Pharmaceutical Co., Ltd. Neovascularization inhibitor containing dienogest as the active ingredient
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