+

WO1996028165A1 - Once-a-month-injectable useful as depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women - Google Patents

Once-a-month-injectable useful as depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women Download PDF

Info

Publication number
WO1996028165A1
WO1996028165A1 PCT/EP1996/001201 EP9601201W WO9628165A1 WO 1996028165 A1 WO1996028165 A1 WO 1996028165A1 EP 9601201 W EP9601201 W EP 9601201W WO 9628165 A1 WO9628165 A1 WO 9628165A1
Authority
WO
WIPO (PCT)
Prior art keywords
month
estradiol
replacement therapy
injectable
once
Prior art date
Application number
PCT/EP1996/001201
Other languages
German (de)
French (fr)
Inventor
Ursula Lachnit-Fixson
Semiramis Aydinlik
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to JP8527295A priority Critical patent/JPH11501649A/en
Priority to PL96322202A priority patent/PL322202A1/en
Priority to SK1239-97A priority patent/SK123997A3/en
Priority to NZ304027A priority patent/NZ304027A/en
Priority to CZ972896A priority patent/CZ289697A3/en
Priority to AU51108/96A priority patent/AU713258B2/en
Priority to EP96907506A priority patent/EP0814811A1/en
Priority to MX9707009A priority patent/MX9707009A/en
Publication of WO1996028165A1 publication Critical patent/WO1996028165A1/en
Priority to NO974255A priority patent/NO974255L/en

Links

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
    • A61K31/56—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
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Definitions

  • the present invention relates to the use of a one-month injection (once-a-month injectable composition) containing an estrogenic and gestagenic component as active ingredients for the manufacture of a medicament for contraception and simultaneous hormone replacement therapy for peri- and premenopausal women.
  • a monthly injection in the sense of the present invention means a hormone preparation which is injected once a month for women of childbearing age for contraception.
  • This hormone preparation contains a gestagenic and an estrogenic component as active substances, each with a long enough effect to achieve a contraceptive effect for a period of one month.
  • progestogen-only injectables are also available, which ensure long-term contraceptive protection, albeit with poor cycle control.
  • US Pat. No. 4,826,831 already discloses a method for the hormonal treatment of menopausal, including perimenopausal and postmenopausal disorders (disorders), which relates in particular to treatment using a progestogen in conjunction with an estrogen.
  • the estrogen can also be continuous or cyclical, i.e. H. with breaks.
  • estrogens and progestogens are mentioned which are suitable for the purposes of this invention, including norethisterone acetate and medroxyprogesterone acetate as progestogens and estradiol valerate.
  • norethisterone acetate and medroxyprogesterone acetate as progestogens and estradiol valerate.
  • it should be possible to use all estrogens and progestogens that are also in oral contraceptives are conceivable. Adequate contraceptive protection is provided by the described
  • Norethisterone acetate / estradiol valerate is also disclosed as a possible combination.
  • progestogen and estrogen used are low: progestogen in a daily amount equivalent to 0.025 mg to 0.075 mg levonorgestrel and estrogen in a daily amount corresponding to 0.5 to 2.0 mg estradiol .
  • the amount to be administered daily is the amount to be administered daily.
  • estradiol valerate 20 mg to 100 mg estradiol valerate are given.
  • Gestagen depot formulation for 3 months should be 50 to 500 mg medroxyprogesterone acetate or 20 to
  • This patent also relates to pharmaceutical compositions for performing them
  • Premenopause begins, onset of ailments, such as hot flushes, dryness of the
  • US Pat. No. 4,826,831 expressly states that oral administration is not a method of contraception.
  • peri- and premenopause should have their conventional meaning as described in "The Controversial Cli acteric", P.A. van Keep et al., Ed., MTP Press (1981) on page 9 can be understood.
  • a one-month injection in the sense of the present invention should be understood to mean both the products already mentioned at the beginning and all other possible combinations of a natural estrogen with a progestogen.
  • the two active components must be present in a depot formulation, the depot effect being achieved either through the special type of pharmaceutical formulation (for example microcrystalline suspension) or rather through the chemical structure of the progestogen and / or estrogen (for example through the esterification of free hydroxyl groups).
  • the main estrogens here are 17 ⁇ -estradiol, estradiol-3-benzoate, estradiol-17-valerate, cypionate, undecylate, enanthate and or other estradiol esters (US Pat. No. 2,611,773, US Pat
  • the gestagen component is preferably selected from the group of compounds
  • Norethisterone acetate, norethisterone acetate, medroxyprogesterone acetate and cyproterone acetate Norethisterone acetate, norethisterone acetate, medroxyprogesterone acetate and cyproterone acetate.
  • Tables LA and 2A list selected estrogens or gestagens to be used according to the present invention, with an indication of the preferred amount range.
  • Tables 1B and 2B show the particularly preferred amounts of the respective estrogen or progestogen which are to be contained in a one-month syringe according to the present invention.
  • the combination of medroxyprogesterone acetate and estradiol cypionate is preferred for producing a one-month syringe for peri- and premenopausal contraception; the combination of norethisterone enanthate / estradiol valerate is particularly preferred.
  • the particularly preferred embodiment based on the progestogen / estrogen combination norethisterone enanthate / estradiol valerate not only offers a prophylactic effect with regard to osteoporosis, but in addition to the bone depletion-inhibiting effect of estrogen, a bone building effect caused by the norethis-terone enanthate is observed in this combination.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

A once-a-month-injectable that contains an oestrogen and a gestagen component as active substances is used to prepare a contraceptive medicament useful at the same time in the hormone replacement therapy for perimenopausal and premenopausal women. A reliable contraceptive effect with a 'natural' oestrogen (without ethinyl oestradiol) is achieved with this medicament, as well as an effective therapy of the first oestrogen deficiency symptoms and the prevention of osteoporosis.

Description

Einmonatsspritze als Depot-Kontrazep ivαm und für die Hormonersatztherapie für peri- und praemenopaαsale Frauen One-month injection as a depot contraceptive ivαm and for hormone replacement therapy for peri- and premenopaαsal women
Die vorliegende Erfindung betrifft die Verwendung einer Einmonatsspritze (once-a-month- injectable-composition) enthaltend eine estrogene und gestagene Komponente als Wirkstoffe zur Herstellung eines Arzneimittels für die Kontrazeption und die gleichzeitige Hormonersatztherapie für peri- und praemenopausale Frauen.The present invention relates to the use of a one-month injection (once-a-month injectable composition) containing an estrogenic and gestagenic component as active ingredients for the manufacture of a medicament for contraception and simultaneous hormone replacement therapy for peri- and premenopausal women.
Einmonatsspritze im Sinne vorliegender Erfindung bedeutet eine Hormonpräparation, die Frauen im gebärfähigen Alter einmal monatlich zur Empfängnisverhütung injiziert wird. In dieser Hormonpräparation sind als aktive Substanzen eine gestagene sowie estrogene Komponente, jeweils mit einer ausreichend langen Wirkung zur Erzielung eines kontrazeptiven Effekts für einen einmonatigen Zeitraum, enthalten.A monthly injection in the sense of the present invention means a hormone preparation which is injected once a month for women of childbearing age for contraception. This hormone preparation contains a gestagenic and an estrogenic component as active substances, each with a long enough effect to achieve a contraceptive effect for a period of one month.
Es sind auch sogenannte progestogen-only injectables verfügbar, die einen länger anhaltenden kontrazeptiven Schutz, allerdings bei schlechter Zykluskontrolle, gewährleisten.So-called progestogen-only injectables are also available, which ensure long-term contraceptive protection, albeit with poor cycle control.
Bekannteste Vertreter einer derartigen Einmonatsspritze sind Cyclofem (HRP 112; Cycloprovera) und Mesigyna (HRP 102). Erstere enthält 25 mg Medroxyprogesteronacetat als gestagene und 5 mg Estradiolcypionat als estrogene Komponente in Mikrokristallsuspension, letztere 50 mg Norethisteronenanthat als gestagene und 5 mg Estradiolvalerat als estrogene Komponente in öliger Lösung. Obwohl die Frauen, die diese Verhütungsmethode wählen, jeden Monat ein Familienplanungszentrum oder einen Arzt zur Verabreichimg der Injektion aufsuchen müssen, werden diese Einmonatsspritzen zur Kontrazeption gut angenommen. Vaginale Blutungen treten wie die Menstruation ziemlich regulär und vorhersehbar auf, was für eine breite Akzeptanz dieser sicheren Methode in vielen Kulturkreisen von herausragender Bedeutung ist. (Biennial Report 1988- 1989, Research in Human Reproduction, WHO).The best-known representatives of such a one-month syringe are Cyclofem (HRP 112; Cycloprovera) and Mesigyna (HRP 102). The former contains 25 mg medroxyprogesterone acetate as a gestagen and 5 mg of estradiol cypionate as an estrogenic component in microcrystalline suspension, the latter 50 mg of norethisterone enanthate as a gestagen component and 5 mg of estradiol valerate as an estrogen component in an oily solution. Although women who choose this method of contraception need to see a family planning center or doctor every month to administer the injection, these one-month injections for contraception are well received. Vaginal bleeding, like menstruation, is fairly regular and predictable, which is of paramount importance for wide acceptance of this safe method in many cultures. (Biennial Report 1988-1989, Research in Human Reproduction, WHO).
Aus dem US-Patent 4,826,831 geht bereits eine Methode für die hormoneile Behandlung menopausaler, einschließlich perimenopausaler und postmenopausaler Störungen (disorders) hervor, die insbesondere eine Behandlung unter der kontinuierlichen Anwendung eines Gestagens in Verbindung mit einem Estrogen betrifft. Das Estrogen kann dabei ebenfalls kontinuierlich oder auch zyklisch, d. h. mit Einnahmepausen, angewendet werden.US Pat. No. 4,826,831 already discloses a method for the hormonal treatment of menopausal, including perimenopausal and postmenopausal disorders (disorders), which relates in particular to treatment using a progestogen in conjunction with an estrogen. The estrogen can also be continuous or cyclical, i.e. H. with breaks.
Es ist eine Vielzahl von Estrogenen und Gestagenen genannt, die für die Zwecke dieser Erfindung geeignet sind, u. a. auch Norethisteronacetat und Medroxyprogesteronacetat als Gestagene sowie Estradiolvalerat. Es sollen prinzipiell alle Estrogene und Gestagene verwendbar sein, die auch in oralen Kontrazeptiva denkbar sind. Ausreichender kontrazeptiver Schutz ist durch die beschriebenenA large number of estrogens and progestogens are mentioned which are suitable for the purposes of this invention, including norethisterone acetate and medroxyprogesterone acetate as progestogens and estradiol valerate. In principle, it should be possible to use all estrogens and progestogens that are also in oral contraceptives are conceivable. Adequate contraceptive protection is provided by the described
Behandlungen ausdrücklich nicht gegeben.Treatments expressly not given.
Norethisteronacetat/Estradiolvalerat ist außerdem als eine mögliche Kombination offenbart.Norethisterone acetate / estradiol valerate is also disclosed as a possible combination.
Die zur Anwendung kommenden Mengen Gestagen und Estrogen sind niedrig: Das Gestagen in einer täglichen Menge, die einer Menge von 0,025 mg bis 0,075 mg Levonorgestrel und das Estrogen in einer täglichen Menge, die einer Menge von 0,5 bis 2,0 mg Estradiol entspricht.The amounts of progestogen and estrogen used are low: progestogen in a daily amount equivalent to 0.025 mg to 0.075 mg levonorgestrel and estrogen in a daily amount corresponding to 0.5 to 2.0 mg estradiol .
Im Falle einer oralen Applikation der Wirkstoffe liegt die täglich zu verabreichende MengeIn the case of oral administration of the active ingredients, the amount to be administered daily is
Estradiolvalerat im Bereich 0,5 mg bis 2,0 mg; für Norethisteronacetat ist eine tägliche Menge von 0,1 mg bis 1,0 mg und für Medroxyprogesteronacetat eine solche von L0 mg bis 15,0 mg angegeben.Estradiol valerate in the range 0.5 mg to 2.0 mg; a daily amount of 0.1 mg to 1.0 mg is given for norethisterone acetate and that of L0 mg to 15.0 mg for medroxyprogesterone acetate.
Die US-PS 4,826,831 umfaßt auch die nicht-orale Anwendung der angegebenen Wirkstoffe mittelsUS Pat. No. 4,826,831 also includes the non-oral use of the specified active ingredients
Implantaten oder durch intramuskuläre Injektion. Die benötigten "täglichen" Dosierungen liegen dann etwas niedriger als im Falle der oralen Applikation aufgrund des direkten Übergangs derImplants or by intramuscular injection. The required "daily" dosages are then somewhat lower than in the case of oral administration due to the direct transition from the
Wirkstoffe in die Blutbahn.Active substances in the bloodstream.
Für ein Estrogenimplant sind 20 mg bis 100 mg Estradiolvalerat angegeben. EineFor an estrogen implant, 20 mg to 100 mg estradiol valerate are given. A
Gestagendepotformulierung für 3 Monate soll 50 bis 500 mg Medroxyprogesteronacetat bzw. 20 bisGestagen depot formulation for 3 months should be 50 to 500 mg medroxyprogesterone acetate or 20 to
400 mg Norethisteronenanthat enthalten.Contain 400 mg of norethisterone enanthate.
Dieses Patent betrifft auch pharmazeutische Zusammensetzungen zur Durchführung dieserThis patent also relates to pharmaceutical compositions for performing them
Methode.Method.
Durch diese Methode werden den mit dem natürlichen Estrogenentzug, der bereits in derThrough this method, those with natural estrogen deprivation who are already in the
Praemenopause beginnt, einsetzenden Beschwerden, wie beispielsweise hot flushes, Trockenheit derPremenopause begins, onset of ailments, such as hot flushes, dryness of the
Vagina, der Osteoporosegefahr, der zunehmenden Gefahr bei Frauen über 60 Jahren einenVagina, the risk of osteoporosis, the increasing risk in women over 60 years old
Myokardinfarkt zu erleiden (kardiovaskuläre Komplikationen), wirkungsvoll begegnet, wobei aber aufgrund der gestagenen Komponente eine Blutungsinduktion unterdrückt, aber das Risiko für dieMyocardial infarction (cardiovascular complications), countered effectively, but suppresses bleeding due to the gestagen component, but the risk for the
Ausbildung von Endome rialcarzinomeπ nicht erhöht wird.Training of endome rialcarzinomeπ is not increased.
In der US-PS 4,826,831 wird ausdrücklich darauf hingewiesen, daß es sich im Falle der oralen Applikation nicht um eine Methode der Empfängnisverhütung handelt.US Pat. No. 4,826,831 expressly states that oral administration is not a method of contraception.
Peri- und Praemenopause sollen im Sinne vorliegender Erfindung in ihrer konventionellen Bedeutung, wie sie in "The Controversial Cli acteric", P.A. van Keep et al., Ed., MTP Press (1981) auf Seite 9 angegeben ist, verstanden werden.In the sense of the present invention, peri- and premenopause should have their conventional meaning as described in "The Controversial Cli acteric", P.A. van Keep et al., Ed., MTP Press (1981) on page 9 can be understood.
Aufgabe der vorliegenden Erfindung ist es, ein Depot-Arzneimittel zur Verfügung zu stellen, welches für Frauen in der Peri- und Praemenopause gleichermaßen für die noch nötige Kontrazeption als auch für die bereits in diesem Lebensabschnitt ratsame hormoneile Substitutionstherapie (Hormone Replacement Therapie = HRT) geeignet ist. Es wurde nunmehr gefunden, daß ein derartiges Arzneimittel für prae- und perimenopausale Frauen überraschenderweise auf der Basis einer Einmonatsspritze hergestellt werden kann. Während durch die in der US-PS 4,826,831 beschriebene Methode Blutungen der behandelten Frauen gerade vermieden werden sollen, tritt bei peri- pzw. praemenopausalen Frauen nach Applikation der erfindungsgemäßen Einmonatsspritze am Ende des Behandlungszeitraumes eine Monatsblutung auf; es wird also keine Amenorrhoe induziert.The object of the present invention is to provide a depot medication which is equally suitable for women in the peri- and premenopause for the contraception still required as well as for hormonal replacement therapy (Hormone Replacement Therapy = HRT), which is advisable in this phase of life is. It has now been found that such a medicament for pre- and perimenopausal women can surprisingly be produced on the basis of a one-month injection. While bleeding of the treated women is to be avoided by the method described in US Pat. No. 4,826,831, peripzw. premenopausal women have a menstrual period after application of the one-month injection according to the invention at the end of the treatment period; so no amenorrhea is induced.
Unter Einmonatsspritze im Sinne vorliegender Erfindung sollen sowohl die bereits eingangs erwähnten Produkte als auch alle anderen denkbaren Kombinationen eines natürlichen Estrogens mit einem Gestagen verstanden werden. Die beiden Wirkkomponenten müssen dabei in einer Depotfoπnulierung vorliegen, wobei der Depoteffekt entweder durch die besondere Art der galenischen Formulierung (beispielsweise Mikrokristallsuspension) oder aber eher durch den chemischen Aufbau des Gestagens und oder Estrogens erreicht wird (beispielsweise durch die Veresterung freier Hydroxygruppen).A one-month injection in the sense of the present invention should be understood to mean both the products already mentioned at the beginning and all other possible combinations of a natural estrogen with a progestogen. The two active components must be present in a depot formulation, the depot effect being achieved either through the special type of pharmaceutical formulation (for example microcrystalline suspension) or rather through the chemical structure of the progestogen and / or estrogen (for example through the esterification of free hydroxyl groups).
Es kommen dabei prinzipiell alle natürlichen Estrogene und alle Gestagene in Betracht, die zurIn principle, all natural estrogens and all progestogens are considered
Verwendung in oralen Kontrazeptiva geeignet sind und die sich in oben erwähnter Weise in eine galenische Formulierung überführen oder chemische Form derivatisieren lassen, die einenAre suitable for use in oral contraceptives and which can be converted into a galenical formulation or derivatized chemical form in the above-mentioned manner
Depoteffekt bewirkt und die als intramuskulär zu verabreichende Arzneiform herstellbar ist.Depot effect and the drug form to be administered intramuscularly can be produced.
Als Estrogene kommen hier in erster Linie 17ß-Estradiol, Estradiol-3-benzoat, Estradiol-17-valerat, - cypionat, -undecylat, -enanthat und oder andere Estradiolester infrage (US-PS 2,611,773, US-PSThe main estrogens here are 17β-estradiol, estradiol-3-benzoate, estradiol-17-valerate, cypionate, undecylate, enanthate and or other estradiol esters (US Pat. No. 2,611,773, US Pat
2,990,414, US-PS 2,054,271, US-PS 2^25,419 und US-PS 2,156,599).2,990,414, U.S. Patent 2,054,271, U.S. Patent 2 ^ 25,419 and U.S. Patent 2,156,599).
Die gestagene Komponente wird vorzugsweise aus der Gruppe der VerbindungenThe gestagen component is preferably selected from the group of compounds
Norethisteronacetat, Norethisteronenenthat, Medroxyprogesteronacetat und Cyproteronacetat ausgewählt.Norethisterone acetate, norethisterone acetate, medroxyprogesterone acetate and cyproterone acetate.
In den folgenden Tabellen LA und 2A sind ausgewählte, gemäß vorliegender Erfindung zu verwendende Estrogene bzw. Gestagene mit Angabe des bevorzugten Mengenbereiches aufgelistet. Aus den Tabellen 1B und 2B gehen die besonders bevorzugten Mengen des jeweiligen Estrogens bzw. Gestagens, die in einer Einmonatsspritze gemäß vorliegender Erfindung enthalten sein sollen, hervor. Tabelle 1A Ta eUelBThe following tables LA and 2A list selected estrogens or gestagens to be used according to the present invention, with an indication of the preferred amount range. Tables 1B and 2B show the particularly preferred amounts of the respective estrogen or progestogen which are to be contained in a one-month syringe according to the present invention. Table 1A Ta eUelB
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0001
Figure imgf000006_0002
Tabelle 2A Tabelle 2BTable 2A Table 2B
Figure imgf000006_0003
Figure imgf000006_0004
Figure imgf000006_0003
Figure imgf000006_0004
Erfindungsgemäß bevorzugt zur Herstellung einer Einmonatsspritze für die peri- und praemenopausale Kontrazeption ist die Kombination Medroxyprogesteronacetat Estradiolcypionat; die Kombination Norethisteronenanthat/Estradiolvalerat ist besonders bevorzugt.According to the invention, the combination of medroxyprogesterone acetate and estradiol cypionate is preferred for producing a one-month syringe for peri- and premenopausal contraception; the combination of norethisterone enanthate / estradiol valerate is particularly preferred.
Als besondere Vorteile der erfindungsgemäß hergestellten Einmonatsspritze, die im Falle praemenopausaler Frauen überraschenderweise sowohl der Kontrazeption als auch der Hormonersatztherapie dienen kann, sind in erster Linie zu erwähnen:As special advantages of the one-month syringe produced according to the invention, which can surprisingly serve both contraception and hormone replacement therapy in the case of premenopausal women:
sicherer kontrazeptiver Effekt ohne Ethinylestradiol mit "natürlichem" Estrogen; damit einhergehende wirksame Therapie der beginnenden Estrogen- Ausfallerscheinungensafe contraceptive effect without ethinyl estradiol with "natural" estrogen; associated effective therapy for the onset of estrogen deficiency symptoms
(Beseitigung der menopausalen Symptome); gleichzeitig optimale Osteoporose-Prävention; hervorragende Toleranz und Zykluskontrolle; praktisch keine Veränderung des Blutdrucks; • sehr niedrige, fast nicht vorhandene unerwünschte Nebenwirkungen und Einflüsse auf metabolische und haemostatische Parameter,(Elimination of menopausal symptoms); optimal osteoporosis prevention at the same time; excellent tolerance and cycle control; practically no change in blood pressure; • very low, almost non-existent undesirable side effects and influences on metabolic and haemostatic parameters,
• Vermeidung einer Leberbelastung sowie gastrointestinaler Störungen aufgrund des parenteralen Anwendungsweges;• avoidance of liver strain and gastrointestinal disorders due to the parenteral route of use;
• Beibehaltung der vorteilhaften Nebenwirkungen oraler Kontrazeptiva (Schutz vor Ovarial- und Endometriumkarzinom und Pelvic Inflammatory Desease [PID]).• Maintaining the beneficial side effects of oral contraceptives (protection against ovarian and endometrial cancer and Pelvic Inflammatory Desease [PID]).
Alle diese Eigenschaften wurden durch eine 3-jährige, klinische Studie mit Mesigyna belegt, wobei am Patientinnenkollektiv 17 über 35 Jahre alte Frauen beteiligt waren.All of these properties were demonstrated in a 3-year clinical study with Mesigyna, in which 17 women over 35 years of age were involved in the patient population.
Die besonders bevorzugte Ausführungsfoπn auf Basis der Gestagen/Estrogen-Kombination Norethisteronenanthat/Estradiolvalerat bietet nicht nur einen prophylaktischen Effekt betreffend die Osteoporose sondern es wird bei dieser Kombination über die knochenabbauhemmendc Wirkung des Estrogens hinaus sogar ein durch das Norethis-teronenanthat hervorgerufener Knochenaufbaueffekt beobachtet. The particularly preferred embodiment based on the progestogen / estrogen combination norethisterone enanthate / estradiol valerate not only offers a prophylactic effect with regard to osteoporosis, but in addition to the bone depletion-inhibiting effect of estrogen, a bone building effect caused by the norethis-terone enanthate is observed in this combination.
FormulierungsbeispieleFormulation examples
r.sγ-πn-^r.sγ-πn- ^
Eine Ampulle enthältContains one ampoule
50 mg Norethisteronenanthat + 5 mg Estradiolvalerat in 1 ml Rizinu≤öl Benzylbeπzoat 6/4 (V/V).50 mg norethisterone enanthate + 5 mg estradiol valerate in 1 ml castor oil benzyl benzoate 6/4 (V / V).
Formulierung mit CyproteronacetatFormulation with cyproterone acetate
Eine Ampulle enthältContains one ampoule
50 mg Cyproteronacetat + 5 mg Estradiolvalerat in 1 ml Rizinusöl/Benzylbenzoat 6/4 (V/V). 50 mg cyproterone acetate + 5 mg estradiol valerate in 1 ml castor oil / benzyl benzoate 6/4 (V / V).

Claims

Patentansprüche claims
1. Verwendung einer Einmonatsspritze (once-a-month-injectable) enthaltend eine estrogene und gestagene Komponente als Wirkstoffe zur Herstellung eines Arzneimittels für die Kontrazeption und die gleichzeitige Hormonersatztherapie für peri- und praemenopausale Frauen.1. Use of a one-month injection (once-a-month-injectable) containing an estrogenic and gestagenic component as active ingredients for the manufacture of a medicament for contraception and simultaneous hormone replacement therapy for peri- and premenopausal women.
2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß die estrogene Komponente aus der Gruppe der Verbindungen 17ß-Estradiol, Estradiol-3-benzoat, Estradiol-17-valerat, -cypionat, - undecylat, -enanthat sowie weiterer Estradiolester ausgewählt ist.2. Use according to claim 1, characterized in that the estrogenic component is selected from the group of the compounds 17ß-estradiol, estradiol-3-benzoate, estradiol-17-valerate, -cypionate, - undecylate, -enanthate and further estradiol esters.
3. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß die gestagene Komponente aus der Gruppe der Verbindungen Norethisteronacetat, Norethisteronenenthat, Medroxyprogesteronacetat, Cyproteronacetat ausgewählt ist.3. Use according to claim 1, characterized in that the gestagen component is selected from the group of the compounds norethisterone acetate, norethisterone enthat, medroxyprogesterone acetate, cyproterone acetate.
4. Verwendung der Kombinationen4. Use of the combinations
Norethisteronananthat/Estradiolvalerat, Medroxyprogesteronacetat/Estradiolcypionat nach den Ansprüchen 2 und 3. Norethisterone ananthate / estradiol valerate, medroxyprogesterone acetate / estradiol cypionate according to claims 2 and 3.
PCT/EP1996/001201 1995-03-16 1996-03-15 Once-a-month-injectable useful as depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women WO1996028165A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP8527295A JPH11501649A (en) 1995-03-16 1996-03-15 Injection for January as a sustained release contraceptive for women in peri-menopause and pre-menopause and for hormone replacement therapy
PL96322202A PL322202A1 (en) 1995-03-16 1996-03-15 Monthly injections as a contraceptive measure for and in substitute hormonal therapy of pre- and in-menopausal female patients
SK1239-97A SK123997A3 (en) 1995-03-16 1996-03-15 Once-a-month-injectable useful as depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women
NZ304027A NZ304027A (en) 1995-03-16 1996-03-15 Once a month injectable contraceptive comprising an estrogenic and gestagenic component for contraception and simultaneous hormone replacement therapy
CZ972896A CZ289697A3 (en) 1995-03-16 1996-03-15 Injection administered once a month as a depot contraception and for hormonal substitution therapy for women in perimenstrual and premenstrual pause
AU51108/96A AU713258B2 (en) 1995-03-16 1996-03-15 Once-a-month-injection as a depot contraceptive and for hormone replacement therapy for perimenopausal and premenopausal women
EP96907506A EP0814811A1 (en) 1995-03-16 1996-03-15 Once-a-month-injectable useful as depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women
MX9707009A MX9707009A (en) 1995-03-16 1996-03-15 Once-a-month-injectable useful as depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women.
NO974255A NO974255L (en) 1995-03-16 1997-09-15 Preparation for once-daily injection month and useful as a depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19510861A DE19510861A1 (en) 1995-03-16 1995-03-16 One-month injection as a depot contraceptive and for hormone replacement therapy for peri- and premenopausal women
DE19510861.2 1995-03-16

Publications (1)

Publication Number Publication Date
WO1996028165A1 true WO1996028165A1 (en) 1996-09-19

Family

ID=7757668

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/001201 WO1996028165A1 (en) 1995-03-16 1996-03-15 Once-a-month-injectable useful as depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women

Country Status (17)

Country Link
EP (1) EP0814811A1 (en)
JP (1) JPH11501649A (en)
KR (1) KR19980703058A (en)
AR (1) AR002283A1 (en)
AU (1) AU713258B2 (en)
CA (1) CA2215382A1 (en)
CZ (1) CZ289697A3 (en)
DE (1) DE19510861A1 (en)
HU (1) HUP9801691A3 (en)
IL (1) IL117516A (en)
MX (1) MX9707009A (en)
NO (1) NO974255L (en)
NZ (1) NZ304027A (en)
PL (1) PL322202A1 (en)
SK (1) SK123997A3 (en)
WO (1) WO1996028165A1 (en)
ZA (1) ZA962177B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0000313D0 (en) 2000-01-10 2000-03-01 Astrazeneca Uk Ltd Formulation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0136011A2 (en) * 1983-08-05 1985-04-03 Pre Jay Holdings Ltd. A method of hormonal treatment of peri-menopausal, menopausal and post-menopausal disorders and multi-preparation pack therefor

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0136011A2 (en) * 1983-08-05 1985-04-03 Pre Jay Holdings Ltd. A method of hormonal treatment of peri-menopausal, menopausal and post-menopausal disorders and multi-preparation pack therefor

Also Published As

Publication number Publication date
DE19510861A1 (en) 1996-09-19
NO974255D0 (en) 1997-09-15
CA2215382A1 (en) 1996-09-19
AR002283A1 (en) 1998-03-11
HUP9801691A3 (en) 1999-03-01
NO974255L (en) 1997-11-14
NZ304027A (en) 2000-05-26
MX9707009A (en) 1997-11-29
SK123997A3 (en) 1998-02-04
IL117516A0 (en) 1996-07-23
AU713258B2 (en) 1999-11-25
IL117516A (en) 2000-07-26
CZ289697A3 (en) 1997-12-17
PL322202A1 (en) 1998-01-19
AU5110896A (en) 1996-10-02
HUP9801691A2 (en) 1998-11-30
ZA962177B (en) 1996-07-29
KR19980703058A (en) 1998-09-05
JPH11501649A (en) 1999-02-09
EP0814811A1 (en) 1998-01-07

Similar Documents

Publication Publication Date Title
DE3916112C2 (en)
DE69118494T2 (en) Contraception procedure and scheme
DE69804918T2 (en) Very low-dose oral contraceptive with less menstrual bleeding and delayed effects
EP0148724B1 (en) Sequential combined multiphase preparation and its use for oral contraception
EP0499348B1 (en) Ovulation-inhibiting agent for hormonal contraception
EP0696454B1 (en) Pharmaceutical preparation for contraception/hormonsubstitution with biogenic estrogen components
EP0628312B1 (en) Anti-contraceptive composition
EP0770388B1 (en) Multiphase contraceptive preparation based on natural estrogens
DE3855606T2 (en) Use of melatonin to make a contraceptive composition
EP0835114B1 (en) Pharmaceutical combined preparation, kit and method for hormonal contraception
DE69432752T2 (en) COMPOSITION FOR SUBSTITUTION THERAPY THAT CONTAINS AT LEAST ONE PROGESTOGEN AND AT LEAST ONE OESTROGEN
EP1310257A2 (en) Hormonal contraceptive combination
DE69327319T2 (en) MINIMIZATION OF BREAST BLEEDING PROGESTERONE BLEED
DE69729956T2 (en) ORAL, ONE-STEP CONCEPT PREVENTION METHOD AND COMBINATION PRODUCT CONTAINING THE STAGE AND ESTROGEN
DE4344462A1 (en) Composition for contraception
DE19654609A1 (en) Therapeutic progestogens for the treatment of premenstrual dysphoric disorder
DE4330234A1 (en) The use of progestogens and competitive progesterone antagonists for the production of pharmaceuticals for female fertility control and compositions comprising a progestogen and a competitive progesterone antagonist
WO1994002103A2 (en) Ovulation inhibitor for hormonal contraception
EP0787002B1 (en) Competitive progesterone antagonists for regulating female fertility as required
WO1996032114A1 (en) Combined hormonal contraception pharmaceutical preparation
DE602004009288T2 (en) USE OF A COMBINATION OF AN AROMATASE HEATHER, A PROGESTINE AND AN ESTROGEN FOR THE TREATMENT OF ENDOMETRIOSIS
DE3787386T2 (en) Composition to be used in the treatment of estrogen insufficiency.
DE69827017T2 (en) COMBINATIONS OF ENDOMETRICALLY PROTECTED AND ENDOMETRICALLY ATROPHOSED AGENTS WITH ESTROGENIC IN ORAL CONCENTRATION PREVENTION
DD238921A5 (en) METHOD FOR PRODUCING A CONTRAZEPTIVE SYNERGISTIC COMPOSITION
WO1996028165A1 (en) Once-a-month-injectable useful as depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 96192615.5

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AU BY CA CN CZ HU JP KR MX NO NZ PL RU SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1996907506

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 1996 527295

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 304027

Country of ref document: NZ

Ref document number: 123997

Country of ref document: SK

Ref document number: 1199700815

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 1019970706467

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2215382

Country of ref document: CA

Ref document number: 2215382

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PV1997-2896

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: PV1997-2896

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1996907506

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 1998 913306

Country of ref document: US

Date of ref document: 19980130

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 1019970706467

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV1997-2896

Country of ref document: CZ

WWR Wipo information: refused in national office

Ref document number: 1019970706467

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1996907506

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载