Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/566—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 having an oxo group in position 17, e.g. estrone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/18—Feminine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to a method of alleviating the symptoms of dysmenorrhea in a person, comprising administering to said person an effective amount of an estrogenic component. More particularly the estrogenic component is an estetrol component, as further defined herein, and the method enjoys a favourable side-effect profile compared to currently available methods.
• Dysmenorrhea is a medical condition characterized by the presence of recurrent, crampy, lower abdominal pain that occurs during menses. Most women begin having dysmenorrhea during adolescence, usually within four to five years of the first menstrual period. Painful periods become less common as women age. For clinical purposes, dysmenorrhea is divided into two broad categories, primary and secondary dysmenorrhea. Primary dysmenorrhea refers to the presence of recurrent, crampy, lower abdominal pain that occurs during menses in the absence of demonstrable disease that could account for these symptoms.
• Secondary dysmenorrhea has the same clinical features, but occurs in women with a disorder that could account for their symptoms, such as endometriosis, adenomyosis, or uterine fibroids.
• Prostaglandins released from endometrial sloughing at the beginning of menses play a major role in inducing contractions (Ylikorkala O, Dawood M Y.; Am J Obstet Gynecol 1978; 130:833).
• the pain starts one to two days before or with the onset of menstrual bleeding and then gradually diminishes over 12 to 72 hours. It is recurrent, occurring in most, if not all, menstrual cycles.
• the pain is usually crampy and intermittently intense, but may be a continuous dull ache. It is usually confined to the lower abdomen and suprapubic area. Although the pain is usually strongest in the midline, some women also have severe back and/or thigh pain.
• the “dysmenorrhea symptoms grade” corresponds to the score obtained by applying the assessment presented in Table 1.
• Nonsteroidal anti-inflammatory drugs are considered the first line of therapy (Proctor M, Farquhar C; Clin Evid 2003; :1994—Zhang W Y, Li Wan Po A.; Br J Obstet Gynaecol 1998; 105:780—French L.; Am Fam Physician 2005; 71:285).
• NSAIDs should be started at the onset of menses and continued for the first one to two days of the menstrual cycle or for the usual duration of crampy pain. Patients with severe symptoms should begin taking NSAIDs one to two days prior to the onset of menses.
• COCs Combined Oral Contraceptive pills
• NSAIDs Dermat A R, et al.; Obstet Gynecol 2005; 106:97.
• COCs prevent menstrual pain by suppressing ovulation, thereby decreasing uterine prostaglandin levels.
• An additional mechanism may result from the reduction of menstrual flow after several months of use.
• COCs may be considered for first-line of therapy because they serve a dual purpose: prevention of both pregnancy and dysmenorrhea.
• estrogens participate in the regulation of the synthesis of a variety of proteins in the liver, such as angiotensinogen, Sex Hormone Binding Globulin (SHBG), ceruloplasmin, Corticosteroid Binding Globulin (CBG), some coagulation factors, coagulation inhibitors or fibrinolysis markers. Changes in these haemostasis markers under the influence of strong estrogens such as EE may collectively contribute to create an imbalance between pro-coagulation and anti-coagulation factors which can enhance the risks of Venous ThromboEmbolism (VTE) events.
• VTE Venous ThromboEmbolism
• SHBG plasma levels are a reliable marker of the influence of an estrogen on the synthesis of these proteins by liver cells. This means that a correlation could exist between the level of SHBG induced by a specific COC and the risk of VTE associated with that COC (Odlind V, et al.; Acta Obstet Gynecol Scand 2002; 81:482).
• the present invention relates to a method of alleviating the symptoms of dysmenorrhea in a person, comprising administering to said person an effective amount of an estrogenic component. More particularly the estrogenic component is an estetrol component, as further defined herein, and the method enjoys a favourable side-effect profile compared to currently available methods.
• one or more of the number, the frequency and the severity of treatment-related side effects is reduced, compared to other dysmenorrhea treatments of similar efficacy.
• the number, frequency and/or severity of VTE events is reduced, compared to other dysmenorrhea treatments of similar efficacy.
• the number, frequency and/or severity of headaches is reduced, compared to other dysmenorrhea treatments of similar efficacy.
• the number, frequency and/or severity of breast pain events is reduced, compared to other dysmenorrhea treatments of similar efficacy.
• the method involves the administration of an effective amount of an estrogenic component and of a progestogenic component.
• the progestogenic component is drospirenone and that component is used at a daily dose of from 0.5 mg to 10 mg, preferably at a daily dose of from 1 mg to 4 mg.
• the estrogenic component is used at a daily dose of from 1 mg to 40 mg, preferably at a daily dose of from 5 mg to 25 mg, even more preferably at a daily dose of from 10 mg to 20 mg.
• the estrogenic component is estetrol monohydrate.
• the estrogenic component is estetrol monohydrate at a daily dose of about 15 mg and the progestogenic component is drospirenone at a daily dose of about 3 mg.
• the present method employs an estrogenic component which is a natural estrogen (i.e. found in nature) and a biogenic estrogen (i.e. occurring naturally in the human body).
• biogenic estrogens are naturally present in the fetal and female body, a good tolerability and safety profile are observed, particularly if the serum levels resulting from the exogenous administration of such estrogens do not substantially exceed naturally occurring concentrations.
• a direct consequence of this good tolerability is the favourable side-effect profile obtained with the method of the invention compared to other methods.
• 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.
• the estrogenic component of the present invention preferably is an estetrol component.
• estetrol component encompasses substances selected from the group consisting of estetrol, esters of estetrol 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; and combinations thereof. Even more preferably, the estetrol component is estetrol (including estetrol hydrates). Most preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.
• progestogenic component is defined as a substance that is capable of triggering a 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.
• an effective amount refers to an amount necessary to obtain a physiological effect.
• the physiological effect may be achieved by one dose or by repeated doses.
• an effective amount refers to an amount which is effective in reducing, eliminating, treating or controlling the symptoms of dysmenorrhea.
• controlling is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of dysmenorrhea, but does not necessarily indicate a total elimination of dysmenorrhea, and is intended to include prophylactic treatment and chronic use.
• Example 5 the present method of alleviating the symptoms of dysmenorrhea has proved surprisingly efficient despite the low daily dosage employed.
• the present inventors believe that the superiority of the present method is in part due to the surprising effect of the estetrol component which is capable of mitigating dysmenorrhea on its own, as illustrated in the clinical results presented in Example 1.
• the estetrol component is capable of alleviating the symptoms of dysmenorrhea allows to decrease those symptoms when the estetrol component is administered alone according to the method of the invention.
• the estetrol component is administered alone during the progestin-free interval of the method of treatment according to the invention, as further described below.
• the present inventors believe that the superiority of the present method is also due to the mild stimulatory effect that the estetrol component has on the endometrium, especially by comparison with the stronger stimulatory effect of ethinyl estradiol, which is the estrogen used in a large number of COCs.
• endometrial thickness was strongly diminished upon administration of the compositions of the invention.
• the thin endometrium contains relatively small amounts of arachidonic acid, the substrate for most prostaglandin synthesis.
• the compositions of the invention reduce both menstrual flow and uterine contractions at menses, thereby decreasing dysmenorrhea.
• the method according to the invention was found to suppress ovulation in 100% of patients and suppression of ovulation is decreasing uterine prostaglandin levels.
• estetrol component Another important benefit of the present estetrol component is derived from its 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
• anticonvulsant agents 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 not dependent on up- and downregulation of microsomal liver enzymes (e.g. P450's) and also are not sensitive to competition with other P450 substrates.
• estetrol at a high concentration of 10 ⁇ mol/l does not inhibit (less than 10%) the major cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) unlike estradiol.
• estradiol exerts a substantial inhibitory effect on CYP2C19 and CYP3A2 of 63% and 19%, respectively.
• ethinyl estradiol which is the estrogen used in a large number of COCs, exerts a substantial inhibitory effect on CYP2C19 and CYP3A4 of 82% and 45%, respectively.
• the terminal half-life of the naturally occurring estrogens ranges from 2 to 14 hours while estetrol is characterized by a terminal half-life of 31.7 hours. Consequently, the use of estetrol in the method of the invention allows for a more than 24-hour coverage of the receptors by the treatment. This pharmacokinetic property enhances the efficacy of the product even in case of low treatment compliance by the user.
• estetrol is associated with 3 mg drospirenone (DRSP) or 150 ⁇ g Levonorgestrel (LNG)
• DRSP drospirenone
• LNG Levonorgestrel
• estrogens ethinylestradiol (EE), E2, E2V, conjugated equine estrogens
• E4 minimally increases triglycerides levels even at higher dosages.
• VTEs venous thromboembolic events
• the use of second generation COCs multiply by 2 the risk of VTE and the use of 3rd and 4th COCs multiply the risk by 4.
• the absolute risk of VTE associated with the use of a specific combined contraceptive can only be assessed during very large epidemiological trials.
• several surrogate markers of the VTE risk can be measured in smaller clinical settings to estimate the risk.
• Example 4 From the clinical results obtained with combinations of E4 and DRSP or LNG, the changes in the surrogate markers of VTE were minimal in comparison to the changes observed with Yaz® (a combination of 20 ⁇ g EE and 3 mg DRSP).
• DRSP is a fourth generation progestin associated with the highest risk of VTE when it is combined with the synthetic estrogen EE. Accordingly, the changes in the surrogate markers of VTE seen with a combination of EE and DRSP are substantial. In comparison, the changes observed with the E4 combinations are minimal even when DRSP is associated to the estrogen.
• the SHBG plasma level changes observed when E4 was associated with 3 mg DRSP were considerably lower (mean percentage change of 7.9% for the 5 mg E4/3 mg DRSP group and of 44.5% for the 10 mg E4/3 mg DRSP group at treatment cycle 3) than the SHBG increases observed with a combination of 20 ⁇ g EE and 3 mg DRSP (mean percentage change of 306.3% for Yaz® at treatment cycle 3).
• the same positive pattern of change was observed with the 14 additional surrogate markers of VTE measured in this trial.
• the present methods usually employ uninterrupted oral administration of the estrogenic component and the progestogenic 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 components are 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 estrogenic and progestogenic components 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 combination of the progestogenic and estrogenic component is suitably administered uninterruptedly during a period of at least 10 days.
• the invention may suitably be reduced to practice in the form of a variety of administration 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 monophasic preparations, which contain dosage units with a constant amount of an estrogen and a progestogen, or bi- or triphasic preparations which have varying levels of estrogen and progestogen; in most cases consisting of relatively constant levels of estrogen with a step-wise increase in progestogen throughout the cycle.
• the combined methods have in common that they are based on a regimen which involves 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.
• an administration-free interval of about 4 days is used.
• a 24 day interval of hormone administration alternates with 4 days during which no hormones are administered.
• a 24 day interval of hormone administration during which an estrogenic component and a progestogenic component are administered alternates with 4 days during which only an estrogenic component is administered (from day 25 to day 28).
• the so called “sequential” method has been proposed.
• Typical of the sequential method is that it comprises two consecutive phases, i.e. one phase during which estrogen and no progestogen is administered and another phase during which a combination of estrogen and progestogen is administered.
• 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.
• Yet another example of a 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 method which is encompassed by the present invention
• 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 oral administration of the combination of the estrogenic component and the progestogenic component during a period of at least 28, preferably at least 60 days.
• one tablet comprising the combination of the estrogenic component and of the progestogenic component is initially taken daily for at least about 24 consecutive days. Subsequently, e.g. during days 25 to 120, the patient may decide to take a tablet-free break of about 4 days. In any case, an about 4-day tablet-free break has to be taken after about 120 days of continuous tablet administration. After each tablet-free break, a new cycle starts with a minimum of about 24 days and a maximum of about 120 days of continuous administration.
• 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 estrogenic 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 oral 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 composition for use in a method of alleviating the symptoms of dysmenorrhea is capable of reducing the number, frequency and/or severity of adverse side effects including VTE, headache, breast pain, and the like, preferably including VTE, headache, and breast pain, more preferably including VTE and headache, and most preferably including VTE.
• the composition according to the present invention is particularly useful for effective treatment of the symptoms of dysmenorrhea while reducing the side effect of VTE at a significantly low frequency and severity.
• haemostatic change is defined as the variation, upon administration of the compositions according to the invention, of the plasma level of one or more markers selected from: Sex Hormone Binding Globulin (SHBG), free tissue factor pathway inhibitor (free TFPI), free and total protein-S, protein-S activity, Corticosteroid Binding Globulin (CBG), Ceruloplasmin, antithrombin III, activated protein C (APC) resistance (e.g.
• SHBG Sex Hormone Binding Globulin
• free TFPI free tissue factor pathway inhibitor
• CBG Corticosteroid Binding Globulin
• Ceruloplasmin antithrombin III
• APC activated protein C resistance
• APTT-based APCr or ETP-based APCr Protein-C activity, D-dimer, Prothrombin, Prothrombin fragment 1+2, Factor VII, Factor VIII, von Willebrand factor, Factor II, PAI-1, tissue-type plasminogen (t-PA), plasminogen, E-selectin, and fibrinogen.
• the “normal range”, when referring to levels of haemostatic markers, refers to the prediction interval that 95% of the population fall into.
• the method does not cause haemostatic change exceeding the boundaries of the normal range after one cycle of treatment, preferably the method does not cause haemostatic change exceeding the boundaries of the normal range after two cycles of treatment, even more preferably the method does not cause haemostatic change exceeding the boundaries of the normal range after three cycles of treatment.
• the method does not cause a change in the level of protein-S which exceeds the boundaries of the normal range.
• the method does not cause a change in the level of free TFPI which exceeds the boundaries of the normal range.
• the estrogenic component of the present invention preferably is an estetrol component, which encompasses substances selected from the group consisting of estetrol, esters of estetrol 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; and combinations thereof. More preferably, the estetrol component is estetrol (including estetrol hydrates). Most preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.
• the estetrol component of the invention may be used at a daily dose of from 0.1 mg to 100 mg.
• the estetrol component of the invention is used at a daily dose of from 1 mg to 40 mg.
• the estetrol component of the invention is used at a daily dose of from 5 mg to 25 mg.
• the estetrol component of the invention is used at a daily dose of from 10 mg to 20 mg.
• estetrol component of the invention is used at a daily dose of about 15 mg.
• dosages may be variable throughout the cycle (bi-phasic, tri-phasic or quadriphasic administration).
• the pharmaceutical composition according to invention is designed for daily administration, i.e. it represents a daily dosage unit.
• the oral dosage unit according to the invention is preferably a solid or semi-solid dosage form such as tablets, capsules, cachets, pellets, pills, powders and granules.
• solid or semi-solid dosage form also encompasses capsules that contain a liquid, e.g. an oil, in which the present estetrol component is dissolved or dispersed.
• Tablets and equivalent solid and semi-solid dosage forms can suitably contain materials such as binders (e.g. hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, other cellulosic materials and starch), diluents (e.g.
• lactose and other sugars starch, dicalcium phosphate and cellulosic materials
• disintegrating agents e.g. starch polymers and cellulosic materials
• lubricating agents e.g., stearates and talc.
• These tablets and equivalent solid and semi-solid dosage forms may be prepared by wet granulation, e.g. using an aqueous solution or an organic solution, as well as by direct compression.
• the progestogenic component used in the present method is selected from the group consisting of progesterone, desogestrel, gestodene, dienogest, levonorgestrel, norgestimate, norethisterone, drospirenone, trimegestone, dydrogesterone, precursors of these progestogens and mixtures thereof
• the progestogenic component of the invention is drospirenone
• it is preferably used at a daily dose of from 0.5 mg to 10 mg, even more preferably of from 1 mg to 4 mg.
• the progestogenic component of the invention is drospirenone and it is used at a daily dose of about 3 mg.
• the daily dose is adjusted such as to give the same pharmacological effect as a dose of 0.5 mg to 10 mg of drospirenone, preferably to give the same pharmacological effect as a dose of 1 mg to 4 mg of drospirenone.
• the composition combines estetrol at a daily dose of from 5 mg to 25 mg with drospirenone at a daily dose of 0.5 mg to 10 mg.
• the composition combines estetrol at a daily dose of from 10 mg to 20 mg with drospirenone at a daily dose of 1 mg to 4 mg. In a yet more preferred embodiment of the invention, the composition combines estetrol at a daily dose of about 15 mg with drospirenone at a daily dose of about 3 mg.
• the composition does not contain any added zinc salts.
• no biocompatible zinc salts are used for the preparation of the compositions according to the invention.
• dysmenorrhea was reported by 11 subjects (21.2%), and frequent dysmenorrhea was reported by 19 subjects (36.5%). The distribution of dysmenorrhea is shown in Table 2 below. Overall, dysmenorrhea was reported by 25% to 53.3% of the subjects included in this trial.
• dysmenorrhea TE-AEs leading to discontinuation occurred once in each of the 20 mg E4 groups (1.3%) but did not occur in any of the 15 mg E4 groups (0%).
• the method of the invention permits to minimize the SHBG level changes from baseline both at Cycle 4 and at Cycle 6, compared to a commercially available COC which also uses a natural estrogen.
• a multicenter, placebo-controlled, randomised study to evaluate the benefits of the method of the invention on alleviating complaints of dysmenorrhea was conducted.
• the study population consisted in healthy female subjects, between 12 and 35 years old, inclusive (at the time of screening), with primary dysmenorrhea (onset ⁇ 3 years post menarche).
• the product according to the method of the invention was a combination tablet with estetrol (15 mg) and drospirenone (3 mg) administered orally once daily in continuous or 24/4-day regimen (i.e. 24 days of active tablets followed by 4 days of placebo tablets). Other doses of estetrol were included in supplementary arms, in addition to the placebo arm.
• Dysmenorrhea pain was defined as pelvic pain during the menstrual/withdrawal bleeding episode and the 2 days before this episode.
• the clinical study demonstrates that the product according to the invention is effective in improving the symptoms of dysmenorrhea.
• a multi-institutional, placebo-controlled trial was conducted with collaborative randomized allocation double-blinded control for dysmenorrhea patients (primary dysmenorrhea patients, and secondary dysmenorrhea patients) aged 16 and older.
• the study drug is a combination tablet containing estetrol (15 mg) and drospirenone (3 mg).
• the tablet has two modes of administration:

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