WO2003018026A1 - Utilisation de composes oestrogeniques combines avec des composes progestogeniques dans une hormonotherapie substitutive - Google Patents

Utilisation de composes oestrogeniques combines avec des composes progestogeniques dans une hormonotherapie substitutive Download PDF

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WO2003018026A1
WO2003018026A1 PCT/NL2002/000333 NL0200333W WO03018026A1 WO 2003018026 A1 WO2003018026 A1 WO 2003018026A1 NL 0200333 W NL0200333 W NL 0200333W WO 03018026 A1 WO03018026 A1 WO 03018026A1
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component
estrogenic
administration
days
progestogenic
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PCT/NL2002/000333
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Herman Jan Tijmen Coelingh Bennink
Evert Johannes Bunschoten
Christian Franz Holinka
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Pantarhei Bioscience B.V.
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Priority claimed from EP01203305A external-priority patent/EP1287817A1/fr
Application filed by Pantarhei Bioscience B.V. filed Critical Pantarhei Bioscience B.V.
Publication of WO2003018026A1 publication Critical patent/WO2003018026A1/fr

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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
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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 a method of hormone replacement in mammals. More particularly the invention is concerned with a method of hormone replacement that comprises the parenteral or rectal administration of a combination of an estrogenic component and a progestogenic component in an effective amount to prevent or treat symptoms of hypoestrogemsm.
  • estrogens are administered to prevent or treat symptoms resulting from estrogen deficiency or hypoestrogemsm.
  • Hypoestrogemsm can occur in both females and males, and can lead to disorders and ailments such as osteoporosis (loss of bone mass), arteriosclerosis, climacteric symptoms such as hot flushes (flashes), sweats, urogenital atrophy, mood disturbances, insomnia, palpitations.
  • Estrogen deficiency has also been associated with cognitive disturbances and Alzheimer's disease.
  • hypoestrogemsm and in particular chronic hypoestrogemsm, is frequently observed in (peri-)menopausal and post-menopausal women. However, it can also result from hypogonadism or castration, as well as from primary ovarian failure, treatment of e.g. breast cancer with aromatase inhibitor and gonadotropin-releasing hormone analogue treatment of benign gynaecological diseases such as endometriosis, adenomyosis, uterine fibroids (leiomyomas), dysmenorrhoea, menorrhagia and metrorrhagia.
  • benign gynaecological diseases such as endometriosis, adenomyosis, uterine fibroids (leiomyomas), dysmenorrhoea, menorrhagia and metrorrhagia.
  • HRT employs continuous administration of effective amounts of an estrogen for prolonged periods of time.
  • the administration of estrogens has been associated, however, with endometrial proliferation in women and it is now widely accepted that "unopposed" estrogen therapy substantially increases the risk of endometrial cancer (Gushing et al., 1998. Obstet. Gynecol.91, 35-39; Tavani et al., 1999. Drugs Aging, 14, 347-357).
  • There is also evidence of a significant increase in breast cancer with long-term (10-15 years) use of estrogen therapy (Tavani et al, 1999. Drugs Aging, 14, 347-357; Pike et al., 2000. Steroids, 65, 659-664).
  • adjunctive progestogen treatment In order to counteract the negative effects of unopposed estrogen therapy, adjunctive progestogen treatment is nowadays commonly applied. Regular progestogen administration is believed to inhibit the continual estrogen stimulation of the endometrium through an anti- proliferative effect and appears to reduce the incidence of endometrial carcinoma in postmenopausal women receiving estrogen replacement therapy (Beral et al., 1999. J. Epidemiol. Biostat, 4, 191-210).
  • Such an adjunctive treatment generally using synthetic progestogens, is given either in continuous combined regimens with estrogen, or added sequentially, typically for about 14 days each month, to continuous estrogen treatment.
  • Endogenous and exogenous estrogens fulfil important central nervous and metabolic functions in the female organism: normal estrogen levels make a decisive contribution to a woman's well-being. Notwithstanding the widespread use of estrogens in HRT methods, there are still some unsolved problems.
  • Known estrogens in particular the biogenic estrogens (i.e. estrogens naturally occurring in the human body), are eliminated from the blood stream very quickly. For instance, for the main human biogenic estrogen 17 ⁇ -estradiol the half-life is around 1 hour.
  • blood serum levels of such biogenic estrogens tend to fluctuate considerably.
  • the serum concentration is usually several times higher than the optimum concentration.
  • serum concentrations will quickly decrease to a level where the estrogen is no longer physiologically active.
  • the most important synthetically altered estrogenic steroid is 17 ⁇ -ethinyl estradiol (EE).
  • EE 17 ⁇ -ethinyl estradiol
  • This estrogen is dominant in oral hormonal contraception and is hardly used in HRT methods because prolonged administration of EE has been associateded with an increased risk of thromboembolism, which deemed to be particularly detrimental in menopausal and postmenopausal females.
  • mestranol has been used in a few cases; mestranol is a "prodrug” that is metabolised to EE in the organism.
  • the liver is a target organ for estrogens.
  • the secretion activity that is affected by estrogens in the human liver includes increased synthesis of transport proteins CBG, SHBG, TBG, several factors that are important for the physiology of blood clotting, and lipoproteins.
  • the strong hepatic estrogenicity of ethinyl estradiol and diethylstilbestrol (DES), especially their effect on haemostasis factors, may explain why these synthetic estrogens have been associated with the enhanced risk of thromboembolism.
  • Other undesirable side-effects that have been reported in relation to the use of synthetic estrogens include fluid retention, nausea, bloating, cholelithiasis, headache and breast pain.
  • R 1? R , R 3 , R 4 independently are a hydrogen atom, a hydroxyl group or an alkoxy group with 1-5 carbon atoms; each of R 5 , R 6) R is a hydroxyl group; and no more than 3 of Ri, R 2 , R 3 , R are hydrogen atoms.
  • estetrol is an estrogen that is produced by the fetal liver during human pregnancy. Unconjugated estetrol levels in maternal plasma peak at about 1.2 ng/ml at term pregnancy and are about 12 times higher in fetal than in maternal plasma (Tulchinsky et al., 1975. J. Clin. Endocrinol. Metab., 40, 560-567).
  • estetrol is a weak estrogen.
  • the estrogenic potency of estetrol has been found to be lower than that of another biogenic estrogen, namely, 17 ⁇ -estradiol, which is considered to be a relatively weak estrogen (e.g. compared to ethinyl estradiol).
  • US 5,468,736 describes a method of hormone replacement therapy involving the administration of estrogen together with an amount of antiprogestin (antiprogestogen), which inhibits estrogen-induced endometrial proliferation in women.
  • antiprogestogen antiprogestogen
  • Example 3 the combined use of estetrol and lilopristone is mentioned. No clues are given in the examples as to the mode and frequency of administration or regarding the dosage level employed.
  • a disadvantage associated with the use of antiprogestogens, such as lilopristone is the risk of inducing abnormal endometrial morphology, i.e. cystic hyperplasia, as has been observed in women who received an antiprogestogen treatment against endometriosis (Murphy et al, 1995. Fertil. Steril., 95, 761-766).
  • US 5,340,586 (Pike et al.) is concerned with compositions and methods which are effective to treat oophorectomised women, wherein an effective amount of an estrogenic composition and an androgenic composition are provided over a period of time.
  • natural and synthetic estrogenic compositions that can be used include natural estrogenic hormones and congeners, including but not limited to estradiol, estradiol benzoate, estradiol cypionate, estradiol valerate, estrone, diethylstilbestrol, piperazine estrone sulfate, ethinyl estradiol, mestranol, polyestradiol phosphate, estriol, estriol hemisuccinate, quinestrol, estropipate, pinestrol and estrone potassium sulfate, and furthermore that equine estrogens, such as equilelinin, equilelinin sulfate and estetrol, may also be employed
  • a contraceptive method comprising the sequential administration of (1) a combination of luteinizing hormone releasing hormone (LHRH) and estrogen and (2) a combination of LHRH and estrogen and progestogen.
  • LHRH luteinizing hormone releasing hormone
  • a contraceptive method comprising administering a gonadotropin hormone releasing hormone (GnRH) composition in an amount effective to inhibit ovulation and administering estrogen and progestogen to maintain serum levels above a defined minimum level.
  • GnRH gonadotropin hormone releasing hormone
  • WO 00/73416 A method for regulating the fertility of a host, comprising contacting host ovarian cells with a safe and effective amount of a pharmaceutical composition comprising an antisense oligonucleotide that is complementary to the nucleotide sequence of the follicle stimulating hormone (FSH) receptor.
  • FSH follicle stimulating hormone
  • the benefits of the present invention may be realised without the co-administration of anti-progestogens, LHRH compositions, GnRH compositions and/or antisense oligonucleotides that are complementary to the nucleotide sequence of the follicle stimulating hormone (FSH) receptor as proposed in the aforementioned publications.
  • the present invention may suitably be applied in individuals who have not been oophorectomised, or in whom the risk of endometrial stimulation by estrogenic compositions is not minimised or absent, other than through the co-administration of a progestogen.
  • the present method does not require the use of a slow release formulation as is dictated by most of the aforementioned US-patents.
  • estetrol and estetrol-like substances have relatively low estrogenic potency, they may effectively be employed in HRT methods because their low potency is compensated for by a relatively high metabolic stability, as demonstrated by a long half-life.
  • An advantageous property of the present estrogenic substances resides in the fact that sex hormone-binding globulin (SHBG) hardly binds these estrogenic substances, meaning that, in contrast to most known estrogens, serum levels are representative for bio-activity and independent of SHBG levels.
  • SHBG sex hormone-binding globulin
  • estrogens Another important benefit of the present estrogenic substances is derived from their relative insensitivity to interactions with other drugs (drug-drug interactions). It is well known that certain drugs may decrease the effectiveness of estrogens, such as ethinyl estradiol, and other drugs may enhance their activity, resulting in possible increased side- effects. Similarly estrogens may interfere with the metabolism of other drugs. In general, the effect of other drugs on estrogens is due to interference with the absorption, metabolism or excretion of these estrogens, whereas the effect of estrogens on other drugs is due to competition for metabolic pathways.
  • estrogen-drug interactions occurs with drugs that may induce hepatic microsomal enzymes which may decrease estrogen plasma levels below therapeutic level (for example, anticonvulsant agents; phenytoin, primidone, barbiturates, carbamazepine, ethosuximide, and methosuximide; antituberculous drugs such as rifampin; antifungal drugs such as griseofulvin).
  • drugs that may induce hepatic microsomal enzymes which may decrease estrogen plasma levels below therapeutic level for example, anticonvulsant agents; phenytoin, primidone, barbiturates, carbamazepine, ethosuximide, and methosuximide; antituberculous drugs such as rifampin; antifungal drugs such as griseofulvin.
  • the present estrogenic substances are less dependent on up- and downregulation of microsomal liver enzymes (e.g. P450's) and also are less sensitive to competition with other P450 substrates. Similarly, they do not interfere significantly in
  • one aspect of the present invention relates to a method of hormone replacement in mammals, which method comprises the parenteral or rectal administration of an estrogenic component and a progestogenic component to a mammal in an amount effective to treat or prevent symptoms of hypoestrogemsm, wherein the estrogenic component is selected from the group consisting of: substances represented by the following formula
  • Ri , R 2 , R 3 , R 4 independently are a hydrogen atom, a hydroxyl group or an alkoxy group with 1-5 carbon atoms; each of R 5 , R ⁇ , R is a hydroxyl group; and no more than 3 of Ri, R , R 3 , R are hydrogen atoms; precursors capable of liberating a substance according to the aforementioned formula when used in the present method; and mixtures of one or more of the aforementioned substances and/or precursors.
  • parenteral administration as used in here encompasses transdermal, intranasal, intravaginal, pulmonary, buccal, subcutaneous, intramuscular and intra-uterine administration.
  • the HRT method according to the invention may advantageously be used to treat all known forms of hypoestrogemsm, e.g. hypoestrogemsm associated with (peri-)menopausal and post-menopausal women, hypoestrogemsm resulting from hypogonadism or castration, as well as hypoestrogemsm resulting from primary ovarian failure, treatment of e.g. breast cancer with aromatase inhibitor and gonadotropin-releasing hormone analogue treatment of e.g. benign gynaecological diseases.
  • hypoestrogemsm e.g. hypoestrogemsm associated with (peri-)menopausal and post-menopausal women, hypoestrogemsm resulting from hypogonadism or castration, as well as hypoestrogemsm resulting from primary ovarian failure
  • Examples of manifestations of hypoestrogemsm that can effectively be treated or prevented with the present method in both females and males include osteoporosis, arteriosclerosis, cognitive disturbances and Alzheimer's disease.
  • the method may also advantageously be used in the (prophylactic) treatment of climacteric symptoms such as hot flushes (flashes), sweats, urogenital atrophy, mood disturbances, insomnia and palpitations.
  • the present method is particularly suited for treating or preventing osteoporosis and climacteric symptoms.
  • estrogenic component encompasses substances that are capable of triggering an estrogenic response in vivo, as well as precursors that are capable of liberating such an estrogenic component in vivo when used in accordance with the present invention.
  • estrogenic components In order for estrogenic components to trigger such a response they normally have to bind to an estrogen receptor, which receptors are found in various tissues within the mammalian body.
  • progestogenic component is defined as a substance that is capable of triggering an progestogenic response in vivo or a precursor which is capable of liberating such a substance in vivo. Usually progestogenic components are capable of binding to a progestogen receptor.
  • estriol is a metabolite of 17beta-estradiol. Both these progestogens and estrogens have found application in contraceptive formulations and/or hormone replacement therapy.
  • estrogemc substances such as tritium labeled estetrol.
  • the present estrogenic substances are distinct from both the biogenic and synthetic estrogens that are commonly applied in pharmaceutical formulations in that they contain at least 4 hydroxyl groups.
  • the present substances are special in that the 5 membered ring in the steroid skeleton comprises 3 hydroxyl substituents rather than 0-2.
  • Known estrogens that contain at least 4-hydroxyl groups and derivatives thereof are: 1, 3, 5(10)-estratrien-2, 3, 15 ⁇ , 16 ⁇ , 17 ⁇ - pentol 2-methyl ether 1, 3, 5(10)-estratrien-2, 3, 15 ⁇ , 16 ⁇ , 17 ⁇ - pentol 2-methyl ether 1, 3, 5(10)-estratrien-2, 3, 16 ⁇ , 17 ⁇ - tetrol 1, 3, 5(10)-estratrien-3, 4, 16 ⁇ , 17 ⁇ - tetrol 4-methyl ether 1, 3, 5(10)-estratrien-3, 15 ⁇ , 16 ⁇ , 17 ⁇ - tetrol 1, 3, 5(10)-estratrien-3, 15 ⁇ , 16 ⁇ , 17 ⁇ - tetrol tetra acetate 1, 3, 5(10)-estratrien-3, 15 ⁇ , 16 ⁇ , 17 ⁇ - tetrol tetra acetate
  • the estrogenic substance applied as the active component in the present composition is a natural estrogen, i.e. an estrogen that is found in nature and especially in mammals. Even more preferably, the estrogenic substance is a so called biogenic estrogen, i.e. an estrogen that occurs naturally in the human body, a precursor of a biogenic estrogen or mixtures thereof. Because biogenic estrogens are naturally present in the fetal and female body, side-effects are not expected to occur, particularly not if the serum levels resulting from the exogenous administration of such estrogens do not substantially exceed naturally occurring concentrations.
  • estetrol serum levels in the fetus are several times higher than those found in pregnant females and knowing that the fetus is particularly vulnerable, estetrol is deemed to be a particularly safe biogenic estrogen.
  • Side-effects are not expected to occur, particularly not if the serum levels resulting from the exogenous administration of such estrogens do not substantially exceed naturally occurring (fetal) concentrations.
  • synthetic estrogens such as ethinyl estradiol there is a (dose dependent) risk of undesirable side-effects, such as thromboembolism, fluid retention, nausea, bloating, cholelithiasis, headache and breast pain.
  • the estrogenic substance contains 4 hydroxyl groups.
  • Ri preferably represents a hydrogen atom.
  • at least 2 more preferably at least 3 of the groups Ri, R 2 , R 3 and represent a hydrogen atom.
  • the estrogenic substances according to the formula encompass various enantiomers since the carbon atoms that carry hydroxyl-substituents R 5 , R 6 and R are chirally active.
  • the present estrogenic substance is 15 ⁇ -hydroxy substituted.
  • the substance is 16 ⁇ -hydroxy substituted.
  • the substances is 17 ⁇ -hydroxy substituted.
  • the estrogenic substances are 15 ⁇ ,16 ⁇ ,17 ⁇ -trihydroxy substituted.
  • R 3 represents a hydroxyl group or an alkoxy group.
  • the groups Ri , R 2 and 1 ⁇ represent hydrogen atoms, in which case, if R 3 , R 5 , R 6 and R are hydroxyl groups, the substance is 1,3,5 (10)-estratrien-3, 15,16,17-tetrol.
  • a preferred isomer of the latter substance is 1,3,5 (10)-estratrien-3, 15 ,16 ,17 ⁇ -tetrol (estetrol).
  • the invention also encompasses the use of precursors of the estrogenic substances that constitute the active component in the present method.
  • These precursors are capable of liberating the aforementioned estrogenic substances when used in the present method, e.g. as a result of metabolic conversion.
  • These precursors are preferably selected from the group of androgenic precursors as well as derivatives of the present estrogenic substances.
  • Suitable examples of androgenic precursors include androgens that can be converted into the present estrogenic substances through in vivo aromatisation.
  • derivatives of the present estrogenic substances that can suitably be used as precursors include such substances wherein the hydrogen atom of at least one of the hydroxyl groups has been substituted by an acyl radical of a hydrocarbon carboxylic, sulfonic acid or sulfamic acid of 1-25 carbon atoms; tetrahydrofuranyl; tetrahydropyranal; or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue.
  • Typical examples of precursors which can suitably be used in accordance with the invention are esters that can be obtained by reacting the hydroxyl groups of the estrogenic substances with substances that contain one or more carboxy (M + OOC-) groups, wherein M " represents a hydrogen or (akali)metal cation.
  • the precursors are derivatives of the estrogenic substances, wherein the hydrogen atom of at least one of the hydroxyl groups in said formula has been substituted by -CO-R, wherein R is a hydrocarbon radical comprising from 1-25 carbon atoms.
  • R is hydrogen, or an alkyl, alkenyl or aryl radical comprising from 1-20 carbon atoms.
  • the present method usually employs uninterrupted parenteral or rectal administration of the estrogenic component during a period of at least 10 days, preferably of at least 20 days.
  • the term "uninterrupted" as used in here means that the estrogenic component is administered at relatively regular intervals, with no (therapeutically) significant interruptions. Naturally, minor interruptions may occur that do not affect the overall effectiveness of the present method, and indeed such aberrations are encompassed by the present invention.
  • the administration regimen is deemed to be continuous if the longest interval between 2 subsequent administrations is not more than 3.5 times as long as the average interval. Even more preferably said longest interval is not more than 2.5 times, most preferably not more than 1.5 times as long as the average interval.
  • the method of hormone replacement therapy preferably, comprises administering the estrogemc component for a period of at least 1 month, more preferably of at least 3 months.
  • the estrogenic and progestogenic component may be administered in separate dosage units. However, it is also possible and indeed very convenient to combine these two components into a single dosage unit.
  • the invention may suitably be reduced to practice in the form of a variety of HRT methods that are known to the person skilled in the art.
  • these methods are the so called “combined” methods.
  • the combined methods make use of preparations that contain a combination of an estrogen and a progestogen.
  • the combined methods have in common that they are based on a regimen which involves administration of the aforementioned combined preparation, followed by an administration-free interval of about 7 days whereby withdrawal bleeding, simulating the natural menses, occurs. Thus 21 day intervals of hormone administration alternate with 7 days during which no hormones are administered.
  • the so called “sequential" method has been proposed. Typical of the sequential method is that it comprises two consecutive phases, i.e.
  • the first sequential methods like the aforementioned combined methods, made use of an administration free interval of about 7 days. More recently, sequential methods have been proposed which do not include an administration-free (or placebo) period, meaning that estrogen is administered throughout the full cycle and that progestogen is co-administered during only part of that cycle.
  • WO 95/17895 (Ehrlich et al.) describes such an uninterrupted sequential method.
  • HRT method which is encompassed by the present invention is the so called "continuous combined" method, which is a particular version of the combined method that uses uninterrupted combined administration of a progestogenic and an estrogenic component during a prolonged period of time, e.g. more than 50 days.
  • continuous combined a particular version of the combined method that uses uninterrupted combined administration of a progestogenic and an estrogenic component during a prolonged period of time, e.g. more than 50 days.
  • no regular menses occur in the continuous combined method as the continuous administration of progestogen in the indicated amounts induces amenorrhoea.
  • the present method comprises the uninterrupted parenteral or rectal administration of the combination of the estrogenic component and the progestogenic component during a period of at least 28, preferably at least 60 days.
  • the method of the invention comprises an interval of at least 2 days, preferably from 3-9 days, most preferably from 5-8 days, during which no progestogenic component and no estrogemc component is administered and wherein the resulting decrease in serum concentration of the progestogenic component and the estrogenic component induces menses.
  • Yet another embodiment of the invention which concerns a sequential method without a significant pause, is characterised in that it comprises the uninterrupted parenteral or rectal administration of the estrogenic component during a period of at least 28 days, preferably at least 60 days, and in that, following the combined administration of the estrogenic component and the progestogenic component, the estrogenic component and no progestogenic component are administered during 3-18 consecutive days, preferably during 5-16 consecutive days and the resulting decrease in serum concentration of the progestogenic component should normally be sufficient to induce menses.
  • the mode of administration employed in the present method is suitably selected from the group consisting of transdermal, intranasal, intravaginal, rectal, pulmonary, buccal, subcutaneous, intramuscular or intra-uterine administration.
  • the present method employs transdermal, intravaginal, intranasal or rectal administration.
  • the present method employs transdermal or intranasal administration.
  • the most preferred mode of administration is transdermal administration.
  • Rectal, intranasal, buccal and pulmonary administration are ideally suited for (at least) once daily administration.
  • Transdermal administration is advantageously applied at frequencies between once a day and once a month.
  • Intravaginal and intra-uterine administrations are advantageously operated at administration frequencies between once weekly and once monthly.
  • Subcutaneous and intramuscular administration are suitably done in the form of depot injections at intervals of 1 week to 6 months, preferably at intervals of 4 weeks to 3 months.
  • the present method preferably utilises administration intervals of 1 day, 1 week or 1 month.
  • Administration intervals of 1 day, 1 week or 1 month.
  • Regimens that employ once daily intranasal administration, once weekly transdermal administration or once monthly intravaginal or subcutaneous administration are particularly preferred.
  • the estrogenic component is preferably administered in an amount effective to achieve a blood serum concentration of at least 1 nanogram per litre, more preferably of at least 10 nanogram per litre, most preferably at least 100 nanogram per litre.
  • the resulting blood serum concentration of the estrogenic component will not exceed 100 ⁇ g per litre, preferably it will not exceed 50 ⁇ g per litre, more preferably it will not exceed 25 ⁇ g per litre.
  • the estrogenic component is usually administered in an amount of less than 1 mg per kg of bodyweight per day, preferably of less than 0.4 mg per kg of bodyweight per day, more preferably of less than 0.2 mg per kg of bodyweight per day.
  • it is advisable to administer in an amount of at least 1 ⁇ g per kg of bodyweight per day.
  • the administered amount is at least 2 ⁇ g per kg of bodyweight per day, more preferably at least 5 ⁇ g per kg of bodyweight per day.
  • the aforementioned dosages are to be construed as averaged daily dosages in case administration intervals of more than 1 day are used.
  • the estrogenic component is usually administered parenterally or rectally in an average dosage of at least 0.05 mg per day, preferably of at least 0.1 mg per day.
  • the average maximum parenteral or rectal dosage is normally kept below 40 mg per day, preferably below 20 mg per day.
  • the present method is executed in accordance with a sequential HRT method without pause.
  • the uninterrupted parenteral administration of the estrogenic component may usually occur at intervals of at least 12 hours, preferably of between 20 hours and 30 days.
  • the relatively high in vivo halflife of the present estrogenic components in comparison to most known estrogens makes it feasible to employ administration intervals that are significantly longer than 1 day. With a view to compliance, however, it is preferred to employ once daily, once weekly or once monthly administration intervals. Naturally the length of the administration interval is largely determined by the mode of parenteral or rectal administration that is employed.
  • the progestogenic component is advantageously administered in an amount which is effective to achieve a blood serum concentration which is equivalent to at least 5 pg/mL norethisterone, preferably to at least 10 pg/mL norethisterone.
  • blood serum concentrations of the progestogenic component will usually remain below the equivalent of 5,000 pg/mL norethisterone. Preferably these concentrations remain below the equivalent of 1,000 pg/mL.
  • the progestogenic component is usually administered in an amount of less than 1 mg per kg of bodyweight per day, preferably of less than 0.2 mg per kg of bodyweight per day. Furthermore, it is advisable to parenterally or rectally administer the progestogenic component in an amount of at least 0.1 ⁇ g per kg of bodyweight per day. Preferably, the parenterally or rectally administered amount is at least 0.3 ⁇ g per kg of bodyweight per day. In humans, the progestogenic component is usually parenterally or rectally administered in an average dosage of at least 5 ⁇ g per day, preferably of at least 15 ⁇ g per day. The maximum dosages normally remain below 50 mg, preferably below 10 mg per day.
  • the progestogen used in the present method is selected from the group consisting of progesterone, desogestrel, etonogestrel, gestodene, dienogest, levonorgestrel, norgestimate, norethisterone, drospirenone, trimegestone, dydrogesterone, precursors of these progestogens and mixtures thereof.
  • the present method also encompasses the co-administration of active principles in addition to the progestogenic and estrogenic component.
  • androgens may advantageously be co-administered in order to prevent symptoms of hypoandrogenicity.
  • a preferred embodiment of the invention comprises the co-administration of an androgenic component.
  • the androgenic component is suitably co-administered in an effective amount to suppress symptoms of hypoandrogenicity.
  • Hypoandrogenicity has been associated with mood disturbances, unfavourable changes in haemostatic parameters and lack of bone mass.
  • androgenic component is defined as a substance that is capable of triggering an androgenic response in vivo or a precursor which is capable of liberating such a substance in vivo. Usually androgenic components are capable of binding to an androgen receptor.
  • Androgenic components that may suitably be employed in the present method may be selected from the group consisting of testosterone esters such as testosterone undecanoate , testosterone propionate, testosterone phenylpropionate, testosterone isohexanoate, testosterone enantate, testosterone bucanate, testosterone decanoate, testosterone buciclate; testosterone; danazol; gestrinone; methyltestosterone; dehydroepiandrosterone (DHEA); DHEA-sulphate; mesterolon; stanozolol; androstenedione; dihydrotestosterone; androstanediol; metenolon; fluoxymesterone; oxymesterone; methandrostenolol; MENT; precursors capable of liberating these androgens when used in the present method and mixtures thereof.
  • testosterone esters such as testosterone undecanoate , testosterone propionate, testosterone phenylpropionate, testosterone isohexanoate, testosterone enantate, testosterone
  • the testosterone esters employed in the present method comprise an acyl group which comprises at least 6, more preferably from 8-20 and preferably 9-13 carbon atoms.
  • Androgens that can be used advantageously in the present method include testosterone esters, testosterone and MENT. Most preferably the employed androgen is testosterone undecanoate.
  • the method leads to an increase in blood serum androgen level of at least 0.1 nmole testosterone equivalent per litre, preferably of at least 0.3 nmole testosterone equivalent per litre.
  • the method leads to an increase in blood serum androgen level of no more than 5 nmole testosterone equivalent per litre, preferably of less than 3 nmole testosterone equivalent per litre and most preferably of less than 1.5 nmole testosterone equivalent per litre.
  • the present method preferably does not employ a gonadotropin hormone releasing hormone composition as described in the aforementioned patents US 5,211,952, US 5,340,584 and US 5,340,585. Similarly, the present method preferably does not employ a luteinizing hormone releasing hormone composition as described in US 4,762,717 and US 5,130,137. Furthermore, the present method preferably does not comprise the co- administration of an anti-progestogen as described in US 5,468,736. The method may also suitably be applied without the co-administration of an antisense oligonucleotide that is complementary to the nucleotide sequence of the follicle stimulating hormone (FSH) receptor (WO 00/73416).
  • FSH follicle stimulating hormone
  • the present method is not suitable for oophorectomised females or for females in whom endometrial stimulation by estrogenic compositions is minimised or absent, e.g. as a result of hysterectomy.
  • Another aspect of the invention relates to a drug delivery system for parenteral or rectal administration that contains the estrogenic component as defined herein before and optionally the progestogenic component as described herein before, which drug delivery system is selected from the group consisting of suppositories, systems for intravaginal delivery, injectable or implantable depot preparations, inhalers, nasal sprays and transdermal delivery systems, wherein the system contains at least 0.01 mg, preferably at least 0.05 mg of the estrogenic component, and an androgenic component in an of at least 25 ⁇ g, preferably of at least 100 ⁇ g.
  • the drug delivery system containing the estrogenic component and the androgenic component may be administered separately from the progestogenic component, in particular if said progestogenic component is adminstered orally.
  • the system additionally contains a progestogenic component in an amount of at least 10 ⁇ g, more preferably of at least 30 ⁇ g of a progestogenic component.
  • the progestogenic component may conveniently be combined with the estrogenic component in a single parenteral or rectal dosage unit, e.g. a single transdermal patch, intravaginal ring, suppository or injection unit.
  • Transdermal delivery systems include patches, gels, tapes and creams, and can contain excipients such as solubilisers, permeation enhancers (e.g. fatty acids, fatty acid esters, fatty alcohols and amino acids), hydrophilic polymers (e.g. polycarbophil and polyvinyl pyrrolidine) and adhesives and tackifiers (e.g. polyisobutylenes, silicone-based adhesives, acrylates and polybutene).
  • solubilisers e.g. fatty acids, fatty acid esters, fatty alcohols and amino acids
  • hydrophilic polymers e.g. polycarbophil and polyvinyl pyrrolidine
  • adhesives and tackifiers e.g. polyisobutylenes, silicone-based adhesives, acrylates and polybutene.
  • Transmucosal delivery systems include patches, suppositories, pessaries, gels, and creams, and can contain excipients such as solubilizers and enhancers (e.g. propylene glycol, bile salts and amino acids), and other vehicles (e.g. polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethyl cellulose and hyaluronic acid).
  • solubilizers and enhancers e.g. propylene glycol, bile salts and amino acids
  • other vehicles e.g. polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethyl cellulose and hyaluronic acid.
  • Injectable depot systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can comprise excipients such as solubility-altering agents (e.g. ethanol, propylene glycol and sucrose) and polymers (e.g. polycaprylactones, and PLGA's).
  • Implantable depot systems include rods and discs, and can contain excipients such as PLGA and polycapryl lactone.
  • Suitable fluid carrier components are physiologically compatible diluents wherein the active agents can be dissolved, suspended.
  • An example of a diluent is water, with or without addition of electrolyte salts or thickeners.
  • the depot formulation can be, for example, an aqueous microcrystalline suspension.
  • Oils are particularly suitable as diluents, with or without the addition of a solubiliser, of a surfactant, or of a suspension or emulsifying agent.
  • suitable oils include arachidis oil, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil.
  • solubilisers include benzyl alcohol and benzyl benzoate. Depot preparations offer the advantage that a single injection or implantation suffices for one or several months. Duration of the depot effect depends the nature of the estrogenic component (the ester precursors being preferred as they display a slower release), the amount of the estrogenic component as well as on the type of carrier substance that releases the active agent. Generally, the duration will be in the range of 10-30 days, but longer or shorter times can also be achieved.
  • Vaginal cornification was chosen as a tissue-specific and estrogen-sensitive endpoint to determine the estrogenicity of estetrol (E4), after subcutaneous administration, in hypoestrogenic rats. 17 ⁇ -estradiol (E2) and vehicle (10% ethanol/sesame oil) served as controls in the bioassay.
  • Uterine weight increase in the rat is more commonly used as a measure of estrogenicity.
  • uterine weight also responds to progesterone, testosterone, and other agents not characteristically regarded as estrogens.
  • follicular fluid from the pig ovary contained a factor(s) that caused cornification/keratinization of the vaginal epithelium in the rat (Allen and Doisy, 1923, JAMA, 81, 819-821; Allen and Doisy, 1924, Am. J. Physiol., 69, 577-588).
  • the so-called vaginal cornification response in rats subsequently provided a bioassay for testing estrogenicity.
  • Vaginal epithelial cornification/keratinization in ovariectomized rats can be produced only by compounds considered to be true estrogens (Jones et al, 1973, Fert. Steril. 24, 284-291). Vaginal epithelial cornification/keratinization represents, therefore, a highly selective endpoint to determine the potency of estrogens (Reel et al, 1996, Fund. Appli. Toxicol. 34, 288-305).
  • vaginal washings were placed on a glass slide and examined by light microscopy to detect the presence or absence of cornified epithelial cells. Vaginal lavages were obtained prior to dosing on days 0-6 and prior to necropsy on day 7.
  • vaginal cornification bioassay was performed in order to determine the estrogenic profile of E4 when given subcutaneously (sc) to ovariectomized adult rats.
  • E2 was used as a positive control.
  • the vehicle (10% ethanol/sesame oil) served as the negative control.
  • Steroids were dissolved in absolute ethanol and then brought to the final concentration with sesame oil (10%) ethanol in sesame oil).
  • the occurrence of vaginal cornification, indicative of an estrogenic response is an "all or none" response. Data are, therefore, expressed as the number of rats showing a vaginal estrogenic response over the number of rats (ratio) treated.
  • vaginal estrogenic response occurred in 8/8 rats by day 2 and persisted through day 7 in rats injected sc with 50 ⁇ g/kg/day E2 for 7 days (Table 1). Animals treated with the vehicle did not exhibit vaginal epithelial cornification (Table 1). The onset of vaginal epithelial cornification was dose-dependent in rats injected sc with 0.1, 0.3, 1.0, and 3.0 mg/kg/day E4 and started at the same day of treatment (Day 2) as observed for E2 (Table 1). At 0.1 mg/kg/day E4 already 4/8 rats and at 0.3 mg/kg/day E4 even 7/8 rats exhibited a vaginal estrogenic response by day 7.
  • Table 1 Vaginal estrogenic response in ovariectomized rats treated subcutaneously (sc) with 17 ⁇ -estradiol (E2) or estetrol (E4). Data are expressed as the number of rats showing vaginal cornification over the number of rats (ratio) treated.
  • estetrol E4 after subcutaneous administration (sc)
  • single dose studies were performed in female Sprague Dawley rats followed by frequent blood sampling over a 24 hours interval.
  • Plasma E4 concentration data were analysed with "WinNonLin, edition 3.1" and involved pharmacokinetic parameters for C m a x , AUCo-24 and half-life. Interestingly, E4 demonstrated a relatively long half-life of 2-3 hours, enabling the detection of bioactive levels of unconjugated E4 at all time points over a 24 hour interval.
  • Human SHBG was purified from transgenic mouse serum, as described previously (Awakumov GV et al, 2000. J Biol Chem 275: 25920-25925).
  • the human SHBG prepared in this way was assessed to be >99% pure by polyacrylamide gel electrophoresis under denaturing conditions. Its steroid-binding characteristics are indistinguishable from SHBG in human serum (Awakumov GV et al., 2000. J Biol Chem 275: 25920-25925).
  • the in vitro assay involved the use of the purified human SHBG and [ 3 H]DHT or [ 3 H]estradiol as labeled ligands.
  • Human SHBG was treated for 30 min at room temperature with a dextran-coated charcoal (DCC) suspension in phosphate buffered saline (PBS) to remove any steroid ligand. After centrifugation (2,000 x g for 10 min) to sediment the DCC, the supernatant containing the human SHBG was diluted in PBS to a concentration of 1 nM based on its steroid binding capacity.
  • DCC dextran-coated charcoal
  • PBS phosphate buffered saline
  • Figure 1 Competitive displacement of [ 3 H]DHT (panel A) and [ 3 H]estradiol (panel B) from the human sex hormone-binding globulin steroid binding site.
  • the unlabeled steroid ligands used as competitors were as follows: estetrol (E4), 17 ⁇ -ethinylestradiol (EE2), 17 ⁇ -estradiol (E2), testosterone (T) and 5 ⁇ - dihydrotestosterone (DHT)
  • estetrol does not bind at all to human SHBG when tested with either [ 3 H]DHT or [ 3 H]estradiol as labeled ligands. This is in marked contrast with reference steroids ethinylestradiol, 17 ⁇ -estradiol, testosterone and 5 ⁇ -dihydrotestosterone, which, in this order, show an increased relative binding affinity for human SHBG. Importantly, estetrol binding to SHBG was negligible when compared with the other estrogens tested, ethinylestradiol and 17 ⁇ -estradiol.
  • the ovariectomized aged rat is used as a model for the human disease osteoporosis. This is an established animal model, recommended by the United States Food and Drug Administration (FDA), to evaluate and assess potential agents for osteoporosis prevention and therapy.
  • FDA United States Food and Drug Administration
  • the anti-resorptive efficacy of estetrol (E4) after subcutaneous administration (sc) is tested by ex vivo measuring total and trabecular bone mineral density and bone strength after 4 weeks of treatment at necropsy. 17 ⁇ -ethinyl-estradiol (EE), 17 ⁇ -estradiol (E2) and vehicle (1 % ethanol/arachidis oil) serve as controls in this bioassay.
  • sc test compound dosing with vehicle, EE (0.3, 1.0, 3.0, 30, or 100 ⁇ g/kg/day), E2 (0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg/day) or E4 (0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg/day).
  • tibiae and femura are removed, cleaned of soft-tissue and fixed and stored in 70% ethanol/saline at 4 °C (tibia) or saline at 4 °C (femura) until further analysis.
  • ex vivo peripheral Quantitative Computed Tomography pQCT is performed on the excised tibiae using a Stratec XCT-RM and associated software (Stratectechnik GmbH, Pforzheim, Germany, software version 5.40). The scans are performed at 12 % of the total length from the proximal end of the tibiae and the mineral content, area and density for total and trabecular bone are determined.
  • ex vivo evaluation of bone biomechanical strength is performed with an indentation test at the distal femura.
  • Prior to mechanical testing femura are rinsed in cold saline and are carefully cleaned of any remaimng adherent soft tissue.
  • a 3 -mm segment of the distal femoral metaphysis is cut directly proximal to the femoral condyle with a low-speed diamond saw under constant saline irrigation.
  • the load is applied with a cylindrical indenter (with a flat testing face of 1.6 mm diameter) to the center of the marrow cavity on the distal face of the segment.
  • the indenter is allowed to penetrate the cavity at a constant displacement of 6 mm/min to a depth of 2 mm before load reversal.
  • the maximum load, stiffness and energy absorbed are determined from load displacement curves. Ultimate strength is calculated by dividing the maximum load by the indenter area.
  • the mo hine-dependent ovariectomized (OVX) rat is used as a model for postmenopausal hot flush.
  • 17 ⁇ -ethinyl-estradiol (EE) and vehicle (hydroxy propyl-beta-cyclodextrin 20% wt/vol) serve as controls in this bioassay.
  • the most common and characteristic symptom of human menopause is the hot flush, which is experienced by over 70% of menopausal females. While the exact mechanism underlying this vasomotor instability is unknown, the characteristic features of the hot flush appear to reflect a centrally mediated adaptation to a progressive decline in the levels of estrogens. In women experiencing the hot flush the symptoms are manifested by 1) rapid, regional elevations in skin temperature; 2) a decrease in core body temperature; 3) an increased heart rate with no change in blood pressure; and 4) closely timed surges in release of luteinizing hormone (LH) and ⁇ -endorphin.
  • LH luteinizing hormone
  • OVX ovariectomized
  • 8-week-old OVX rats (6 animals per group) are sc treated with vehicle, EE (0.3 mg/kg/day) or E4 (0.1, 0.3, 1.0, or 3.0 mg/kg/day) for seven consecutive days prior to, and on the morning of naloxone-induced opiate withdrawal in morphine-dependent animals.
  • vehicle EE (0.3 mg/kg/day) or E4 (0.1, 0.3, 1.0, or 3.0 mg/kg/day)
  • animals Three days prior to the commencement of dosing, animals are anesthetized using a ketamine/xylazine anesthetic mixture and undergo a bilateral ovariectomy.
  • Morphine dependency is induced by implantation of subcutaneous pellets containing 75-mg morphine. The first pellet is implanted five days before the hot flush session under a light inhalation anesthesia.
  • two additional morphine pellets are implanted under the same conditions.
  • the animals are placed in a test cage. Following a 5 - 10 minute adaptation period, the rats are anesthetized with ketamine HC1 10 minutes prior to the hot flush session.
  • a temperature sensitive electrode is fixed to the ventral surface of the tail with tape and the electrode is connected to a multichannel temperature recorder. The tail-skin temperature is recorded until it is stable and the animals are then injected with naloxone HC1 (1 mg/kg). The temperature recordings are continued for a period of 60 minutes and the temperature.
  • all animals are killed by CO 2 asphyxiation followed by cervical dislocation.
  • Treatment with vehicle is not effective in preventing the naloxone-induced TST increases in the morphine addicted OVX rats.
  • EE at the single dose tested of 0.3 mg/kg/day, prevents the naloxone-induced TST increase in the morphine addicted OVX rats.
  • Subcutaneous treatment with E4 shows a clear dose-dependent effect in preventing the naloxone-induced TST increase in the morphine addicted OVX rats to a similar degree as the potent estrogen (EE).
  • Suitable formulations for the transdermal administration of estrogens are known in the art, and may be employed in the methods of the present invention.
  • suitable transdermal patch formulations for the administration of exogenous estrogen are described in US 4,460,372 (Campbell et al.), US 4,573,996 (Kwiatek et al.), US 4,624,665 (Nuwayser), US 4,722,941 (Eckert et al.), US 5,223,261 (Nelson et al.), the disclosures of which are hereby incorporated by reference.
  • the reservoir contains the estrogenic component and is in fluid contact with the permeable surface layer.
  • the transdermal patch is adhered to the skin by the adhesive layer on the permeable surface layer, such that the permeable surface layer is in substantially continuous contact with the skin when the transdermal patch is adhered to the skin.
  • the estrogenic component contained in the reservoir of the transdermal patch is transferred via the permeable surface layer, through the adhesive layer, and to and through the skin of the subject.
  • the transdermal patch may suitably include one or more penetration-enhancing agents in the reservoir that enhance the penetration of the estrogenic component through the skin.
  • suitable materials which may comprise the backing layer are well known in the art of transdermal patch delivery, and any conventional backing layer material may be employed in the transdermal patch of the instant invention.
  • suitable backing layer materials include but are not limited to polyester film, such as high density polyethylene, low density polyethylene or composites of polyethylene; polypropylene; polyvinyl chloride, polyvinylidene chloride; ethylene-vinyl acetate copolymers; and the like.
  • suitable permeable surface layer materials are also well known in the art of transdermal patch delivery, and any conventional material which is permeable to the estrogenic component, may be employed in the transdermal patch of the instant invention.
  • suitable materials for the permeable surface layer include but are not limited to dense or microporous polymer films such as those comprised of polycarbonates, polyvinyl chlorides, polyamides, modacrylic copolymers, polysulfones, halogenated polymers, polychloroethers, acetal polymers, acrylic resins, and the like.
  • dense or microporous polymer films such as those comprised of polycarbonates, polyvinyl chlorides, polyamides, modacrylic copolymers, polysulfones, halogenated polymers, polychloroethers, acetal polymers, acrylic resins, and the like.
  • Specific examples of these types of conventional permeable membrane materials are described in U.S. Pat. No. 3,797,494 to Zaffaroni.
  • suitable adhesives which may be coated on the backing layer to provide the adhesive layer are also well known in the art and include, for example pressure sensitive adhesives such as those comprising acrylic and/or methacrylic polymers.
  • suitable adhesives include polymers of esters of acrylic or methacrylic acid (e.g., n-butanol, n- pentanol, isopentanol, 2-methyl butanol, 1-methyl butanol, 1-methyl pentanol, 3-methyl pentanol, 3-methyl pentanol, 3 -ethyl butanol, isooctanol, n-decanol, or n-dodecanol esters thereof) alone or copolymerized with ethylenically unsaturated monomers such as acrylic acid, methacrylic acid, acrylamide, methacrylamide, N-alkoxymethyl acrylamides, N- alkoxymethyl methacrylamides, N-t-butylacrylamide, it
  • the adhesive layer should be inert to the estrogenic component, and should not interfere with the transdermal delivery of the estrogenic component through the permeable surface layer.
  • Pressure sensitive adhesives are preferred for the adhesive layer of the transdermal patch to facilitate the application of the patch to the skin of the subject.
  • Suitable penetration-enhancing agents are well known in the art as well.
  • conventional penetration-enhancing agents include alkanols such as ethanol, hexanol, cyclohexanol, and the like; hydrocarbons such as hexane, cyclohexane, isopropylbenzene; aldehydes and ketones such as cyclohexanone, acetamide; N,N-di(lower alkyl)acetamides such as N,N-diethylacetamide, N,N-dimethyl acetamide,; N-(2-hydroxyethyl)acetamide; esters such as N,N-di-lower alkyl sulfoxides; essential oils such as propylene glycol, glycerine, glycerol monolaurate, isopropyl myristate, and ethyl oleate; salicylates; and mixtures of any of the above.
  • transdermal patch which is suitable for the transdermal delivery of the estrogenic component according to the present invention
  • said estrogenic component is incorporated into the adhesive layer rather than being contained in a reservoir.
  • patches are conventionally known and include, for example, the CL ⁇ MERA.®. patch available from Berlex.
  • This type of transdermal patch comprises a backing layer and an adhesive/drug layer.
  • the adhesive/drug layer has the combined function of adhering the patch to the skin of the subject and containing the estrogenic component, which is to be administered.
  • the active ingredient is leached from the adhesive/drug layer to and through the skin of the subject when the patch is adhered to the skin.
  • the adhesive/drug layer comprises a relatively homogeneous mixture of the selected adhesive and the active ingredient.
  • the adhesive/drug layer comprises a coating substantially covering one surface of the backing layer.
  • the adhesive/drug layer may also include a penetration enhancing agent such as those described above by incorporating the penetration enhancing agent into the substantially homogeneous mixture of the adhesive and the active ingredient.
  • the transdermal patches according to the present invention may include a variety of additional excipients which are conventionally employed to facilitate the transdermal administration of the estrogenic component.
  • excipients include but are not limited to carriers, gelling agents, suspending agents, dispersing agents, preservatives, stabilisers, wetting agents, emulsifying agents, and the like. Specific examples of each of these types of excipients are well known in the art and any conventional excipients may be employed in the transdermal patches of the instant invention.
  • the amount of estrogenic component contained in the transdermal patch formulations will depend upon the precise form of estrogenic component to be administered, but should be sufficient to deliver at least 20 ⁇ g per day.
  • the amount of progestogenic component to be administered is typically equivalent to an amount of at least 100 ⁇ g norethisterone acetate per day.
  • the transdermal patches are designed to be worn for several days before replacement is required. Thus the amount of estrogenic component in the patch must be sufficient to permit the administration of at least 20 ⁇ g per day for a period of several days.
  • a transdermal patch according to the present invention which is designed to administer around 400 ⁇ g of estetrol and 250 ⁇ g norethisterone acetate per day for seven (7) days would contain approximately 40 mg of the estrogen and approximately 25 mg of the progestogen. Based upon this information, one skilled in the art would be able to establish the necessary amount of estrogenic component to be included in a given transdermal patch to achieve the delivery of the correct daily dose of estrogenic component.
  • Suitable nontoxic pharmaceutically acceptable carriers for use in a drug delivery system for intranasal administration of the present estogenic component will be apparent to those skilled in the art of nasal pharmaceutical formulations. For those not skilled in the art, reference is made to "Remington's Pharmaceutical Sciences", 4th edition, 1970. Obviously, the choice of suitable carriers will depend on the exact nature of the particular nasal dosage form desired, e.g. whether the estrogenic component is to be formulated into a nasal solution (for use as drops or as a spray), nasal microspheres, a nasal suspension, a nasal ointment or a nasal gel, as well as on the identity of the estrogenic component.
  • estetrol and 15 mg of progesterone are combined with 10 mg of Tween 80. That mixture is then combined with a quantity of isotonic saline sufficient to bring the total volume to 50 ml.
  • the solution is sterilised by being passed through a 0.2 micron Millipore filter.
  • the intravaginal drug delivery vehicle may suitably take the form of a vaginal ring.
  • Vaginal rings are torous shaped devices designed to deliver a relatively constant dose of drug to the vagina usually over a period of weeks to months. Typically, they are made of a poly EVA elastomer and the estrogenic component is released by diffusion though the elastomer.
  • the vaginal ring is designed to regulate the release rate of the estrogenic component so as to provide the user with the appropriate daily dose.
  • the solubility of the estrogemc component in the ring elastomer the surface area of the drug reservoir, the distance the drug must diffuse through the ring body to reach its surface and the molecular weight of the drug.
  • 58 mm core rings are prepared as follows. Fifty grams of Silastic 382 ® are mixed with 0.3 g of stannous octoate, transferred to a 50 cc plastic syringe and injected into four brass ring moulds. After 45 minutes, the moulds are opened, the rings removed, the flash is trimmed and the rings are cut open at a 45° angle. A mixture of 84.4 g Silastic 382®, 24.4 g of micronised estetrol and 12.2 g micronised levonorgestrel are mixed in a Teflon bowl. The mixture is transferred to a Lucite coating cup with a bottom opening of 8.7 mm. The open rings are heated at 110°C for 30 minutes, cooled and weighed.
  • the open rings weigh approximately 9.8 g.
  • the open rings are pulled through the coating cup and dipped in a solution of 0.67% stannous octoate in toluene (w/v).
  • the open ring is again heated at 110°C for 30 minutes and reweighed.
  • the weight of the coated open ring is approximately 10.3 g and the weight of the coating on the open rings is therefore approximately 0.5 g.
  • a 16.5 cm long piece of silicone rubber tubing having 6.3 mm diameter and 0.3 mm wall thickness is swollen in hexane and the open ring coated with the medicated layer is placed inside the silicone rubber tubing.
  • the hexane is evaporated at room temperature and the tubing contracted to the size of the open ring forming an outer layer having a thickness of 0.2 mm.
  • estetrol containing depot formulation can suitably be prepared as set forth below.
  • estetrol ester e.g. estetrol valerate esters
  • a significantly lower release rate can be obtained.
  • Such low release rates are particularly advantage if the depot injections are to be administered at relatively long time intervals, e.g. intervals of more than 1 week.

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Abstract

La présente invention concerne une méthode de substitution hormonale destinée aux mammifères, consistant à administrer un composé oestrogénique et un composé progestogénique par voie parentérale ou rectale à un mammifère, en quantité suffisante pour traiter des symptômes de l'hypo-oestrogénie ou prévenir l'apparition de symptômes de l'hypo-oestrogénie. Le composé oestrogénique est sélectionné dans le groupe comprenant : des substances représentées par la formule générale (I) dans laquelle R1, R2, R3, R4 désignent indépendamment un atome d'hydrogène, un groupe hydroxy ou un groupe alcoxy comprenant 1 à 5 atomes de carbone, chacun des R5, R6, R7 désigne un groupe hydroxy, et trois des R1, R2, R3, R4, au plus, désignent des atomes d'hydrogène ; des précurseurs capables de libérer une substance correspondant à ladite formule générale (I) lorsqu'ils sont utilisés dans la présente méthode ; et des mélanges d'un ou de plusieurs desdits précurseurs et/ou substances. La présente invention concerne également un système d'administration conçu pour être utilisé par voie parentérale ou rectale, renfermant ledit composé oestrogénique et un composé androgénique. Ce système d'administration est sélectionné dans le groupe comprenant des suppositoires, des systèmes d'administration intra-vaginale, des inhalateurs, des systèmes pour pulvérisation nasale et des systèmes d'administration transdermique.
PCT/NL2002/000333 2001-08-31 2002-05-23 Utilisation de composes oestrogeniques combines avec des composes progestogeniques dans une hormonotherapie substitutive WO2003018026A1 (fr)

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WO2006084083A2 (fr) * 2005-02-03 2006-08-10 Duramed Pharmaceuticals, Inc. Dispositifs de distribution d'agents dans le tractus vaginal
EP1511496B1 (fr) * 2002-06-11 2006-09-27 Pantarhei Bioscience B.V. Methode permettant de traiter ou de prevenir des troubles a mediation immune et formulation pharmaceutique utilisee dans ladite methode
EP2383279A1 (fr) 2011-07-19 2011-11-02 Pantarhei Bioscience B.V. Procédé de préparation d'estetrol
EP3106148A1 (fr) 2015-06-18 2016-12-21 Mithra Pharmaceuticals S.A. Unité posologique orodispersible contenant un composant d'estétrol
WO2016203006A1 (fr) 2015-06-18 2016-12-22 Mithra Pharmaceuticals S.A. Unité galénique orodispersible contenant un composant estetrol
WO2016203044A1 (fr) 2015-06-18 2016-12-22 Mithra Pharmaceuticals S.A. Comprimé orodispersible contenant de l'estétrol
WO2016203009A1 (fr) 2015-06-18 2016-12-22 Mithra Pharmaceuticals S.A. Comprimé orodispersible contenant de l'estétrol
US9884064B2 (en) 2013-12-12 2018-02-06 Donesta Bioscience B.V. Orally disintegrating solid dosage unit containing an estetrol component
US10000524B2 (en) 2002-11-08 2018-06-19 Donesta Bioscience B.V. Synthesis of estetrol via estrone derived steroids
WO2019202141A1 (fr) * 2018-04-19 2019-10-24 Estetra Sprl Composés et leurs utilisations pour soulager des symptômes associés à la ménopause
WO2019202142A1 (fr) * 2018-04-19 2019-10-24 Estetra Sprl Composés et leurs utilisations pour soulager des symptômes associés à la ménopause
US11053273B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US11053274B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US11896602B2 (en) 2016-08-05 2024-02-13 Estetra Srl Method for preventing pregnancy
WO2024074700A1 (fr) * 2022-10-07 2024-04-11 Neuralis Sa Compositions topiques comprenant un composant d'estétrol et utilisation desdites compositions pour la cicatrisation de plaies

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