JP2018533542A - Methods for the management of dysmenorrhea and menstrual pain - Google Patents

Abstract

The present invention relates to a method for managing dysmenorrhea comprising the administration of an estrogen component preferably selected from the group consisting of estetrol and estetrol-like compounds. It has surprisingly been found that estetrol-like compounds can alleviate dysmenorrhoea when used alone or in combination with a progestogenic component, which is another Taking advantage of the effects obtained with the composition, it has a favorable side effect profile compared to currently available methods.

Description

  The present invention relates to a method of alleviating the symptoms of dysmenorrhea in a human, comprising administering to said human an effective amount of an estrogen component. More particularly, the estrogen component is an estetrol component as further defined herein, and the method enjoys a suitable side effect profile as compared to currently available methods.

  Dysmenorrhea is a medical condition characterized by the presence of relapsing convulsive lower abdominal pain that occurs during menstruation. Most women begin to experience dysmenorrhea during the adolescence, usually within 4 to 5 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 dysmenorrhoea.

  Primary dysmenorrhoea refers to the presence of relapsing convulsive lower abdominal pain that occurs during menstruation in the absence of demonstrable diseases that can explain these symptoms.

  Secondary dysmenorrhoea occurs in women with identical clinical characteristics but with disorders that can explain their symptoms, such as endometriosis, adenomyosis or fibroids.

Between 50 and 90 percent of women with primary dysmenorrhea and reproductive age are known to report painful menstrual period experience. Most of these women are young and have primary dysmenorrhoea. The prevalence of primary dysmenorrhoea decreases with advancing age (Non-Patent Document 1).

  Primary dysmenorrhoea has been associated with changes in prostaglandin synthesis and metabolism. Prostaglandins released from endometrial shedding at the onset of menses play a major role in the induction of contractions (Non-patent Document 2).

  The pain starts 1 to 2 days before or with the onset of menstrual bleeding and then gradually decreases over 12 to 72 hours. Most, if not all, of the menstrual cycle will recur. The pain is usually spastic, intermittently strong, but may be persistent and dull. It is usually confined to the lower abdomen and the suprapubic area. Pain is usually strongest on the midline, but some women also have severe back pain and / or femoral pain.

  The severity of pain ranges from mild to severe (Table 1 below) (Non-Patent Document 3).

  As used herein, "dysmenorrhea symptom grade" corresponds to the score obtained by applying the evaluation presented in Table 1.

  It is important to note that there is no physical finding associated with primary dysmenorrhoea and that primary dysmenorrhoea does not have any laboratory abnormalities or abnormal findings in imaging studies. Thus, the diagnosis must confirm that the patient has no evidence of other disorders that may explain pain. In particular, disorders such as endometriosis, uterine adenomyosis, fibroids, ovarian cysts, among others, have been associated with secondary dysmenorrhoea.

Treatment Options for Primary Dysmenorrhoea Non-steroidal Anti-Inflammatory Drugs (NSAIDs) are considered the first choice of therapy (Non-patent Literature 4- Non-patent Literature 5- Non-patent Literature 6).

  The NSAID is started at the beginning of menstruation and must be continued during the first 1-2 days of the menstrual cycle or during the normal period of convulsive pain. Patients with severe symptoms should begin taking NSAIDs 1 to 2 days before the onset of menstruation.

  Patients who can not respond to or tolerate NSAIDs may be given combined oral contraceptive pills (COCs) [7]. COC suppresses ovulation, thereby preventing menstrual pain by reducing uterine prostaglandin levels. An additional mechanism can be attributed to the reduction in menstrual flow several months after use.

  In sexually active women, COC may be considered the first choice of therapy as it serves a dual purpose: preventing both pregnancy and dysmenorrhea.

  A systematic review of randomized trials of estrogen-progestin contraceptives for the treatment of primary dysmenorrhoea reported significant benefits of treatment (a pooled OR of 2.99, 95% CI 1.76 ~ 5.07) (Non-patent Document 8).

  A few trials compare different doses of estrogen for the treatment of primary dysmenorrhoea; the above reviews refer to low (≦ 35 mcg) and moderate (> 35 mcg) estrogen doses for pain relief. It was concluded that there was no clear difference in efficacy between the various pill preparations, which was similar.

  However, further data obtained from observational studies and other randomized trials demonstrated the efficacy of very low doses of estrogen pills for the treatment of dysmenorrhea (Non-Patent Document 9-Non-Patent Document 10) Non-patent document 11 Non-patent document 12 non-patent document 13).

  However, all these approaches have relied on COC using synthetic estrogens such as ethynyl estradiol (EE). In such cases there is a risk of (dose-dependent) undesirable side effects such as thromboembolism, fluid retention, nausea, abdominal distension, cholelithiasis, headache and chest pain.

  Estrogen is a variety of proteins in the liver such as angiotensinogen, sex hormone binding globulin (SHBG), ceruloplasmin, corticosteroids binding globulin (CBG), some blood coagulation factors, blood coagulation inhibitors, fibrinolytic markers, etc. The fact that it is involved in the regulation of the synthesis of is particularly important. Changes in these hemostatic markers under the influence of strong estrogens such as EE can jointly contribute to create an imbalance between procoagulant and anticoagulant factors, which causes venous thromboembolism (VTE) ) Can increase the risk of an event.

  SHBG plasma levels are a reliable marker of the effects of estrogen on the synthesis of these proteins by liver cells. This means that there may be a correlation between the level of SHBG induced by a particular COC and the risk of VTE associated with that COC (14).

  Cohort studies conducted on a sufficient number of subjects are required to assess the risk of VTE with a particular COC, but various hemostatic markers and carrier proteins (such as SHBG) are limited For a given number of subjects, it can be measured to estimate this risk.

  Thus, there is still a need for therapeutic approaches that on the one hand have as few side effects as possible while on the other hand they find to be extremely efficient in the management of dysmenorrhea.

Sundell G. Et al., Br J Obstet Gynaecol 1990; 97: 588. Ylikorkala O, Dawood MY. Am J Obstet Gynecol 1978; 130: 833 Andersch B, Milsom I. Am J Obstet Gynecol 1982; 144: 655 Proctor M, Farquhar C; Clin Evid 2003; Zhang WY, Li Wan Po A. Br J Obstet Gynaecol 1998; 105: 780 French L. Am Fam Physician 2005; 71: 285 Davis AR et al .; Obstet Gynecol 2005; 106: 97 Wong CL et al; Cochrane Database Syst Rev 2009; CD002120 Davis AR et al .; Obstet Gynecol 2005; 106: 97 Callejo J et al; Contraception 2003; 68: 183 Winkler UH et al .; Contraception 2004; 69: 469 Endrikat J et al; Contraception 1995; 52: 229 Hendrix SL, Alexander NJ; Contraception 2002; 66: 393 Odlind V et al .; Acta Obstet Gynecol Scand 2002; 81: 482

[Means for Solving the Problems]
The present invention relates to a method of alleviating the symptoms of dysmenorrhea in a human, comprising administering to said human an effective amount of an estrogen component. More particularly, the estrogen component is an estetrol component as further defined herein, and the method enjoys a suitable side effect profile as compared to currently available methods.

  In one aspect of the method, one or more of the number, frequency and severity of side effects associated with the treatment are reduced as compared to other dysmenorrhea treatments of similar efficacy.

  In one embodiment of the present invention, the number, frequency and / or severity of VTE events are reduced as compared to other dysmenorrhea treatments of similar efficacy.

  In another embodiment of the invention, hemostatic changes beyond the boundaries of the normal range, as further defined herein, do not occur upon administration of a composition of the invention.

  In a further embodiment of the invention, the number, frequency and / or severity of headaches are reduced compared to other dysmenorrhea treatments of similar efficacy.

  In yet another embodiment of the present invention, the number, frequency and / or severity of chest pain events are reduced as compared to other dysmenorrhea treatments of similar efficacy.

  In one embodiment of the invention, the method comprises the administration of an effective amount of an estrogen component and of a progestogenic component.

  In some embodiments of the invention, the estrogen and progestogenic components are included in a single dosage unit. In a further embodiment, the dosage unit is a daily dosage unit.

  In a further embodiment, the progestogenic component is drospirenone, which component is used in a daily dose of 0.5 mg to 10 mg, preferably in a daily dose of 1 mg to 4 mg.

  In still further embodiments, the estrogen component is used in a daily dose of 1 mg to 40 mg, preferably in a daily dose of 5 mg to 25 mg, even more preferably in a daily dose of 10 mg to 20 mg. In certain embodiments, the estrogen component is estetrol monohydrate.

  In a particular embodiment of the invention, the estrogen component is about 15 mg daily dose of estetrol monohydrate and the progestogenic component is about 3 mg daily dose drospirenone.

  The method uses an estrogen component which is a natural estrogen (ie, found in nature) and a biological estrogen (ie, naturally occurring in the human body).

  Because bioestrogen is naturally present in the fetus and female body, it is particularly good if the serum levels resulting from exogenous administration of such estrogens do not substantially exceed the naturally occurring concentrations. Tolerability and safety profiles are observed. The direct result of this good tolerance is the preferred side effect profile compared to the other methods obtained when using the method of the invention.

Definitions As used throughout this document, the term "estrogen component" is a substance capable of causing an estrogenic response in vivo, as well as liberating such an estrogen component in vivo when used according to the present invention Includes precursors that are capable of In order for the estrogen component to cause such a response, they usually have to bind to the estrogen receptor, which is found in various tissues in the mammalian body.

  The estrogen component of the present invention is preferably an estetrol component. As used throughout this document, the term "estetrol component" refers to estetrol; at least one hydrogen atom of the hydroxyl group is substituted by an acyl radical of 1 to 25 carbons hydrocarbon carboxylic acid, sulfonic acid or sulfamic acid And a substance selected from the group consisting of esters of estetrol and a combination thereof. Even more preferably, the estetrol component is estetrol (including estetrol hydrate). Most preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.

  The term "progestogenic component" is defined as a substance capable of causing a progestogenic response in vivo or a precursor capable of releasing such a substance in vivo Be done. Usually, progestogenic components are capable of binding to the progestogen receptor.

  The term "about" in the context of the disclosed invention refers to measurable values such as parameters, amounts, time periods, etc., as long as such variables are suitable for implementation, and It is meant to encompass variables of +/- +/- 10% or less, more preferably +/- 5% or less, even more preferably +/- 1% or less of a particular value. However, it should be understood that the value to which the modifier "about" refers is itself also specifically disclosed.

  The term "effective amount" refers to the amount necessary to obtain a physiological effect. Physiological effects may be achieved by one dose or by repeated doses. In particular, "effective amount" refers to an amount that is effective to reduce, eliminate, treat or control the symptoms of dysmenorrhoea. The term "controlling" refers to any process that may slow, interrupt, stop or interrupt the progression of dysmenorrhea but does not necessarily indicate complete elimination of dysmenorrhea and preventative treatment And chronic use.

  As shown in Example 5, the present method of reducing the symptoms of dysmenorrhea proved to be surprisingly effective despite the low daily doses used. While not wishing to be bound by theory, the present inventors believe that the superiority of the present method is somewhat due to the natural dysmenorrhea, as demonstrated in the clinical results presented in Example 1. It is believed to be due to the surprising effect of the estetrol ingredient that can be alleviated.

  In fact, administration of low doses of estrogen is known to reduce menstrual migraine headaches, but for dysmenorrhea it is a fact that no such effect has been reported so far. The particularity of the present finding that the estetrol component is capable of reducing the symptoms of dysmenorrhea is that the estetrol component reduces these symptoms when administered alone according to the method of the present invention. to enable. In one particular embodiment of the method, the estetrol component is administered alone during the progestin-free interval of the method of treatment of the invention, as described further below.

  It was even more unexpected that a significant number of scientific publications characterized estetrol as a weak estrogen, so at the doses used in the clinical trials reported in the examples, dysmenorrhea symptoms It was not foreseen that such a positive effect on management would be observed.

  Again, while not wishing to be bound by theory, the present inventors also note that the superiority of the method is also particularly in comparison to the stronger stimulatory effect of ethynyl estradiol, an estrogen used in many COCs. It is believed that this is due to the mild stimulation effect of the estetrol component on the endometrium. As a result, it has been found that the thickness of the endometrium is strongly reduced by the administration of the composition of the present invention. Thin endometrium contains relatively small amounts of arachidonic acid, a substrate for most prostaglandin synthesis. As a result of these changes in the endometrium, the compositions of the present invention reduce both menstrual flow and uterine contractions, thereby reducing dysmenorrhea.

  In addition, the method of the invention is found to inhibit ovulation in 100% of patients, which inhibits uterine prostaglandin levels.

  In a comparative study, surprisingly, the combination of estetrol and drospirenone as a progestogenic component is in the management of symptoms of dysmenorrhea as estetrol and as a progestogenic component It turned out to be more effective than the combination with levonorgestrel. This is illustrated by the results of the clinical trial reported in Example 2.

  Another important benefit of the present estetrol component stems from its relative insensitivity to interactions with other drugs (drug interactions). It is well known that certain drugs can reduce the potency of estrogens such as ethynyl estradiol and that other drugs can enhance their activity and lead to the possibility of increased side effects. Similarly, estrogen can interfere with the metabolism of other drugs. In general, the effect of other drugs on estrogen is by interference with the absorption, metabolism or excretion of these estrogens, whereas the effect of estrogen on other drugs is by competition for metabolic pathways.

  The clinically most important group of estrogen-drug interactions are drugs that can induce liver microsomal enzymes that can reduce estrogen plasma levels below therapeutic levels (eg, anticonvulsants; phenytoin, primidone, barbituric acid, carbamazepine, Ethosuximide and methosuccimid; antituberculous agents such as rifampin; antifungal agents such as griseofulvin). The estrogenic agent is not dependent on the up and down regulation of microsomal liver enzymes (eg, P450s) and is not sensitive to competition with other P450 substrates. Likewise, they do not interfere significantly with the metabolism of other drugs.

  In particular, high concentrations of estetrol at 10 μmol / l, unlike estradiol, do not (less than 10%) inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). In fact, estradiol exerts a substantial inhibitory effect on 63% and 19% of CYP2C19 and CYP1A2, respectively. Similarly, the ethynyl estradiol, an estrogen used in many COCs, exerts a substantial inhibitory effect on 82% and 45% of CYP2C19 and CYP3A4, respectively.

  The above observations serve to explain the reason why the estetrol component of the present invention suffers little drug-drug interaction and thus has a very consistent or predictable effect. Thus, the efficacy of the estrogenic substances of the invention is highly reliable.

  Furthermore, the terminal half-life of naturally occurring estrogen is in the range of 2-14 hours, and estetrol is characterized by a terminal half-life of 31.7 hours. As a result, the use of estetrol in the method of the present invention allows more than 24 hours of therapeutic effect of the receptor. This pharmacokinetic profile enhances the efficacy of the product even with low therapeutic compliance of the user.

  When estetrol (E4) is used together with 3 mg drospirenone (DRSP) or 150 μg levonorgestrel (LNG), the bleeding profile and cycle control are physiological estrogens, ie estradiol valerate (E2V) It should be noted that it improves as compared to other mixed oral contraceptives that use or estradiol (E2).

  A study evaluating the bleeding patterns and cycle control of various E4 / DRSP or E4 / LNG combinations compared to commercially available tetraphasic mixed oral contraceptives containing E2V and desogestrel (DSG), 15 mg of E4 / The DRSP combination and the 20 mg E4 / LNG combination were both associated with a lower incidence of unplanned bleeding / pointing hemorrhage days than the comparator. Furthermore, in the case of the E4-containing preparation, in particular the combination of E4 and DRSP, the absence of regression bleeding (also called amenorrhea) was considerably less than with the comparison. Finally, the average number of days with unscheduled / bloated hemorrhages by cycle is also significantly less with the 15 mg E4 / DRSP combination as compared with the E2V / DNG preparation The This was also the case when compared to publicly available data on commercially available mixed oral contraceptives containing nomegestrol acetate (NOMAC) and E2 as estrogen.

  In addition, the daily use of currently marketed estrogens (ethynyl estradiol (EE), E2, E2V, conjugated equine estrogens) involves dose proportionality of triglyceride levels. High levels of triglycerides in the bloodstream in the human body have been linked to atherosclerosis and also to the risk of heart disease and stroke. In contrast to currently available estrogens, E4 only increases triglyceride levels to a minimum, even at higher doses.

  Finally, the use of mixed contraceptives has been associated with an increased risk of venous thromboembolism events (VTEs). Compared to non-users, the use of second generation COC doubles the risk of VTE and the use of third and fourth generation COC quadruples the risk. The absolute risk of VTE associated with the use of certain mixed contraceptives can only be assessed during very large epidemiological trials. However, as desired by the European Medicinal Agency, some surrogate markers of VTE risk can be measured in smaller clinical settings to estimate risk.

  As shown in Example 4, from the clinical results obtained with the combination of E4 and DRSP or LNG, the change of the surrogate marker of VTE is Yaz ® (combination of 20 μg EE and 3 mg DRSP) Was minimal compared to the change observed when using DRSP is a fourth generation progestin with the highest risk of VTE when combined with synthetic estrogens EE. Thus, the changes in surrogate markers of VTE seen with combinations of EE and DRSP are significant. By comparison, the change observed with the E4 combination is minimal even with the combination of DRSP and estrogen. For example, the change in SHBG plasma levels observed when E4 was accompanied by 3 mg of DRSP was observed when SHBG augmentation was observed when using a combination of 20 μg of EE and 3 mg of DRSP (Yaz (treatment cycle 3 Significantly less than the 306.3% mean change percentage of the registered trademark) (at treatment cycle 3, 7.9% of the 5 mg E4 / 3 mg DRSP group and 44 of the 10 mg E4 / 3 mg DRSP group). .5% average change percentage). A similar positive pattern of change was observed when using 14 additional surrogate markers of VTE measured in this trial.

Methods of Treatment The method usually employs uninterrupted oral administration of the estrogenic and progestogenic components for a period of at least 10 days, preferably at least 20 days.

  As used herein, the term "continuous" means that the components are administered at relatively regular intervals, with no (therapeutically) significant interruption. Of course, small interruptions that do not affect the overall effectiveness of the method can occur, and indeed such deviations are encompassed by the present invention. In a preferred embodiment, more arithmetically, if the maximum interval between two subsequent administrations is less than or equal to 3.5 times the average interval, the dosing regimen appears to be continuous Be Even more preferably, said longest interval is less than or equal to 2.5 times the average interval, most preferably less than or equal to 1.5 times.

  In this method, the estrogen and progestogenic components can be administered in separate dosage units. However, it is also possible to combine these two components into a single dosage unit, which is, in fact, very advantageous.

  In the methods of the present invention, the combination of progestogenic and estrogenic components is suitably administered continuously for at least 10 days.

  The invention can also be practiced in the form of various administration methods known to those skilled in the art. Among these methods is the so-called "combined" method. The combination method is a single-phase preparation containing a dosage unit having a constant amount of estrogen and progestogen, or in most cases, a variation consisting of a relatively constant level of estrogen and progestogen over time throughout the cycle Use biphasic or triphasic preparations with different levels of estrogen and progestogen. The combination methods have in common that they are based on a treatment plan that results in a withdrawal bleeding that simulates natural menstruation, with intervals of about 7 days without dosing. Thus, 21 day intervals of hormone administration alternate with 7 days where no hormone is administered.

  In a preferred embodiment of the method of the invention, a non-administrative interval of about 4 days is used. In this embodiment, the 24 day interval of hormone administration alternates with 4 days where no hormone is administered.

  In yet another preferred embodiment of the method of the present invention, the 24-day interval of hormonal administration at which the estrogen component and the progestogenic component are administered, and four days at which only the estrogen component is administered (days 25 to 28) Day) happens alternately.

  A so-called "continuous" method has been proposed as an alternative to the above combined method. Unique to the continuous method is that it comprises two continuous phases: one phase in which estrogen is administered and no progestogen is administered and another phase in which the combination of estrogen and progestogen is administered. is there. The first continuous method, such as the combination method above, utilizes a dosing interval of about 7 days. More recently, there is a continuous method which means that estrogen is administered throughout the entire cycle and that progestogen is co-administered for only part of that cycle, without the non-administrative (or placebo) phase. ,Proposed. WO 95/17895 (Ehrlich et al.) Describes such an uninterrupted continuous process.

  Yet another example of a method encompassed by the present invention is a special version of a combination method using uninterrupted co-administration of progestogenic and estrogenic components for extended periods of time, eg, more than 50 days There is a so-called "continuous combined" method. In contrast to the conventional combination and continuous methods, continuous administration of progestogen in the amounts indicated induces amenorrhea so that regular menstruation does not occur with continuous combination.

  In one embodiment of the invention in connection with a continuous combination method, the method comprises uninterrupted combination of an estrogenic component and a progestogenic component for a period of at least 28 days, preferably at least 60 days. Includes oral administration.

  In another embodiment of the invention relating to continuous and combined methods using significant non-administrative intervals, the methods of the invention result in the progestogenic and estrogenic components being not administered A reduction in serum concentrations of progestogenic and estrogenic components induces an menstruation comprising an interval of at least 2 days, preferably 3 to 9 days, most preferably 5 to 8 days.

  Yet another embodiment of the present invention directed to a continuous method without significant rest comprises continuous oral administration of the estrogen component for a period of at least 28 days, preferably at least 60 days, and the estrogen component and pro After co-administration of the guestogen component (progestogenic component), the estrogen component is administered for 3 to 18 consecutive days, preferably for 5 to 16 consecutive days, and the progestogenic component is not administered, resulting in The lowering of the serum concentration of the progestogenic component is characterized in that it should usually be sufficient to induce menstruation.

  According to the invention, the composition for use in the method of reducing dysmenorrhea symptoms comprises VTE, headache, chest pain etc., preferably comprising VTE, headache and chest pain, more preferably, It is possible to reduce the number, frequency and / or severity of adverse side effects, including VTE and most preferably VTE. The compositions of the present invention are particularly useful for the effective treatment of dysmenorrhea symptoms while reducing the side effects of VTE with relatively low frequency and severity.

  In certain embodiments of the invention, the method does not cause hemostatic changes beyond the boundaries of the normal range. As used herein, “hemostatic change” refers to sex hormone binding globulin (SHBG), free tissue factor pathway inhibitor (free TFPI), free and total protein S, protein S upon administration of the composition of the present invention. Activity, corticosteroid binding globulin (CBG), ceruloplasmin, antithrombin III, activated protein C (APC) resistant (eg 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 Fluctuation and definition of plasma level of multiple markers It is.

  The markers listed above are well known to the person skilled in the art and methods for determining their level are within the general general knowledge of the person skilled in the art.

  As used herein, "normal range" when referring to the level of a hemostatic marker refers to the predicted interval into which 95% of the population falls.

  In one embodiment of the present invention, the method does not cause hemostatic changes beyond the boundaries of the normal range after one cycle of treatment, preferably the method hemostatics beyond the boundaries of the normal range after two cycles of treatment Not causing a change, even more preferably, the method does not cause a hemostatic change beyond the boundaries of the normal range after 3 cycles of treatment.

In another particular embodiment of the invention, the method does not cause a change in the level of protein S beyond the boundaries of the normal range.
In another particular embodiment of the invention, the method does not cause changes in the level of free TFPI beyond the boundaries of the normal range.

Composition The estrogen component of the present invention is preferably an estetrol component, which is an estetrol; a hydrocarbon carboxylic acid of 1 to 25 carbon atoms, at least one hydrogen atom of a hydroxyl group, sulfonic acid or Included are substances selected from the group consisting of esters of estetrol which are substituted by the acyl radical of sulfamic acid and combinations thereof. Even more preferably, the estetrol component is estetrol (including estetrol hydrate). Most preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.

  The estetrol component of the present invention may be used at a daily dose of 0.1 mg to 100 mg. Preferably, the estetrol component of the invention is used at a daily dose of 1 mg to 40 mg. Even more preferably, the estetrol component of the present invention is used at a daily dose of 5 mg to 25 mg. Even more preferably, the estetrol component of the invention is used at a daily dose of 10 mg to 20 mg.

  In the most preferred embodiment, the estetrol component of the invention is used at a daily dose of about 15 mg.

  In other embodiments, the dosage can be varied throughout the cycle (biphasic, triphasic or tetraphasic administration).

  Examples of progestogenic components which can be suitably used according to the invention are levonorgestrel, norgestimate, norethisterone, didorgesterone, drospirenone, 3-β-hydroxydesogestrel, 3-ketodesogestrel, 17-deacetylnorge. Sumimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, amgestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethythelone, ethinodiol diacetate, flurogestone acetate, gastrinone, Guestden, gestrinone, hydroxymethyl progesterone, hydroxy progeste , Linestrenol, mecylogestone, medroxyprogesterone, megestrol, mele, gesterol (mele, gestrol), nomegestrol, norethindrone, norethynodrel, norgestrel (including d-norgestrel and di-norgestrel) Norgestolione, normethisterone, progesterone, kingestanol, (17α) -17-hydroxy-11-methylene-19-norpregna-4, 15-diene-20-in-3-one, tibolone, trimegestone, algestone -Acetophenide, Nestorone, Promegestone, 17-hydroxyprogesterone ester, 19-nor-17 hydroxyproges Ron, 17α-ethynyltestosterone, 17α-ethynyl-19-nortestosterone, d-17β-acetoxy-13β-ethyl-17α-ethynylgon-4-en-3-one oxime, 6β, 7β; 15β, 16β-dimethylene-3- Oxo-17-pregna-4,9 (11) -diene-21, 17β-carbolactone or tanaproget and releasing these progestogens in vivo when used in the method The precursor of these compounds which can be mentioned is mentioned.

  Preferably, the progestogen components used in the method are progesterone, desogestrel, gestodene, dienogest, levonorgestrel, norgestimate, norethisterone, drospirenone, trimegestone, didgergesterone, precursors of these progestogens. And a mixture of these.

  When the progestogenic component of the invention is drospirenone, it is preferably used at a daily dose of 0.5 mg to 10 mg, even more preferably 1 mg to 4 mg. In the most preferred embodiment, the progestogenic component of the invention is drospirenone and is used at a daily dose of about 3 mg.

  If a different progestogenic component is used, preferably the daily dose is 1 mg to 4 mg dose of drospirenone so as to bring about the same pharmacological effect as the dose of 0.5 mg to 10 mg drospirenone It is adjusted to bring about the same pharmacological effect.

  In a preferred embodiment of the invention, the composition combines 5 mg to 25 mg daily dose of estetrol and 0.5 mg to 10 mg daily dose of drospirenone. In a more preferred embodiment of the invention, the composition combines 10 mg to 20 mg daily dose of estetrol and 1 mg to 4 mg daily dose of drospirenone. In an even more preferred embodiment of the invention, the composition combines about 15 mg daily dose of estetrol and about 3 mg daily dose of drospirenone.

  The invention has been described above with reference to several exemplary embodiments. Modifications and alternative implementations of several parts or elements are possible and included within the scope of protection as defined in the appended claims.

Example 1
During the study, healthy female subjects were treated with 10 or 20 mg E4 alone (n = 10 and 11, respectively) or E4 in combination with either progesterone (P) or desogestrel (DSG) (n = 15 or The treatment was carried out for one 28-day cycle using any one of 16, respectively.

  At baseline, occasional dysmenorrhea was reported by 11 subjects (21.2%) and frequent dysmenorrhea was reported by 19 subjects (36.5%). The distribution of dysmenorrhoea is shown in Table 2 below. Overall, dysmenorrhoea was reported by 25% to 53.3% of subjects included in this trial.

  As shown in Table 3 for adverse events (TE-AE) that occurred under treatment below, there were less reports of dysmenorrhea during the treatment phase compared to the morbidity recorded at baseline. Interestingly, E4 alone appeared to have a positive effect on the prevalence of dysmenorrhea without any dose-related proportions.

Example 2
In this clinical study comparing different doses and different combinations of estrogenic and progestogenic components according to the invention, overall, at baseline, 68.9% of subjects have ever experienced dysmenorrhea And occasionally in 40.4% of subjects was frequent in 28.5% of subjects.

  Dysmenorrhoea is a progestogen, as shown in Table 4 below, extracted from treatment-emergent adverse events (TE-AE) reported by at least two subjects in any treatment group When the (progestogenic) component was drospirenone, it was reported more rarely than when it was levonorgestrel.

  Furthermore, it is also surprisingly found in Table 4 that the lowest dose of estrogen component (15 mg daily) leads to less reporting of dysmenorrhea as TE-AE than the higher dose (20 mg daily). Be

  Finally, dysmenorrhea TE-AE leading to the interruption 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%).

Example 3
The combination of an estrogenic component and a progestogenic component according to the invention is also carried out 1, with a dose of 0, 2 or 3 mg of dienogesto, marketed similarly as natural estrogen (Bayer HealthCare, Germany as Qlaira®). Drug-related adverse events (on the treatment reported by at least two subjects in any treatment group) in this clinical study compared to over-the-counter contraceptive treatment using a 2 or 3 mg dose of estradiol valerate) The number of adverse events (TE-AE)) and the level of SHBG markers were monitored.

  As shown in Table 5 below, 13 subjects (equivalent to 16.7%) were treated with headache-related TE in the treatment group using a commercial product based on estradiol valerate and dienogest -Only 6 subjects (corresponding to 7.6%) were reported in the group reporting AE and treated with a combination of 15 mg estetrol and 3 mg drospirenone. Thus, the number of headache-related events has been shown to be quite low for the treatment of the present invention.

  In addition, the number of adverse events associated with chest pain was similar and extremely low for the two treatments (appearance of only 1.3%).

  In addition to this study, the combination of E4 / DRSP and E2V / DNG to women (group of patients called "starter") who started with changes in SHBG concentration, as well as combined contraception Were evaluated sequentially during cycles 4 and 6 of the administration of Women were defined as starters when they did not use hormonal contraceptives three months prior to randomization. This "washout" period allowed the SHBG levels to exclude patients affected by previous COCs used.

  The results in terms of change from baseline are shown in Table 6 below.

  As is apparent from Table 6, the methods of the present invention minimize SHBG level changes from baseline to both cycles 4 and 6 as compared to commercially available COCs that also use natural estrogens. Make it possible.

Example 4
20 μg ethynyl estradiol with 3 mg drospirenone marketed as contraceptive treatment (Yaz® by Bayer HealthCare, Germany) as a combination of two of the estrogenic component and the progestogenic component according to the invention. In this clinical study compared to used), several hemostatic markers as well as carrier proteins are measured and changes from baseline to the end of cycle 3 in these parameters are presented below in Table 7.

  A big difference was observed between the DRSP combination containing 20 μg of EE and those using 5 or 10 mg of E4: prothrombin fragment 1 + 2 plasma levels of the procoagulant marker are reduced when using different E4 / DRSP combinations However, it increased when using EE / DRSP (+ 63% from baseline 3 months use). These opposite results indicate that an increase in the thrombosis marker prothrombin fragment 1 + 2 is linked to the type of estrogen (here EE vs E4) (and dose). Furthermore, natural anticoagulants are not altered (antithrombin III, protein S activity) or slightly reduced (free TFPI) by the combination containing E4, and usually reduced by EE / DRSP. As before, activated partial thromboplastin time (APTT), which is related to sensitivity to APC, hardly changes in all preparations, but normalized APC sensitivity ratio used E4 combination Although unaltered, resistance to protein C was strongly increased by the EE / DRSP combination. When using a combination of E4 and DRSP, there was a slight reduction in fibrinolytic parameters such as tPA and D-dimer levels, as well as no procoagulant marker increase.

  The SHBG increase was significant (+ 306%) when using the EE / DRSP combination. All combinations of E4 (5, 10 mg) and DRSP showed a moderate increase in SHBG. It should be noted that SHBG is considered to be the most relevant biomarker of the estrogenic effect of COC on liver metabolism (Odlind V. et al .; Acta Obstet Gynecol Scand 2002; 81: 482).

  CBG and ceruloplasmin are basically synthesized under the influence of estrogen and are considerably less sensitive to the androgenic action of progestins. In the E4 and DRSP groups, increasing the dose of estrogen resulted in a slight increase from baseline for CBG and ceruloplasmin. However, a much greater change from baseline was observed in the EE / DRSP group compared to the E4 treatment group.

Example 5
A multicenter open label placebo controlled randomized study was conducted to evaluate the benefits of the method of the present invention for reducing dysmenorrhea complaints.

  The study population consisted of healthy female subjects (at the time of screening), including 12 to 35 years, with primary dysmenorrhoea (onset <3 years after menarche).

  The product of the method of the invention is administered orally once daily on a continuous or 24/4 day treatment regimen (ie 24 days of active tablet followed by 4 days of placebo tablet) (15 mg) And drospirenone (3 mg). In addition to the placebo dose group, the adjuvant dose group included other doses of estetrol.

  The efficacy of the method of the invention was mainly demonstrated by following the change between the baseline and treatment evaluation periods in terms of the number of days with dysmenorrhea pain.

  Dysmenorrhagic pain was defined as a menstrual / recurrent bleeding episode and pelvic pain during the two days prior to this episode.

Second, efficacy was followed by daily scoring of dysmenorrhea pain according to the following scale.
0-no pain;
1- Mild pain, no need for analgesics;
2-Moderate pain, need for analgesics;
3-Severe pain, need for analgesics.

Further efficacy evaluations were performed as follows:
1. Changes between baseline evaluation period and end of treatment evaluation period, in terms of days with pelvic pain, independent of the occurrence of vaginal bleeding
2. The change between the baseline and treatment evaluation periods, regarding the number of days with pelvic pain during unplanned bleeding,
3. Change between baseline and treatment evaluation period for Rescue medication Use. Rescue medication Use is a standardized intake of 200 mg ibuprofen tablets.
4. Percentage of participants with dysmenorrhea pain that interfered with work / school and society or other activities,
5. Percentage of participants and time / day, with dysmenorrhea pain taking work away from work, at baseline, 3 months and final exam (after 6 months)
6. Percentage of participants satisfied with study treatment,
7. Physiotherapy, alternative medicine, acupuncture, osteopathy, medical counseling, massage, herbs in the treatment of dysmenorrhea pain, as assessed by filling in Resource Use Questionnaire (converted for Europe) System supplement / tea own cost,
8. Improvement of the patient during the course of the study, according to the Clinical Global Impression Scale (CGI), filled out by the researcher
9. The Clinical Global Impression Scale (CGI) written by the participants, which is the participant's assessment in the clinical global impression, and its improvement scores during the course of the study,
10. General, as assessed by the General Health and Well-being Questionnaire SF-36, at baseline, at 3 months and at the final exam, using the SF-36 self-administered questionnaire Health, physical pain, physical function and social function, mental health and vitality, a measure of general health used to assess patient populations and to compare health status across different populations.

  Clinical studies demonstrate that the product of the method of the invention is effective in ameliorating the symptoms of dysmenorrhea.

Claims (17)

  A composition for use in a method of reducing dysmenorrhea symptoms in humans, comprising an effective amount of an estetrol ingredient.   The composition for use according to claim 1, further comprising a progestogenic component.   3. The method according to claim 1 or 2, wherein said method results in the reduction of one or more of the number, frequency and severity of treatment related side effects when compared to other dysmenorrhea treatments of similar efficacy. Composition for use.   The progestogen component comprises progesterone, desogestrel, gestodene, dienogest, levonorgestrel, norgestimate, norethistrone, drospirenone, drospirenone, trimegestone, didrogesterone, precursors of these progestogens, and mixtures thereof A composition for use according to claim 3, selected.   A composition for use according to claim 4, wherein the progestogenic component is drospirenone.   A composition for use according to any one of the preceding claims, wherein the estetrol component is used in a daily dose of 1 mg to 40 mg, preferably in a daily dose of 5 mg to 25 mg.   Composition for use according to claim 5, wherein drospirenone is used in a daily dose of 0.5 mg to 10 mg, preferably in a daily dose of 1 mg to 4 mg.   8. The use for any one of claims 1 to 7, wherein the method of administration is a combination method with a non-administration interval of about 7 days, preferably with a non-administration interval of about 4 days. Composition.   9. Composition for use according to any one of the preceding claims, wherein the estetrol component is estetrol, preferably estetrol monohydrate.   10. A composition for use according to claim 9, comprising a daily dose of about 15 mg of estetrol.   11. The composition for use according to claim 10, further comprising about 3 mg daily dose of drospirenone.   A composition for use according to any of the preceding claims, formulated as an oral dosage unit.   13. The composition for use according to claim 12, wherein the oral dosage unit is formulated to correspond to a daily dosage unit.   A composition for use according to any one of the preceding claims, wherein the dysmenorrhoic condition is ameliorated after one cycle of administration.   15. The composition for use according to claim 14, wherein the dysmenorrhea symptom grade is improved by at least one unit.   A composition for use according to any one of the preceding claims, wherein the hemostatic change does not exceed the boundaries of the normal range after one cycle of administration. The following dosing patterns:
-Alternating with a 4-day interval (days 25 to 28) in which only the estrogen component is administered-a 24-day interval in which the estrogen component and the progestogenic component are administered, said claim being used Composition for use according to any one of the preceding claims.