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WO2004041288A1 - Therapie de remplacement d'hormone a l'aide de drospirenone - Google Patents

Therapie de remplacement d'hormone a l'aide de drospirenone Download PDF

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Publication number
WO2004041288A1
WO2004041288A1 PCT/IB2002/004628 IB0204628W WO2004041288A1 WO 2004041288 A1 WO2004041288 A1 WO 2004041288A1 IB 0204628 W IB0204628 W IB 0204628W WO 2004041288 A1 WO2004041288 A1 WO 2004041288A1
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Prior art keywords
woman
aldosterone
progestational
diseases
use according
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PCT/IB2002/004628
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English (en)
Inventor
Siegfried Meyerhofer
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Bayer Pharma AG
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Schering AG
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Priority to PCT/IB2002/004628 priority Critical patent/WO2004041288A1/fr
Priority to AU2002368326A priority patent/AU2002368326A1/en
Priority to JP2004549480A priority patent/JP2006508945A/ja
Priority to DK03769738.0T priority patent/DK1558265T3/da
Priority to PT03769738T priority patent/PT1558265E/pt
Priority to PCT/IB2003/004946 priority patent/WO2004041289A1/fr
Priority to ES03769738T priority patent/ES2338781T3/es
Priority to DE60330888T priority patent/DE60330888D1/de
Priority to AT03769738T priority patent/ATE454155T1/de
Priority to EP03769738A priority patent/EP1558265B1/fr
Priority to AU2003278434A priority patent/AU2003278434A1/en
Publication of WO2004041288A1 publication Critical patent/WO2004041288A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition comprising drospirenone as the sole therapeutically active agent and to methods of treating symptoms and diseases related to deficient levels of progesterone, in particularly to methods of simulataneous treating symptoms and diseases related to deficient levels of progesterone and aldosterone-mediated diseases such as cardiovascular diseases.
  • renin- angiotensin-aldosterone system renin- angiotensin-aldosterone system
  • Aldosterone has been known to exert its activities through activation of mineralocorticoid receptors present in the epithelia of the kidney, colon and sweat glands whereby aldosterone promote the retention of sodium and the excretion of potassium.
  • ACE inhibitors that act through inhibition of the angiotensin-converting enzyme.
  • aldosterone via its activation of the mineralocorticoid receptors in the hearth, blood vessels or brain is capable of mediating several pathophysiological actions like for example stroke, cardiac fibrosis, ventricular hypertrophy, myocardial necrosis, heart failure (congestive heart failure), sudden cardiac death and/or myocardial infarction.
  • pathophysiological actions like for example stroke, cardiac fibrosis, ventricular hypertrophy, myocardial necrosis, heart failure (congestive heart failure), sudden cardiac death and/or myocardial infarction.
  • peri-menopause The period immediately before and after the onset of menopause is termed peri-menopause, and averages about 4 years.
  • Peri-menopause is characterised by irregular and abnormal bleeding, which can be controlled by treatment with progesterone.
  • Eplerenone is an example of such a drug(Martin and Krum; Eplerenone. Current opinion in investigational drugs, 2001, 2(4), 521-525). Eplerenone has beneficial cardioprotection (Hamedii and Chadow: The promise of selective aldosterone receptor antagonist for the treatment of hypertension and congestive hearth failure. Curr Hypertens Rep, 2000, Aug 5 2(4), 378-383, Delayani et al: Eplerenone; a selective aldosterone receptor antagonist (SARA), cardiovascular Drug Rev 2001 FAII, 19(3) 185-200).
  • SARA selective aldosterone receptor antagonist
  • Drospirenone has unlike other drospirenone (DRSP), a 17 ⁇ -spirolactone and an analog to spirolactone. Drospirenone has unlike other drospirenone (DRSP), a 17 ⁇ -spirolactone and an analog to spirolactone. Drospirenone has unlike other drospirenone (DRSP), a 17 ⁇ -spirolactone and an analog to spirolactone. Drospirenone has unlike other
  • Drospirenone binds to the mineralocorticoid receptor in competition with aldosterone so as to provide a strong antimineralocorticoid activity. Drospirenone is about 8 times as potent as spironolactone (Polfow et al; dihydrospirorenone, a novel synthetic progestagen, characterisation of binding to different receptor proteins. Contraception, 1992, 46, 561-
  • Drospirenone is known from the patent DE 19633685 and the patent application WO 98067838 that both relates to a process for producing drospirenone, 6 ⁇ ,7 ⁇ ;15 ⁇ ;16 ⁇ - dimethylene-3-oxo-17 ⁇ -preg-4-ene-21,17-carbolactone.
  • Plasma aldosterone levels may be affected by administering drospirenone: In a study implying administration of drospirenone alone or drospirenone in combination with ethinylestradiol demonstrated that the plasma aldosterone levels increased in both groups of therapy. (Oelkers et al: Effect of an oral contraceptive containing drospirenone in the
  • Drospirenone is further known from its use in contraception (WO 01/15701.) and for HRT (WO/52857)
  • Spironolactone (17-hydroxy-7-alpha-mercapto-3-oxo-17-alpha-pregn-4-ene-21-carboxylic acid gamma-lactone acetate) is used as an hypertensive and diuretic drug and belongs to the group of spirolactones, wherein drospirenone also belongs. Spironolactone has been shown to decrease the morbidity and mortality among patients with severe heart failure who were already receiving ACE inhibitor therapy. Thus, an additive effect was observed (Pitt et al; the effect of spironolactone on morbidity and mortality in patients with severe heart failure. New Engl. J Med, vol 341, no 10, pp 709717, 1999). Spironolactone is an effective aldosterone antagonist, but is thought to have considerable side effects in recommended daily dosages, e.g. increasing the risk of cancer. Spironolactone may also give major disruptions in the balance of minerals within the body.
  • WO 01/95892 relates to the treatment of aldosterone mediated pathogenic effects such as cardiovascular diseases in a subject that has salt sensitivity or an elevated dietary sodium intake or both by administering one or more aldosterone antagonists such as spironolactone.
  • WO 02/09759 relates to the treatment of inflammation-related cardiovascular disorders such as aetherosclerosis in a subject by administering an aldosterone antagonist and a cyclooxygenase-2 inhibitor.
  • the aldosterone antagonist being a spirolactone-type compound (spironolactone) and an epoxy-steroidal aldosterone antagonist.
  • WO 01/34132 relates to the treatment, inhibiting or preventing pathogenic change resulting from vascular injury in a human subject by administering an aldosterone antagonist.
  • WO 95/15166 relates to the treatment of an aldosterone antagonist such as spironolactone and epoxymexrenone for inhibiting myocardial fibrosis in that the dosage used may not disrupt a patients normal electrolyte and water-retention balance.
  • drospirenone an agent with combined progestational and antimineralocorticoid activity antagonises the action of aldosterone mediated through mineralocorticoid receptors present in the hearth, blood vessels and brain. This observation has advantageous implications to the current hormone replacement therapy of peri-and post-menopause since the woman will benefit from the reduced risk of developing aldosterone-mediated disease, in particular cardiovascular diseases.
  • agents with combined actions on progestational and mineralocorticoid receptors in particular those agents having similar potency as drospirenone in the antagonism of aldosterone via the mineralocorticoid receptors and/or having similar potency as drospirenone in progestational actions, are anticipated by the present invention.
  • a first aspect of the invention relates to a composition for treating aldosterone-mediated diseases comprising as the sole therapeutically active agent drospirenone and/or pharmaceutically acceptable salts thereof.
  • Further aspects of the invention relate to the use of an agent exhibiting progestational and antimineralocorticoid activity for the preparation of a medicament for treating the conditions as mentioned below in items 1-3. Moreover, further aspects relates to a therapeutic method comprising administering an agent exhibiting progestational and antimineralocorticoid activity to a woman for treating the conditions as mentioned below in items 1-3.
  • an agent exhibiting progestational and antimineralocorticoid activity for treating aldosterone- mediated diseases in peri and post-menopausal women may also implicate the concurrent use of an estrogen. Therefore, still further aspects of the invention relate to uses for preparation of a medicament and to therapeutic methods comprising; 4) an estrogen and an agent exhibiting progestational and antimineralocorticoid activity for simultaneous treating and/or preventing diseases, disorders and symptoms associated with deficient endogenous levels of estrogen and aldosterone-mediated diseases in a woman; or
  • the beneficial effects on aldosterone-mediated diseases in a woman in peri-menopause and post-menopause may be achieved by the combination of one agent exhibiting antimineralocorticoid effect and substantially no or low progestational activity and a second agent exhibiting substantially no antimineralocorticoid effect, but progestational effect.
  • the agent exhibiting progestational and antimineralocorticoid activity is drospirenone.
  • an interesting aspect of the invention relates to uses for preparation of a medicament and to therapeutic methods comprising drospirenone in a daily deliverable dose of 0.1 to 5 mg for the preparation of a medicament for treating and/or preventing aldosterone-mediated diseases in a subject in need thereof.
  • an agent exhibiting progestational and antimineralocorticoid activity is intended to denote an agent that has a relative binding affinity to the antimineralocorticoid receptor and the progestational receptor in the order of drospirenone.
  • a compound is characterised as "an agent exhibiting progestational and antimineralocorticoid activity” when the relative binding affinity to the progestational receptor and the relative binding affinity to the mineralocorticoid receptor as determined in relation to the binding affinity of drospirenone with respect to these two receptors is in the range of 50% to 150%, preferably in the range of 75% to 125%, more preferably in the range of 85% to 115%.
  • progesterone is intended to mean that the plasma concentration of progesterone has, for at least one month as determined on a daily basis, been lower than the concentration range expected during luteal phase of the menstrual cycle.
  • the expected progesterone plasma concentration during luteal phase is in the range between 30 and 110 nmol/l.
  • deficient endogenous levels of progesterone is intended to mean progesterone plasma concentrations lower than 200 nmol to 300 nmol.
  • the plasma concentrations of progesterone in a pregnant woman rise steadily until they peak at the end of the third trimester in the range of 320-700 nmol/l.
  • menopause characterises the time in a woman's life when the ovaries stop producing estrogen. Menopause is usually recognised by the cessation of menstrual periods. Other symptoms of menopause include flashes, mood changes, difficulty sleeping, and vaginal dryness. In the present context, the term menopause is understood as the last natural (ovary -induced) menstruation. It is a single event and a result of an age- dependent dysfunction of the ovarian follicles. Menopause results from the ovaries decreasing their production of the sex hormones estrogen and progesterone. When the number of follicles falls below a certain threshold (a bleeding threshold), the ovaries can no longer produce mature follicles and sex hormones.
  • a certain threshold a bleeding threshold
  • the ability to reproduce capability ends with menopause. If a woman is not menstruating because she has had a hysterectomy or endometrial ablation, other symptoms of menopause often alert her that menopause is starting.
  • the average age of the onset of menopause is 51 years, and it most commonly occurs from age 47 to 53.
  • the term "peri-menopause” characterises the period immediately before and after the onset of menopause, and averages 4 years. Furthermore, the peri-menopause is characterised by abnormal and irregular bleeding.
  • the peri-menopausal phase begins with the onset of climacteric symptoms when the cycle becomes irregular and ends one year after menopause. The end of peri-menopausal phase can be identified after a protracted period of time without bleeding.
  • post-menopause is the phase that begins at menopause and continues until death.
  • the term "irregular bleeding” characterises any uterine bleeding, outside the regular monthly menstrual periods of non-pregnant women. Uterine bleeding are irregular if menstrual cycles or menstrual periods are too short, too long, too frequent, too infrequent, or occur at irregular intervals which falls outside the regular 26-30 days menstrual cycle. The menstrual period is classified as too long when being delayed with 15 to 50 days or more to the expected onset of said bleeding.
  • abnormal bleeding characterises heavy bleeding typically soaking through enough sanitary protection products to require changing more than every one or two hours, having a period that lasts over seven days.
  • Abnormal bleeding does not include bleeding in women who have already reached menopause, abnormal uterine bleeding due to side effects of hormone replacement therapy, abnormal bleeding as a symptom of uterine cancer , as a result of a consequence of abnormal blood clotting normally, an inherited bleeding disorder or because of a medical illness that affects levels of blood platelets.
  • the term "lack of ovulation” relates to the condition in a woman, where the woman has stopped ovulating.
  • the condition is characterised by a relative blood level of luteinizing hormone greater than 30 IU/L in a peri-menopausal /menopausal woman, in comparison with a menstruating woman with a level of 5-22 IU/L or 30-250 IU/L in respectively the follicular or luteal phase or midcycle phase.
  • a woman that is in need of progesterone replacement therapy qualifies a woman that is deficient in endogenous levels of progesterone, a woman that is pregnant and in risk of miscarriage, a woman that experience irregular bleeding, abnormal bleeding.
  • epoxy-steroidal aldosterone receptor antagonist is intended to denote one or more agents characterised by a steroid-type nucleolus and an epoxy moiety attached to the nucleolus and which agent or compound binds to the aldosterone receptor as a competitive inhibitor of the action of aldosterone itself at the receptor site, so as to modulate the receptor-mediated activity of aldosterone.
  • non-epoxy-steroidal aldosterone receptor antagonist is intended to denote one or more agents characterised by a steroid-type nucleolus and with no epoxy moiety attached to the nucleolus and which agent binds to the aldosterone receptor as a competitive inhibitor of the action of aldosterone itself at the receptor site, so as to modulate the receptor- mediated activity of aldosterone.
  • steroidal denotes a nucleus provided by a cyclopenteno-phenathrene moiety, having the conventional four ring members.
  • epoxy-steroidal is intended to embrace a steroidal nucleus having one or a plurality of epoxy-type moieties attached thereto.
  • terapéuticaally effective amount is intended to qualify the amount of an agent for the use in therapy, which will achieve the goal of a wanted response in reducing, preventing or treating symptoms, conditions or disorders related to a disease, preferably while avoiding adverse side effects.
  • preventing includes either prevention of the onset of a clinical evident disorder altogether or preventing the onset of a preclinically evident stage of disorder in individuals.
  • aldosterone antagonist is denoted to include any substance that reduces the activity of aldosterone as a result of inhibiting its binding to the antimineralocorticoid receptor. It does not include substances, which reduce the amount of aldosterone synthesized or secreted by the adrenal cortex. Mespirenone is an example of an inhibitor of aldosterone synthesis.
  • aldosterone-mediated diseases encompasses diseases mediated through a compound binding to the aldosterone receptor site, and hereby modulating the receptor- mediated activity of aldosterone.
  • spironolactone refers to a molecule comprising a lactone structure coupled via a spiro configuration to a steroid structure or steroid derivative.
  • selective aldosterone antagonist relates to a compound that has a relative binding affinity to the antimineralocorticoid receptor and the progestational receptor in the 2004/041288
  • a compound is characterised as a "selective aldosterone antagonist" when the relative binding affinity to the progestational receptor and the relative binding affinity to the mineralocorticoid receptor as determined in relation to the binding affinity of eplerenone to these two receptors is in the range of 50% to 150%, preferably in the range of 75% to 125%, more preferably in the range of 85% to 115%.
  • progestin with substantially no antimineralocorticoid effect qualifies to a compound that has a relative binding affinity to the mineralocorticoid receptor in relation to drospirenone of less than 1%, preferably of less than 0.2% such as of less than 0.01%.
  • progestin with low antimineralocorticoid effect qualifies to a compound that has a relative binding affinity to the mineralocorticoid receptor in relation to drospirenone of less than less than 10%, preferably less than 5% such as less than 2%.
  • relative binding affinity to the progestational receptor is characterised by the binding affinity of a test agent relatively to that of drospirenone as determined in cytosol fractions containing expression vector for a animal or human progestational receptor, respectively.
  • the assay can be carried out incubating the cytosols with an appropriate radiolabeled reference substances, for which the relative binding affinity value is set at 100 % and the steroid competitor, as described in K. Pollow et al. Contraception, 46:561-574, 1992.
  • the relative binding affinity is determined relatively to eplerenone
  • relative binding affinity to the mineralocorticoid receptor is characterised by the binding affinity of a test agent relatively to that of drospirenone as determined on the basis of similar doses of the two agents in cytosol fractions containing expression vector for a animal or human mineralocorticoid receptor, respectively.
  • the assay can be carried out incubating the cytosols with an appropriate radiolabeled reference substances, for which the relative binding affinity value is set at 100 % and the steroid competitor, as described in K. Pollow et al. Contraception, 46:561-574, 1992.
  • the relative binding affinity is determined relatively to eplerenone.
  • a compound is characterised as having low anti-mineralocorticoid effect or low progestational effect when the binding affinity to the relevant receptors of the test agent relatively to drospirenone is less than 10%, preferably less than 5% such as less than 2%.
  • a compound is characterised as having substantially no anti-mineralocorticoid effect or substantially no progestational effect when the binding affinity to the relevant receptors of O 2004/041288
  • the compound relatively to drospirenone is less than 1%, preferably less than 0.2% such as less than 0.01%.
  • a compound is characterised as having a selective aldosterone antagonism when the binding affinity of the compound relatively to eplerenone with regard to the progestational receptor and the mineralocorticoid receptor is in the range of 50% to 150%, preferably in the range of 75% to 125%, more preferably in the range of 85% to 115%.
  • a compound is characterised as having a progestational and anti-mineralocorticoid effect similar to drospirenone when the binding affinity of the compound relatively to drospirenone with regard to the progestational receptor and the mineralocorticoid receptor is in the range of 50% to 150%, preferably in the range of 75% to 125%, more preferably in the range of 85% to 115%.
  • esters, ethers, products or salts are intended to encompass esters, ethers, products or salts.
  • the invention lies in part in the beneficial dual action of drospirenone and other agents with a pharmacological and biochemical profile similar to drospirenone in the treatment of symptoms, diseases and disorders associated with deficient endogenous levels of progesterone in a woman, preferably in a dosage wherein the woman has a reduced risk of developing aldosterone-mediated diseases such as cardiovascular diseases.
  • this action is mediated with drospirenone as the sole therapeutically active agent.
  • Treatment of women having low endogenous levels of progesterone with an agent possessing combined progestational and antimineralocorticoid effect may be of benefit to those women who are susceptible to aldosterone-mediated diseases such as cardiovascular diseases.
  • a first aspect of the invention relates to a composition
  • a composition comprising as the sole therapeutically active agent drospirenone or derivatives thereof, and optionally pharmaceutical excipient(s) or carrier(s).
  • drospirenone is intended to include any geometric isomer of drospirenone, metabolites of drospirenone and/or derivatives of drospirenone as long as they exhibit the same pharmacological and biochemical actions as drospirenone itself.
  • the isomers, metabolites or derivatives of drospirenone may have a progestational and anti-mineralocorticoid effect similar to drospirenone when the binding affinity of the test agent relatively to drospirenone with regard to the progestational receptor and the mineralocorticoid receptor is in the range of 50% to 150%, preferably in the range of 75% to 125%.
  • Drospirenone may be in the form of an ester or prodrug such as an oxyiminopregnane carbolactone as disclosed in WO 98/24801.
  • a second aspect of the invention relates to the treatment of deficient endogenous levels of progesterone in a woman such as to the use of an agent exhibiting progestational and antimineralocorticoid activity for the preparation of a medicament for treating symptoms, diseases or disorders associated with deficient endogenous levels of progesterone in a woman.
  • an agent is the sole therapeutically active agent and the agent is preferably drospirenone.
  • the second aspect of the invention relates to a therapeutic method for treating, alleviating or preventing symptoms, diseases or disorders associated with deficient endogenous levels of progesterone comprising administering to a woman an agent exhibiting progestational and antimineralocorticoid activity.
  • the agent exhibiting progestational and antimineralocorticoid activity is the sole therapeutically active agent.
  • Deficient endogenous levels of progesterone may be found in a woman for a number of reasons. Mainly, deficient endogenous levels of progesterone can be depicted in a woman experiencing irregular bleeding, abnormal bleeding, lack of ovulation, peri-menopause or post-menopause. Also a pregnant woman may suffer from deficient endogenous levels of progesterone in that a pregnant woman normally will have high levels of progesterone in order to avoid risk of miscarriage. Furthermore, deficient endogenous levels of progesterone are related to endometriose and other gynecological disorders.
  • the invention relates to the treatment and/or prevention of irregular bleeding, abnormal bleeding, lack of ovulation, peri-menopause, post-menopause, risk of miscarriage, endometriose and/or other gynecological disorders.
  • the uses and therapeutic methods are preferably directed to a peri-menopausal woman.
  • the uses and methods of therapy of the invention are also directed to a woman susceptible to aldosterone-mediated diseases such as cardiovascular diseases.
  • Such women may be healthy but nonetheless being in the risk of developing cardiovascular diseases, in particular upon experiencing deficient endogenous levels of progesterone, such as a woman in peri-menopause or in post-menopause, or such as a pregnant woman in risk of miscarriage or hypertension.
  • aspects of the invention relates to uses for preparation of a medicament and to therapeutic methods comprising an agent exhibiting progestational and antimineralocorticoid activity for treating and/or preventing aldosterone-mediated diseases in a woman that is in need of progesterone replacement therapy.
  • the dosage of the agent exhibiting progestational and antimineralocorticoid activity that is effective in treating and/or preventing aldosterone-mediated diseases in a woman, such as achieving reduced risk of cardiovascular diseases is important to the invention.
  • the agent exhibiting progestational and antimineralocorticoid activity may be used in a dosage that are below of the dosage resulting in treating symptoms associated with peri-menopause, post-menopause, prevention of miscarriage in a pregnant woman, prevention of hypertension of a pregnant woman.
  • the dosage of the agent exhibiting progestational and antimineralocorticoid activity may be effective in reducing the risk of developing aldosterone-mediated diseases arising from aldosterone antagonism at the mineralocorticoid receptor, but not effective in treating symptoms and diseases associated with deficiencies in the endogenous levels of progesterone in a woman.
  • the dosage does not result in regular bleeding (cycle control) and/or normal bleeding in a woman or prevention of miscarriage in a pregnant woman.
  • the uses and therapeutic methods of the invention include that the woman is in concurrent therapy with one or more alternative progestin(s) in dosages that will provide regular bleeding (cycle control), normal bleeding, treat endometriose and/or treat other gynecological disorders in a woman, or prevention of miscarriage in a pregnant woman.
  • alternative progestins may include those having low or substantially no aldosterone receptor blocker effect /antimineralocorticoid effect in comparison to drospirenone.
  • Such progestins are characterised by having low antimineralocorticoid effect.
  • a dosage of the agent exhibiting progestational and antimineralocorticoid activity that provides beneficial effects to the cardiovascular system while simultaneous treating deficiencies in the endogenous levels of progesterone in a woman.
  • a still further aspect of the invention relates to uses for preparation of a medicament and to therapeutic methods comprising an agent exhibiting progestational and antimineralocorticoid activity for simultaneous treating and/or preventing symptoms associated with low endogenous levels of progesterone and aldosterone-mediated diseases in a woman.
  • progesterone low endogenous levels of progesterone are an indication of peri-menopause in a woman.
  • post-menopausal women does also have low endogenous levels of progesterone or even lack of progesterone for which reason post-menopausal women may have beneficial effect upon administering an agent exhibiting progestational and antimineralocorticoid activity.
  • post-menopausal women are often also in need of therapy with estrogens. Therefore, in further embodiments of the invention, the woman that is in need of progesterone replacement therapy, e.g. a woman with deficient levels of endogenous progesterone may be in concurrent therapy with estrogens. This relates for example to a woman that has entered the post-menopause period, where the production of estrogens in the ovaries has stopped.
  • a still further aspect of the invention relates to uses for preparation of a medicament and to therapeutic methods comprising an agent exhibiting progestational and antimineralocorticoid activity for treating and/or preventing aldosterone mediated diseases in a woman in need of estrogen replacement therapy
  • the medicament may comprise an estrogen and the therapeutic method may comprise concurrent administering of an estrogen.
  • a further aspect of the invention relates to uses for preparation of a medicament and to therapeutic methods comprising an agent exhibiting progestational and antimineralocorticoid activity and one or more estrogen(s) for simultaneous treating symptoms, diseases or disorders associated with deficient endogenous levels of estrogen and aldosterone-mediated diseases in a woman.
  • the estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17 ⁇ -estradiol sulfate, 17 ⁇ -estradiol sulfate, equilin sulfate, 17 ⁇ - dihydroequilin sulfate, 17 ⁇ -dihydroequilin sulfate, equilenin sulfate, 17 ⁇ -dihydroequilenin sulfate andl7 -dihydroequilenin sulfate or mixtures thereof.
  • conjugated equine estrogens such as estrone sulfate, 17 ⁇ -estradiol sulfate, 17 ⁇ -estradiol sul
  • Particularly interesting estrogens are selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or mixtures thereof, notably estradiol, estradiol valerate, estradiol benzoate and estradiol sulfamates. Most preferred are estradiol or estradiol sulfamates, particularly estradiol.
  • the deficient levels of estrogen may be caused by natural menopause, peri-menopause, post-menopause, hypogonadism, castration or primary ovarian failure.
  • the diseases, disorders and symptoms may be any of or a mixture of the following conditions: hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and/or osteoporosis.
  • the agent exhibiting progestational and antimineralocorticoid activity may be a non-epoxy spironolactone-type steroidal compound such as spironolactone or drospirenone.
  • the non-epoxy spironolactone-type steroidal compound may further be characterised by having a relative binding affinity to the mineralocorticoid receptor and the progestational receptor of substantially the same order as drospirenone.
  • the agent exhibiting progestational and antimineralocorticoid activity is drospirenone. A number of side-effects among them serious effects such as cancer has been reported for Spironolactone when used in therapeutically active doses.
  • drospirenone is advantageous in that it has dual actions (progestational and antagonism of aldosterone-mediated diseases) within the same dosage range. Furthermore, in some dosages drospirenone may antagonise aldosterone-mediated diseases without affecting the progestational activity.
  • an evident feature of the present invention include an therapeutically active agent for treating aldosterone-mediated diseases in for example peri- and post- menopausal women in that such an agent should be capable of providing both progestational and antimineralocorticoid activity.
  • an agent should be capable of providing both progestational and antimineralocorticoid activity.
  • such a combined activity may result from the combination of a selective aldosterone antagonist and a progestin with low or substantially no antimineralocorticoid effect.
  • further aspects of the invention relates to uses for preparation of a medicament and to therapeutic methods comprising a combination of a selective aldosterone antagonist and a progestin with substantially no or low antimineralocorticoid effect for treating and/or preventing aldosterone-mediated diseases in a woman that is in need of progesterone replacement therapy.
  • a still further aspect relates to uses for preparation of a medicament and to therapeutic methods comprising a combination of a selective aldosterone antagonist and a progestin with substantially no or low antimineralocorticoid effect and an estrogen for simultaneous treating and/or preventing diseases, disorders and symptoms associated with deficient endogenous levels of estrogen and aldosterone mediated diseases in a woman.
  • Still another aspect relates to uses for preparation of a medicament and to therapeutic methods comprising a combination of a selective aldosterone antagonist and a progestin with substantially no or low antimineralocorticoid effect for treating and/or preventing aldosterone mediated diseases in a woman in need of estrogen replacement therapy.
  • the selective aldosterone antagonist may be an epoxy spironolactone-type steroidal compound such as eplerenone (epoxymexrenone) or canrenoate.
  • progestins with substantially no or low antimineralocorticoid effect are known. Examples are, but not limited to norethisterone; norethisterone acetate; levonorgestrel; gestodene; norgestilmate; dienogest; medroxyprogesterone acetate; megestrol acetate; chlormadinone acetate; or cyproterone acetate.
  • the progestins may be in the form of its derivates such as esters, ethers or salts, preferably esters.
  • Progesterone may have a lower antimineralocorticoid effect than drospirenone and eplerenone, in particular at those doses that are clinically relevant for exhibiting progestational effect. For that reason progesterone or a derivative thereof such as an ester or salt may also be a suitable progestin for use.
  • the aldosterone-mediated diseases, disorders or conditions of the present invention relates to those diseases that results from the activation of aldosterone receptors (mineralocorticoid receptor) by aldosterone in that this activation has been shown to be a key step in the chain of events leading to a number of diseases originating in the tissue where such receptors are found.
  • the aldosterone-mediated diseases may be mediated in whole or in part, by aldosterone present in the brain, heart and blood vessels
  • aldosterone-mediated diseases examples include cardiovascular diseases; renal dysfunction; liver diseases; cerebrovascular diseases; vascular diseases; retinopathy; neuropathy; insulinopathy; edema; endothelial dysfunction; baroreceptor dysfunction; migraine headaches.
  • Hypertension may also be an aldosterone-mediated disease, but it is a disease that are thought to be, at least in part, mediated by mineralocorticoid receptors in the kidney and not to the direct activation of aldosterone receptors in the hearth or brain.
  • the aldosterone-mediated disease is a cardiovascular disease.
  • cardiovascular diseases are heart failure such as congestive heart failure; arrhythmia; diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, impaired diastolic filling; systolic dysfunction; ischemia; hypertropic cardiomyopathy; sudden cardiac death; myocardial and vascular fibrosis; impaired arterial compliance; myocardial necrotic lesions; vascular damage; myocardial infarction; left ventricular hypertrophy; decreased ejection fraction; cardiac lesions; vascular wall hypertrophy; endothelial thickening; and fibrinoid necrosis of coronary arteries.
  • heart failure such as congestive heart failure; arrhythmia; diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, impaired diastolic filling; systolic dysfunction; ischemia; hypertropic cardiomyopathy; sudden cardiac death; myocardial and
  • the women in therapy with the agent exhibiting antimineralocorticoid and progestational effect is healthy, but may nonetheless be susceptible to cardiovascular diseases.
  • the woman to be treated may not has salt sensitivity or an elevated dietary sodium intake or both.
  • cardiovascular diseases as mentioned in here may not relate to inflammation-related cardiovascular disorders such as aetherosclerosis and the subject or woman may not need to be in concurrent therapy with ACE-inhibitors, cyclooxygenase-2 inhibitors and/or ⁇ -blockers.
  • ACE-inhibitors cyclooxygenase-2 inhibitors
  • ⁇ -blockers a mononuclear semiconductor semiconductor s, cyclooxygenase-2 inhibitors and/or ⁇ -blockers.
  • the dosage used of the agent exhibiting antimineralocorticoid and progestational effect may not disrupt a patients normal electrolyte and water-retention balance
  • the preventive effect of an agent exhibiting antimineralocorticoid and progestational on cardiovascular diseases may be investigated in human or animal studies by methods known to the person skilled in the art.
  • the end-point for determining prevention of cardiovascular diseases may for example be based on the incidences of stroke, incidences of myocardial infarct, incidences of congestive heart failure, incidences of vascular or myocardial fibrosis during long-term studies in a placebo-controlled study or a comparison study involving progestins with substantially no anti-mineralocorticoid effect as the control medication, optionally with concurrent therapy with estrogens.
  • cardiovascular diseases may be observed by a physician and through the result of laboratory analyses, such as blood gas analyses or abnormal blood parameters.
  • arterial hypertension can be induced in rodents using different techniques: a) renovascular hypertension induced by surgically placing a constricting band around the right renal artery, to induce unilateral renal ischemia. b) infrarenal banding to mechanically constrict blood flow through the aorta below the junction where the renal arteries branch off. (elevated blood pressure in the kidneys. c) aldosterone infused directly into the rodents at a fixed rate via an implanted pump.
  • the spontaneously hypertensive rodents of the stroke-prone substrane is characterised by an increased development of severe hypertension, cerebrovascular lesions, and malignant nephrosclerosis.
  • the rodents are monitored for hypertension, and plasma aldosterone, systolic and diastolic blood pressure, left ventricular and diastoic pressure, left ventricular dP/dt, body weight, and heart rate.
  • the rodents is sacrificed and compared between the different groups of treated with either an active agent or placebo, by examination of the heart, microscopic evaluation of the cerebrovascular damages a histopathologic analysis of the kidneys.
  • L- NAME/Ang II/NaCI Hypertensive rats (Delayani et al; eplerenone, a selective aldosterone receptor antagonist. Cardiovascular Drug Reviews vol, 19, No 3, p 185-200).
  • the mineralocorticoid receptor binding in vivo of an agent may be investigated in adrenolectomized rats by measuring radiolabelled aldosterone bound to receptors in the kidney, hearth, blood vessels, brain or other organs in the presence of the agent. (Delayani et al; eplerenone, a selective aldosterone receptor antagonist. Cardiovascular Drug Reviews vol, 19, No 3, p 185-200).
  • the aldosterone-mediated diseases may also relate to renal dysfunction such as glomerulosclerosis; end-stage renal disease; diabetic nephropathy; reduced renal blood flow; increased gloumerular filtration fraction; proteinuria, decreased gloumerual filtration fraction; decreased creatinine clearance; microalbuminuria; renal arteriopathy; iscemetic lesions; thrombotic lesions; global fribinoid necrosis; focal thrombosis of glomerual capillaries; swelling and prliferation of intracapillary and/or extracapillary cells; expantion of reticulated mesangial matrix with or without significant hypercellularity; and/or malignant nephrosclerosis.
  • liver diseases may be mediated through aldosterone activation of mineralocorticoid receptors. Such liver dieases may be liver cirrhosis, liver ascites or hepatic congestion.
  • the aldosterone-mediated diseases relate to cerebrovascular disease including stroke.
  • the uses and therapeutic actions of the present invention implies treating of vascular diseases such as thrombotic vascular disease; proliferative arteriopathy; atherosclerosis; decreased vascular compliance; and/or endothelial dysfunction.
  • vascular diseases such as thrombotic vascular disease; proliferative arteriopathy; atherosclerosis; decreased vascular compliance; and/or endothelial dysfunction.
  • the uses and therapeutic methods of the invention are preferably intended to a peri-menopause woman. That is to say the period before entering menopause.
  • the woman is in the age from about 40 to 55.
  • the suitable age may also be from about 45 to 53, about 45 to 52, 46 to 52, 48 to 52 or from about 47 to 51 dependent on when the individual women experiences irregular bleeding or other symptoms on deficient endogenous levels of progestogen.
  • the uses and therapeutic methods of the invention may not be limited to women of that age. Some women enter the menopause in a much younger age such as for example when they are in theirs thirties due to hypogonadal activities. Other women will enter the menopause upon hysterectomy.
  • the uses and therapeutic methods of the invention is intended to healthy women, e.g. women with a systolic blood pressure less than 140 mm Hg such as less than 130 mm Hg or 120 mm Hg or a diastolic blood pressure less than 105 mm Hg, such as less than 95 mm Hg, 85mm Hg or 75 mm Hg or combinations of said systolic blood pressure and diastolic blood pressure.
  • a systolic blood pressure less than 140 mm Hg such as less than 130 mm Hg or 120 mm Hg or a diastolic blood pressure less than 105 mm Hg, such as less than 95 mm Hg, 85mm Hg or 75 mm Hg or combinations of said systolic blood pressure and diastolic blood pressure.
  • An alternative characteristic of a healthy woman relates to the body mass index.
  • the woman has a body mass index in the range from about 16 to 35 in that the body mass index in older woman may be in the higher end of that range without being denoted obesive.
  • the body-mass index should be lower than 35. Therefore, the body-mass index of a woman is preferably in the range from about 18 to 32, even more preferably in the range from about 18 to 29, most preferably in the range from about 19 to 28, such as most preferably in the range from about 20 to 27.
  • the uses and therapeutic methods of the invention may be effective in treating aldosterone-mediated diseases in women having risk or even increased risk of cardiovascular diseases such as women with a systolic blood pressure greater than 130 mm Hg or a diastolic blood pressure greater than 85 mm Hg or both.
  • the woman in risk may also be characterised by having activities ratio of plasma aldosterone (ng/dL) to plasma renin (ng/mL/hr) greather than about 30.
  • Women with risk factors can promote the development of arteriosclerosis.
  • risk factors are smoking, overweight, stress, genetic disposition, high blood pressure, disorders of lipid metabolism, lack of exercise and/or diabetes.
  • cardiovascular diseases A subject, such as a woman, may be susceptible to cardiovascular diseases for a number of reasons such as because of hypertension, genetic disorders, race, diabetes, life-style, over-weight, smoking or food-intake.
  • the woman is pregnant.
  • the uses for preparation of a medicament and therapeutic methods of the invention comprises an agent exhibiting progestational and anti-mineralocorticoid for the treatment of hypertension in a pregnant woman.
  • the agent exhibiting progestational and anti-mineralocorticoid effect is drospirenone.
  • the dosage of drospirenone is effective in achieving regular and/or bleeding patterns in a woman, e.g. providing cycle control.
  • Such doses may relate to drospirenone in a daily deliverable dose ranging from about 0.02 to 5 mg, preferably ranging from about 0.1 mg to 3 mg or from about 0.25 mg to 3 mg, such as 0.1, 0.25 mg, 0.5 mg, 1, 2 or 3 mg.
  • the dosage of drospirenone would not implicate progestational activity but merely anti-mineralocorticoid effect.
  • drospirenone is in a daily deliverable dose ranging from about 0.02 to 5 mg, preferably in the range from about 0.1 to 5 mg, more preferably in the range from about 0.1 mg to 3 mg, more preferably in the range from about 0.1 to 2 mg, more preferably in the range from about 0.1 mg to 1 mg, more preferably in the range from 0.1 mg to 0.5 mg, most preferably in the range from about 0.1 mg to 0.4 mg.
  • a still further aspect of the invention relates to the use of drospirenone in a daily deliverable dose of 0.02 to 5 mg for the preparation of a medicament for treating and/or preventing aldosterone-mediated diseases in a subject in need thereof.
  • the subject may preferably be a woman, but not necessarily a woman in peri- or post-menopause.
  • the dose of drospirenone may preferably be in the range from about 0.02 to 5 mg, preferably in the range from about 0.1 to 5 mg, more preferably in the range from about 0.1 mg to 3 mg, more preferably in the range from about 0.1 to 2 mg, 5 more preferably in the range from about 0.1 mg to 1 mg, more preferably in the range from 0.1 mg to 0.5 mg, most preferably in the range from about 0.1 mg to 0.4 mg., such as such as 0.05 mg, 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, or 1 mg. It may further be the understanding that such daily deliverable doses may be for oral administration, orally deliverable doses.
  • drospirenone can be administered in dosages which are effective for preventing myocardial fibrosis but insufficient to substantially increase sodium excretion or substantially reduce potassium retention, reduce hypertension, reduce water retention, affect blood pressure, and/or lower arterial blood
  • the daily or monthly deliverable dose of drospirenone may not significantly alter the blood pressure but antagonise the cardiac effects of aldosterone.
  • the antialdosteronic effect and progestational effect according to the invention may depend on the dosage of the agent exhibiting antimineralocorticoid effect and
  • the agent according to this invention may be delivered daily to the blood plasma, the mineralocorticoid receptor and/or the progestational receptor for a number of days within
  • Cycle is intended to mean a period of time that is repeated for every 21 to 35 days.
  • the delivery of the agent may be for at least 5 days up to 35 days.
  • the agent is delivered for at least 10 days, such as 12 days, such as 15 days, such as 20 days, such as 21, 22, 23, 24, 25, 26, 27, or 28 days within each cycle of 21 to 35 days,
  • the delivery is in interrupted manner, which means that the agent is delivered for a period of time, which is followed by a period with no agent delivered, which is then followed by a period with delivery of the agent. Also, it means that no agent is delivered for a period of time, followed by delivery of agent, followed by no delivery of agent. This cycling of delivery of an agent may be repeated 1 to
  • each delivery of agent may for example be conducted for 1, 3, 7, 14 or 21 days.
  • the length of the period with delivery of agent may be similar, minor or greater than the period with no delivery.
  • the agent exhibiting progestational and antimineralocorticoid activity is administered sequentially, which relates to an interrupted manner.
  • the agent of the invention, such as an agent exhibiting progestational and antimineralocorticoid activity is administered continuously within a treatment cycle of 21 to 35 days.
  • the dose delivered by the agent may vary throughout the period of 21 to 35 days or it may be the same. Thus, in some embodiments, the dose delivered varies throughout the period of 21 to 35 days. For example, the dose may be lower in the first half, such as within the first 10 days, of the period of 21 to 35 days than in the second half, such as the last 10 days, of the period of 21 to 35 days. Conversely, it may also be suitable to use a higher dose in the first half, such as within the first 10 days, of the period of 21 to 35 days than in the second half, such as the last 10 days of the period of 21 to 35 days.
  • composition according to the invention may be formulated in any suitable manner.
  • the composition is formulated, according to the person skilled in the art, as a dosage unit for oral or topical administration.
  • the composition is formulated for oral delivery of the active agent.
  • the dosage unit formulated for oral administration may be a solid, semisolid or fluid formulation.
  • the solid dosage units may be selected from the group consisting of uncoated tablets, modified-release tablets, gastro-resistant tablets, orodispersible tablets, effervescent tablets, chewable tablets, soft capsules, hard capsules, modified-release capsules, gastro-resistant capsules, uncoated granules, effervescent granules, coated granules, gastro-resistant granules, modified -release granules, and powders for oral administration; and the fluids are selected from the group consisting of solutions, suspensions or emulsions.
  • the dosage units for topical administration may be selected from the group consisting of creams, gels, emulsions, suspensions, lotions, suppositories, enemas, pessaries, vaginal capsules, vaginal tablets, pads, sponges, plasters and transdermal delivery systems.
  • the dosage units for parenteral administration may be selected from the group consisting of solutions, suspensions, emulsions, gels, implantation tablets or implants.
  • dosage units comprising combinations of active agents such as a selective aldosterone antagonist and a progestin with low or substantially no antimineralocorticoid effect can occur concomitantly or independently. That is to say that the combination is administered in a single dosage form or as more than one dosage form such as one agent administered as a solid and the other agent as a fluid.
  • one agent may be formulated for oral administration whilst the other is formulated for transdermal or subcutaneous administration.
  • both agents are administered as solids formulated for oral administration.
  • an interesting embodiment of the invention comprises a dosage unit wherein the drospirenone is in micronized form or in the form of a cyclodextrin inclusion complex.
  • the dosage unit of the present invention comprises carriers or excipients, which may act to promote dissolution of both active substances.
  • carriers and excipients include substances that are readily soluble in water such as cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone.
  • polyvinylpyrrolidone might be particularly helpful to promote dissolution.
  • pharmaceutically acceptable carriers and excipients are intended to mean substances, which are substantially harmless to the individual to which the dosage unit will be administered. Such an excipient normally fulfils the requirements given by the national drug agencies. Official pharmacopeias such as the British Pharmacopeia, the United States of America Pharmacopeia and the European Pharmacopeia set standards for well-known pharmaceutically acceptable excipients.
  • Suitable pharmaceutically acceptable excipients according to the invention include all kinds that may be used for solid, semi-solid and fluid dosage units.

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Abstract

L'invention concerne des procédés de traitement de maladies induites par l'aldostérone telles que des maladies cardiovasculaires en période de périménopause ou de postménopause de la femme par administration d'un agent à activité antiminéralocorticoïde et progestationelle, notamment la drospirénone.
PCT/IB2002/004628 2002-11-05 2002-11-05 Therapie de remplacement d'hormone a l'aide de drospirenone Ceased WO2004041288A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
PCT/IB2002/004628 WO2004041288A1 (fr) 2002-11-05 2002-11-05 Therapie de remplacement d'hormone a l'aide de drospirenone
AU2002368326A AU2002368326A1 (en) 2002-11-05 2002-11-05 Hormone replacement therapy with drospirenone
JP2004549480A JP2006508945A (ja) 2002-11-05 2003-11-05 抗−アルドステロン性プロゲスチンを用いての心血管保護
DK03769738.0T DK1558265T3 (da) 2002-11-05 2003-11-05 Anvendelse af dropspirenon til behandling af hypertension
PT03769738T PT1558265E (pt) 2002-11-05 2003-11-05 Utilização da drospirenona para o tratamento da hipertensão
PCT/IB2003/004946 WO2004041289A1 (fr) 2002-11-05 2003-11-05 Protection cardiovasculaire a l'aide de progestines anti-aldosteroniques
ES03769738T ES2338781T3 (es) 2002-11-05 2003-11-05 Uso de la drospirenona para el tratamiento de una hipertension.
DE60330888T DE60330888D1 (de) 2002-11-05 2003-11-05 Verwendung von drospirenon zur behandlung von hypertension
AT03769738T ATE454155T1 (de) 2002-11-05 2003-11-05 Verwendung von drospirenon zur behandlung von hypertension
EP03769738A EP1558265B1 (fr) 2002-11-05 2003-11-05 Utilisation de la drospirenone pour le traitment de l'hypertension
AU2003278434A AU2003278434A1 (en) 2002-11-05 2003-11-05 Cardiovascular protection using anti-aldosteronic progestins

Applications Claiming Priority (1)

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PCT/IB2002/004628 WO2004041288A1 (fr) 2002-11-05 2002-11-05 Therapie de remplacement d'hormone a l'aide de drospirenone

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DE102005056527A1 (de) * 2005-11-25 2007-07-12 Grünenthal GmbH Verwendung einer Kombination aus Ethinylestradiol und Chlormadinonacetat zur Herstellung eines Arzneimittels
WO2012116859A1 (fr) * 2011-03-01 2012-09-07 Frank Lehmann-Horn Utilisation d'antagonistes des récepteurs de l'aldostérone pour le traitement d'un dysfonctionnement sexuel féminin et de migraines
US9592245B2 (en) 2010-04-15 2017-03-14 Bayer Intellectual Property Gmbh Very low-dosed solid oral dosage forms for HRT
CN113750108A (zh) * 2015-06-23 2021-12-07 莱昂实验室制药股份有限公司 用于过重女性患者的基于屈螺酮的避孕药

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WO2002017895A2 (fr) * 2000-08-28 2002-03-07 Pharmacia Corporation Utilisation d'un antagoniste du recepteur d'aldosterone pour ameliorer la fonction cognitive
WO2002055086A2 (fr) * 2001-01-11 2002-07-18 Schering Aktiengesellschaft Procede de traitement hormonal substitutif et forme d'administration correspondante
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US6083528A (en) * 1995-09-28 2000-07-04 Schering Aktiengesellschaft Hormone replacement therapy method and hormone dispenser
US20020136775A1 (en) * 1998-12-09 2002-09-26 Thosar Shilpa S. Controlled release eplerenone compositions
WO2000038725A1 (fr) * 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons utilisees dans le cadre de troubles cardio-vasculaires
WO2001052857A1 (fr) * 2000-01-18 2001-07-26 Schering Aktiengesellschaft Drospirenone pour therapie de remplacement d'hormone
WO2002009683A2 (fr) * 2000-07-27 2002-02-07 Pharmacia Corporation Therapie anti-aldosterones destinee a prevenir ou traiter les troubles lies a une inflammation
WO2002017895A2 (fr) * 2000-08-28 2002-03-07 Pharmacia Corporation Utilisation d'un antagoniste du recepteur d'aldosterone pour ameliorer la fonction cognitive
WO2002055086A2 (fr) * 2001-01-11 2002-07-18 Schering Aktiengesellschaft Procede de traitement hormonal substitutif et forme d'administration correspondante

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005056527A1 (de) * 2005-11-25 2007-07-12 Grünenthal GmbH Verwendung einer Kombination aus Ethinylestradiol und Chlormadinonacetat zur Herstellung eines Arzneimittels
US9592245B2 (en) 2010-04-15 2017-03-14 Bayer Intellectual Property Gmbh Very low-dosed solid oral dosage forms for HRT
WO2012116859A1 (fr) * 2011-03-01 2012-09-07 Frank Lehmann-Horn Utilisation d'antagonistes des récepteurs de l'aldostérone pour le traitement d'un dysfonctionnement sexuel féminin et de migraines
CN113750108A (zh) * 2015-06-23 2021-12-07 莱昂实验室制药股份有限公司 用于过重女性患者的基于屈螺酮的避孕药

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