KR102780201B1 - How to manage menstrual cramps and menstrual pain - Google Patents

Abstract

The present invention relates to a method for the management of menstrual cramps, preferably involving the administration of an estrogen component selected from the group consisting of estetrol and estetrol-like compounds. Surprisingly, it has been found that estetrol-like compounds, when used alone or in combination with a progestogen component, are capable of alleviating menstrual cramps, with a favorable side-effect profile compared to currently available methods and to an extent that surpasses the results obtained with other compositions.

Description

How to manage menstrual cramps and menstrual pain

The present invention relates to a method for alleviating symptoms of menstrual cramps in a human, comprising administering to said human an effective amount of an estrogen component. In particular, the estrogen component is an estetrol component as further described herein, wherein said method enjoys a favorable 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 menstruation. Most women experience dysmenorrhea during adolescence, usually within four to five years of their first menstrual period. Painful periods become less common as women age. For clinical purposes, dysmenorrhea is divided into two broad categories: primary dysmenorrhea and secondary dysmenorrhea.

Primary dysmenorrhea refers to the presence of recurrent, crampy lower abdominal pain that occurs during menstruation, without a demonstrable disease that can cause this symptom.

Secondary dysmenorrhea has the same clinical characteristics, but occurs in women who also have conditions that can cause these symptoms, such as endometriosis, adenomyosis, or uterine fibroids.

Primary dysmenorrhea

It has been reported that between 50 and 90 percent of reproductive-aged women have experienced painful menstrual periods. The majority of these women are young and have primary dysmenorrhea. The prevalence of primary dysmenorrhea decreases with age (Sundell G. et al.; Br J Obstet Gynaecol 1990; 97:588).

Primary dysmenorrhea has been associated with alterations in prostaglandin synthesis and metabolism. Prostaglandins released from the sloughing endometrium during the early menstrual period play an important role in the induction of contractions (Ylikorkala O, Dawood MY.; Am J Obstet Gynecol 1978; 130:833).

Pain begins one to two days before or with the onset of menstrual bleeding and gradually lessens over 12 to 72 hours. It is recurrent and occurs during most, if not all, menstrual cycles. The pain is usually crampy and intermittently severe, but can be a constant dull ache. It is usually confined to the lower abdomen and suprapubic area. The pain is usually strongest in the midline, but some women also have severe back pain and/or thigh pain.

Pain severity ranges from mild to severe (Table 1 below) (Andersch B, Milsom I.; Am J Obstet Gynecol 1982; 144:655).

The “dysmenorrhea symptom scale” used in our hospital corresponds to the scores obtained by applying the evaluation presented in Table 1.

[Table 1 - Verbal multidimensional scoring system for the assessment of dysmenorrhea]

It is important to note that there are no physical findings associated with primary dysmenorrhea, and primary dysmenorrhea is not associated with abnormal findings on imaging studies or any laboratory abnormalities. Therefore, diagnosis should be made to ensure that the patient does not have signs of other diseases that could be the cause of the pain. In particular, diseases such as endometriosis, adenomyosis, fibroids, and ovarian cysts have been associated with secondary dysmenorrhea.

Primary Treatment Options for Menstrual Pain

Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered first-line treatment (Proctor M, Farquhar C; Clin Evid 2003; :1994 - Zhang WY, 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 menstruation and continued for the first day or two of the menstrual cycle or for the usual duration of crampy pain. Patients with severe symptoms should start taking NSAIDs one or two days before the onset of menstruation.

Combined oral contraceptive pills (COCs) may be given to patients who do not respond to or cannot tolerate NSAIDs (Davis AR, et al.; Obstet Gynecol 2005; 106:97). COCs prevent menstrual cramps by suppressing ovulation, thereby reducing uterine prostaglandin levels. Additional mechanisms may result from a decrease in menstrual flow after several months of use.

In sexually active women, COCs may be considered first-line treatment because they serve a dual purpose: preventing both pregnancy and dysmenorrhea.

A systematic review of randomised trials of estrogen-progestin contraceptive pills for the treatment of primary dysmenorrhea reported a significant benefit of treatment (pooled OR of 2.99, 95% CI 1.76 to 5.07) (Wong CL, et al.; Cochrane Database Syst Rev 2009; :CD002120).

Few trials have compared different doses of estrogen for the treatment of primary dysmenorrhea; reviews concluded that pain relief was similar for low (≤35 mcg) and high (>35 mcg) estrogen doses, and that there were no clear differences in efficacy between different pill preparations.

However, additional data from observational studies and other randomized trials have supported the efficacy of very low-dose estrogen pills for the treatment of dysmenorrhea (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).

However, all these approaches have relied on COCs, which use synthetic estrogens such as ethinyl estradiol (EE). In these cases, there is a risk of (dose-dependent) unwanted side effects, including thromboembolism, fluid retention, nausea, bloating, cholelithiasis, headache and breast pain.

Of particular importance is the fact that estrogen participates in the regulation of the synthesis of various 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. Under the influence of strong estrogens such as EE, changes in these haemostasis markers may collectively contribute to the creation of an imbalance between pro- and anti-coagulation factors, which may increase the risk of venous thromboembolism (VTE) events.

SHBG plasma levels are a reliable marker of the influence of estrogens on the synthesis of this protein by hepatocytes. This suggests that a correlation may exist between the levels of SHBG induced by specific COCs and the risk of VTE associated with these COCs (Odlind V, et al.; Acta Obstet Gynecol Scand 2002; 81:482).

Cohort studies conducted on sufficient numbers of subjects are needed to assess the risk of VTE with specific COCs, and different markers of haemostasis and carrier proteins (such as SHBG) may be measured to assess this risk in a limited number of subjects.

Therefore, there remains a need for therapeutic approaches that, on the one hand, have as few side effects as possible in the management of menstrual pain, while, on the other hand, demonstrating high efficiency.

The present invention relates to a method for alleviating symptoms of dysmenorrhea in a human, comprising administering to said human an effective amount of an estrogen component. In particular, said estrogen component is an estetrol component as further described herein, wherein said method enjoys a favorable side effect profile compared to currently available methods.

In one aspect of the present invention, one or more of the number, frequency, and severity of treatment-related adverse effects is reduced compared to other dysmenorrhea treatments of similar efficacy.

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

In another embodiment of the present invention, hemostatic changes exceeding the normal range boundaries further described herein do not occur upon administration of the composition of the present invention.

In a further embodiment of the present invention, the number, frequency and/or severity of headaches is reduced compared to other antimenstrual pain treatments of similar efficacy.

In another aspect of the present invention, the number, frequency and/or severity of breast pain events is reduced compared to other antimenstrual pain treatments of similar efficacy.

In one aspect of the invention, the method involves administering effective amounts of an estrogen component and a progestogen component.

In some embodiments of the invention, the estrogen component and the progestogen component are contained in a single dosage unit. In a further embodiment, the dosage unit is a daily dosage unit.

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

In another further embodiment, the estrogen component is used in a daily dosage of 1 mg to 40 mg, preferably in a daily dosage of 5 mg to 25 mg, more preferably in a daily dosage of 10 mg to 20 mg. In a specific embodiment, the estrogen component is estetrol monohydrate.

In certain embodiments of the invention, the estrogen component is estetrol monohydrate in a daily dosage of about 15 mg and the progestogen component is drospirenone in a daily dosage of about 3 mg.

The method of the present invention utilizes estrogen components that are natural estrogens (i.e., found in nature) and biogenic estrogens (i.e., naturally occurring in the human body).

Since biogenic estrogens are naturally present in the fetus and the female body, a good tolerability and safety profile is observed, especially when serum levels resulting from exogenous administration of these estrogens do not significantly exceed naturally occurring concentrations. A direct consequence of this good tolerability is the favorable side effect profile achieved by the method of the present invention compared to other methods.

definition

The term "estrogen component" as used throughout this document, when utilized in accordance with the present invention, includes not only substances capable of triggering an estrogenic response in vivo, but also precursors capable of liberating such estrogenic components in vivo. In order for estrogenic components to trigger such a response, they must generally bind to estrogen receptors found in various tissues within the mammalian body.

The estrogen component of the present invention is preferably an estetrol component. The term "estetrol component" as used throughout this document includes a substance selected from the group consisting of estetrol, esters of estetrol, and combinations thereof, wherein at least one hydrogen atom of a hydroxyl group is replaced by an acyl radical of a hydrocarbon carboxylic acid, a sulfonic acid or a sulfamic acid having 1 to 25 carbon atoms. 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 agent" is defined as a substance capable of triggering a progestogenic response in vivo, or a precursor capable of liberating such a substance in vivo. Typically, a progestogenic agent is capable of binding to a progestogen receptor.

The term "about" as used herein to indicate a measurable value, including a parameter, an amount, a temporal duration, and the like, is intended to include variations of +/- 10% or less, more preferably +/- 5% or less, and even more preferably +/- 1% or less, and variations from the stated value, so long as such variations are suitable to perform the disclosed invention. However, it will be understood that the value to which the modifier "about" refers is also specifically disclosed per se.

The term "effective amount" means an amount sufficient to achieve a physiological effect. The physiological effect may be achieved by a single dose or by repeated doses. In particular, an "effective amount" means an amount effective to reduce, eliminate, treat or control the symptoms of menstrual cramps. The term "control" is intended to mean any process that may slow, hinder, arrest or stop the progression of menstrual cramps, but does not necessarily imply complete elimination of menstrual cramps, and is intended to include prophylactic treatment and chronic use.

As described in Example 5, the method of the present invention for relieving symptoms of menstrual cramps has been surprisingly proven to be effective even when used at a low daily dosage. Without wishing to be bound by theory, the inventors of the present invention believe that the superiority of the method of the present invention is due in part to the remarkable effect of the estetrol component which can relieve menstrual cramps per se, as illustrated by the clinical results shown in Example 1.

In fact, while it is known that administration of low doses of estrogen reduces menstrual migraine, this effect has not always been reported for dysmenorrhea. The uniqueness of the present discovery that the estetrol component can alleviate the symptoms of dysmenorrhea when administered alone according to the method of the present invention allows for such symptoms to be reduced. In one particular embodiment of the method, the estetrol component is administered alone during the progestin-free interval of the treatment method according to the present invention, as further described below.

A significant number of scientific publications have characterized estrogen as a weak estrogen, so it is all the more unexpected that such a positive effect on the management of dysmenorrhea symptoms would not have been observed at the doses used in the clinical trials reported in the examples.

Without wishing to be bound by theory again, the inventors of the present invention believe that the superiority of the present method is also due to the stimulatory effect of the estrogen component on the endometrium - particularly compared to the stronger stimulatory effect of ethinyl estradiol, the estrogen used in many COCs. As a result, it has been found that the endometrial thickness is strongly reduced upon administration of the composition of the present invention. The thin endometrium contains relatively small amounts of arachidonic acid, the substrate for the synthesis of most prostaglandins. As a result of these changes in the endometrium, the composition of the present invention reduces both menstrual flow and uterine contractions during menstruation, thereby reducing menstrual cramps.

Moreover, the method according to the present invention was found to inhibit ovulation in 100% of patients, and inhibition of ovulation decreases uterine prostaglandin levels.

In a comparative study, surprisingly, the combination of estetrol and drospirenone as a progestogen was found to be more effective in managing dysmenorrhea symptoms than the combination of estetrol and levonorgestrel as a progestogen. This is illustrated by the results of the clinical trial reported in Example 2.

Another important advantage of the estetrol component of the present invention derives from its relative insensitivity to interactions with other drugs (drug-drug interactions). It is well known that certain drugs can decrease the effectiveness of estrogens, such as ethinyl estradiol, and that other drugs can enhance their activity - possibly resulting in increased side effects. Similarly, estrogens can 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 such estrogens, whereas the effect of estrogens on other drugs is due to competition for metabolic pathways.

The most clinically significant group of estrogen drug interactions occur with drugs that can induce hepatic microsomal enzymes, which can reduce estrogen plasma levels to subtherapeutic levels (e.g., anticonvulsant agents; phenytoin, primidone, barbiturates, carbamazepine, ethosuximide, and methosuximide; antituberculous drugs such as rifampin; antifungal drugs such as griseofulvin). The estrogenic substances of the present invention do not rely on up- and down-regulation of hepatic microsomal enzymes (e.g., P450) and are insensitive to competition with other P450 substrates. Similarly, they do not significantly interfere with the metabolism of other drugs.

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

The above observations explain why the estrogen component of the present invention suffers little from drug-drug interactions and produces very consistent, i.e. predictable, collisions. Therefore, the efficacy of the estrogen substance of the present invention is very reliable.

Furthermore, while the terminal half-life of naturally occurring estrogens ranges from 2 to 14 hours, estetrol is characterized by a terminal half-life of 31.7 hours. Thus, the use of estetrol in the methods of the present invention allows for a therapeutic coverage of the receptors of more than 24 hours. This pharmacokinetic property enhances the efficacy of the product even in cases of poor treatment compliance by the user.

It should be noted that when estetrol (E4) is associated with 3 mg of drospirenone (DRSP) or 150 μg of levonorgestrel (LNG), the bleeding profile and cycle control are improved compared to other combined oral contraceptives using physiological estrogens, i.e. estradiol-valerate (E2V) or estradiol (E2).

In a study evaluating bleeding patterns and cycle control of different E4/DRSP or E4/LNG combinations, both the 15 mg E4/DRSP and 20 mg E4/LNG combinations were associated with a lower incidence of unscheduled bleeding/spotting days than the comparators, compared with a marketed quadriphasic combined oral contraceptive containing E2V and desogestrel (DSG). Furthermore, the absence of withdrawal bleeding (also referred to as amenorrhea) was significantly reduced with the E4-containing formulations compared with the comparators, particularly when E4 was associated with DRSP. Finally, the mean number of days per cycle with unscheduled bleeding/spotting was also reduced more with the 15 mg E4/DRSP combination than with the E2V/DNG formulation. This was also the case when compared with publicly available data on marketed combined oral contraceptives containing E2 as an estrogen, particularly with respect to nomegestrol acetate (NOMAC).

Moreover, daily use of currently available estrogens (ethinylestradiol (EE), E2, E2V, conjugated equine estrogens) is associated with a dose-proportional increase in triglyceride levels. In humans, high blood triglyceride levels have been linked to atherosclerosis and, by extension, the risk of heart disease and stroke. In contrast to currently available estrogens, E4 causes minimal increases in triglyceride levels even at higher doses.

Finally, combined contraceptive use is associated with an increased risk of venous thromboembolic events (VTE). Compared with non-users, use of second-generation COCs increases the risk of VTE by twofold, and use of third- and fourth-generation COCs increases the risk by fourfold. The absolute risk of VTE associated with the use of a particular combined contraceptive can only be estimated during very large epidemiological trials. However, as requested by the European Medicines Agency, several surrogate markers of VTE risk have been measured in smaller clinical settings to allow for an estimate of risk.

As described in Example 4, from the clinical outcomes obtained with the combination of E4 and DRSP or LNG, the changes in surrogate markers of VTE were minimal compared to the changes measured with Yaz® (combination of 20 μg EE and 3 mg DRSP). DRSP is the fourth generation progestin associated with the highest risk of VTE when combined with the synthetic estrogen EE. Therefore, the changes in surrogate markers of VTE seen with the combination of EE and DRSP are significant. In comparison, the changes observed with the E4 combination are minimal even when DRSP is combined with estrogen. For example, the SHBG plasma level changes observed in association with E4 in combination with 3 mg DRSP were significantly lower (mean percentage change of 7.9% for the 5 mg E4/3 mg DRSP group and mean percentage change of 44.5% for the 10 mg E4/3 mg DRSP group at cycle 3) than the SHBG increases observed with the combination of 20 μg EE and 3 mg DRSP (mean percentage change of 306.3% for Yaz® at cycle 3). The same positive pattern of change was observed with 14 additional surrogate markers of VTE measured in this trial.

Treatment method

The method of the present invention utilizes uninterrupted oral administration of an estrogen component and a progestogen component, typically for a period of at least 10 days, preferably at least 20 days.

The term "uninterrupted" as used herein means that the components are administered at relatively regular intervals without (therapeutically) significant interruptions. Naturally, minor interruptions may occur which do not affect the overall effectiveness of the method of the present invention, and in fact such aberrations are encompassed by the present invention. In a preferred embodiment, more arithmetically, the dosing regimen is considered continuous if the longest interval between two subsequent administrations is longer than the mean interval but less than 3.5 times. Even more preferably, said longest interval is longer than the mean interval but less than 2.5 times, and most preferably, said longest interval is longer than the mean interval but less than 1.5 times.

In the method of the present invention, the estrogen component and the progestogen component may be administered in separate dosage units. However, it is also possible and in fact very convenient to combine these two components in a single dosage unit.

In the method according to the present invention, the combination of a progestogen component and an estrogen component is suitably administered without interruption for a period of at least 10 days.

The invention can be suitably adapted to be practiced in the form of various administration methods known to those skilled in the art. The so-called "combined" method is one of these methods. In most cases containing a relatively constant level of estrogen with a stepwise increase in progestogen throughout the cycle, the combined method uses a monophasic preparation containing dosage units with constant amounts of estrogen and progestogen, or a biphasic or triphasic preparation with varying levels of estrogen and progestogen. The combined method has in common that it is based on a regimen with a non-administration interval of about 7 days, which results in withdrawal bleeding simulating natural menstruation. Thus, 21-day intervals of hormone administration can alternate with 7 days of hormone-free administration.

In a preferred embodiment of the method of the present invention, a non-administration interval of about 4 days is utilized. In this embodiment, 24-day intervals of hormone administration may alternate with 4 days of hormone-free administration.

In another preferred embodiment of the method of the present invention, 24-day intervals of hormone administration in which estrogen and progestogen components are administered alternate with 4 days (days 25 to 28) in which only estrogen components are administered.

As an alternative to the above-mentioned combination method, the so-called "sequential" method has been proposed. The sequential method comprises two consecutive phases, i.e. one phase in which estrogen is administered but no progestogen is administered, and another phase in which a combination of estrogen and progestogen is administered. The first sequential method used a non-administration interval of about 7 days, similar to the above-mentioned combination method. More recently, a sequential method has been proposed which does not include a non-administration (or placebo) period, meaning that estrogen is administered throughout the entire cycle and a progestogen is co-administered only during a part of this cycle. WO 95/17895 (Ehrlich et al.) describes such an uninterrupted sequential method.

Another example of a method encompassed by the present invention is the so-called "continuous combined" method, which is a specific version of a combination method utilizing uninterrupted combined administration of a progestogen component and an estrogen component for an extended period of time, for example, more than 50 days. In contrast to the usual combined and sequential methods, in the continuous combined method, the continuous administration of the indicated amount of progestogen induces amenorrhoea, so that regular menstruation does not occur.

In one embodiment of the present invention involving a continuous combination method, the method comprises uninterrupted oral administration of a combination of an estrogen component and a progestogen component for a period of at least 28 days, preferably at least 60 days.

In another embodiment of the present invention involving sequential and combined methods utilizing significant non-administration-intervals, the methods of the present invention comprise an interval of at least 2 days, preferably 3-9 days, most preferably 5-8 days, during which no progestogen component and no estrogen component are administered, resulting in a decrease in the serum concentrations of the progestogen component and the estrogen component inducing menstruation.

Another aspect of the present invention relating to a sequential method without significant pause comprises uninterrupted oral administration of an estrogen component for a period of at least 28 days, preferably at least 60 days, characterized in that after the combined administration of the estrogen component and the progestogen component, the estrogen component is administered for 3 to 18 consecutive days, preferably 5 to 16 consecutive days, and the resulting decrease in the serum concentration of the progestogen component should be sufficient to induce menstruation normally.

According to the present invention, a composition for use in a method for alleviating symptoms of dysmenorrhea can reduce the number, frequency and/or severity of side effects including VTE, headache, breast pain, etc., 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 the effective treatment of dysmenorrhea symptoms while reducing the side effects of VTE to a significantly lower 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, "change in hemostasis" is defined as a change in plasma levels of one or more markers selected from the following, in response to administration of a composition according to the invention: 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. APCr based on APTT or APCr based on ETP), protein-C activity, D-dimer, prothrombin, prothrombin fragment 1+2, factor VII, factor VIII, von Willebrand factor, factor II, PAI-1, tissue type Tissue-type plasminogen (t-PA), plasminogen, E-selectin, and fibrinogen.

The markers listed above are well known to those skilled in the art, and methods for measuring their levels are within the general knowledge of those skilled in the art.

When referring to levels of hemostasis markers, the term “normal range” as used herein refers to the prediction interval within 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 does not cause hemostatic changes beyond the boundaries of the normal range after two cycles of treatment, and more preferably the method does not cause hemostatic changes beyond the boundaries of the normal range after three cycles of treatment.

In another specific 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 specific embodiment of the invention, the method does not cause a change 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 includes a substance selected from the group consisting of estetrol, esters of estetrol and combinations thereof, wherein at least one hydrogen atom of a hydroxyl group is replaced by an acyl radical of a hydrocarbon carboxylic acid, a sulfonic acid or a sulfamic acid having 1 to 25 carbon atoms. 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 can be used in a daily dosage of 0.1 mg to 100 mg. Preferably, the estetrol component of the present invention is used in a daily dosage of 1 mg to 40 mg. More preferably, the estetrol component of the present invention is used in a daily dosage of 5 mg to 25 mg. Even more preferably, the estetrol component of the present invention is used in a daily dosage of 10 mg to 20 mg.

In a most preferred embodiment, the estetrol component of the present invention is used in a daily dosage of about 15 mg.

In other embodiments, dosing may vary throughout the cycle (biphasic, triphasic or isobaric dosing).

Examples of progestogen components that may be suitably utilized according to the present invention include: levonorgestrel, norgestimate, norethisterone, dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel, 17-deacetylnorgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, amgestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate. acetate), gastrinone, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol, mecirogestone, medroxyprogesterone, megestrol, mele, gestrol, nomegestrol, norethindrone, norethynodrel, norgestrel (including d-norgestrel and dl-norgestrel), norgestrienone, normethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4, 15-dien-20-yn-3-one, tibolone, trimegestone, algestone-acetophenide, nestorone, promegestone, 17-hydroxyprogesterone ester, 19-nor-17hydroxyprogesterone, 17alpha-ethynyltestosterone, 17alpha-ethynyl-19-nortestosterone, d-17beta-acetoxy-13beta-ethyl-17alpha-ethynylgon-4-en-3-one oxime, 6beta, 7beta; 15beta, 16beta-dimethylene-3-oxo-17-pregna-4,9(11)-diene-21, 17beta-carbolactone or Tanaproget and precursors of these compounds capable of liberating these progestogens in vivo when used in the present invention.

Preferably, the progestogen component used in the method of the present invention is selected from the group consisting of progesterone, desogestrel, gestodene, dienogest, levonorgestrel, norgestimate, norethisterone, drospirenone, trimegestone, dydrogesterone, precursors of these progestogens, and mixtures thereof.

When the progestogen component of the present invention is drospirenone, it can be preferably used in a daily dosage of 0.5 mg to 10 mg, and more preferably in a daily dosage of 1 mg to 4 mg. In a most preferred embodiment, the progestogen component of the present invention is drospirenone, and it is used in a daily dosage of about 3 mg.

When different progestogen components are used, the daily dosage is adjusted so that, for example, a dosage of 0.5 mg to 10 mg of drospirenone provides the same pharmacological effect, and preferably a dosage of 1 mg to 4 mg of drospirenone provides the same pharmacological effect.

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

The present invention has been described above with reference to many exemplary embodiments. Modifications and alternative implementations of some or all of the elements are possible and fall within the scope of protection defined in the appended claims.

[ Example ]

[ Example 1]

During this study, healthy female subjects were treated with 10 or 20 mg of E4 alone (n=10 and 11, respectively) or in combination with progesterone (P) or desogestrel (DSG) (n=15 or 16, respectively) for one 28-day cycle.

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

[Table 2 - At the baseline report]

As shown in Table 3 of the treatment-emergent adverse events (TE-AEs) below, the incidence of dysmenorrhea during the treatment period was lower than the incidence recorded at baseline. Interestingly, E4 alone appeared to have a positive impact on the incidence of dysmenorrhea without any dose-related proportionality.

[Table 3 - Adverse reactions occurring after treatment]

.

[ Example 2]

In this clinical study comparing different dosages and different combinations of estrogen and progestogen components according to the present invention, overall, at baseline, 68.9% of the subjects had previously experienced dysmenorrhea, 40.4% of the subjects had occasionally experienced dysmenorrhea, and 28.5% of the subjects had frequently experienced dysmenorrhea.

As shown in Table 4 below, which is an excerpt from the treatment-emergent adverse events (TE-AEs) reported by at least two subjects within any treatment group, dysmenorrhea was reported less frequently when the progestogen was drospirenone than when the progestogen was levonorgestrel.

Moreover, quite surprisingly, Table 4 also shows that the lowest dose of estrogen component (15 mg daily) resulted in fewer reports of dysmenorrhea as a TE-AE than the higher dose (20 mg daily).

[Table 4 - Adverse reactions occurring after treatment]

Finally, dysmenorrhea TE-AE leading to discontinuation occurred once in each 20 mg E4 group (1.3%), but did not occur in any of the 15 mg E4 groups (0%).

[ Example 3]

In this clinical study comparing the combination of estrogen and progestogen components according to the present invention with commercially available contraceptive treatments that also utilize natural estrogens (estradiol valerate in doses of 1, 2 or 3 mg and dienogest in doses of 0, 2 or 3 mg, marketed as Qlaira ® by Bayer HealthCare, Germany), the number of drug-related adverse events (treatment-emergent adverse events (TE-AEs) reported by at least two subjects in any treatment group) and the levels of the SHBG marker were monitored.

As shown in Table 5 below, 13 subjects (corresponding to 16.7%) in the treatment arm using the commercially available product based on estradiol valerate and dienogest reported TE-AEs related to headache, whereas only 6 subjects (corresponding to 7.6%) in the group treated with the combination of 15 mg estetrol and 3 mg drospirenone reported TE-AEs related to headache. Thus, the number of headache related reactions appeared to be much lower in the treatment according to the present invention.

Moreover, the number of adverse reactions related to breast pain was similar in both treatments and very low (occurring only in 1.3%).

[Table 5 - Adverse reactions occurring after treatment]

In addition to this study, changes in SHBG concentrations were sequentially assessed at baseline and during Cycle 4 and Cycle 6 of the combination of E4/DRSP and E2V/DNG in women initiating combined contraception (a group of patients called “initiators”). A woman was defined as an initiator if she had not used hormonal contraception in the 3 months prior to randomization. This “wash-out” period allowed the exclusion of patients in whom SHBG levels were affected by previously used COCs.

The results for changes from baseline are presented in Table 6 below.

[Table 6 - At the baseline Cycle 4 and At the baseline [Mean percentage change in SHBG levels to cycle 6]

The present method allows to minimize SHBG level changes from baseline to both cycle 4 and cycle 6 compared to commercial COCs which also utilize natural estrogens, as evident from Table 6.

[ Example 4]

In this clinical study comparing two combinations of estrogen and progestogen components according to the present invention with a commercially available contraceptive treatment (Yaz ®, marketed by Bayer Healthcare, Germany, which uses 20 microg ethinyl estradiol with 3 mg drospirenone), carrier proteins as well as some haemostasis markers were measured and the changes in these parameters from baseline to the end of cycle 3 are presented in Table 7 below.

[Table 7 - E4/ DRSP or EE / DRSP's Concurrent use In women using hemostatic parameters and carrier About protein At the baseline [Mean (SD) percentage change by the end of treatment cycle 3]

E4, estetrol; EE, ethinyl estradiol; DRSP, drospirenone; APC, activated protein C; TFPI, free tissue factor pathway inhibitor; tPA, tissue plasminogen; CBG, corticosteroid-binding globulin; SHBG, sex hormone-binding globulin.

A number of differences were observed between the DRSP combinations containing 20 microg EE and those containing 5 or 10 mg E4: Plasma levels of the procoagulant marker prothrombin fragment 1 + 2 were decreased with the different E4/DRSP combinations, whereas they were increased with EE/DRSP (+63% from baseline to 3 months of use). These contradictory results indicate that the increase in the thrombosis marker prothrombin fragment 1 + 2 is coupled to the type (and dose) of estrogen (here, EE vs. E4). Furthermore, natural anticoagulants were either unchanged (antithrombin III, protein S activity) or slightly decreased (free TFPI) by the E4 containing combinations, whereas they were generally decreased by EE/DRSP. In contrast, as usual, activated partial thromboplastin time (APTT), which is associated with sensitivity to APC, was hardly changed by all agents and the normalized APC sensitivity ratio was not altered by the E4 combination, whereas resistance to protein C was strongly increased by the EE/DRSP combination. With the combination of E4 and DRSP, there was a slight decrease in fibrinolysis parameters such as tPA and D-dimer levels, concomitant with a non-increase in procoagulant markers.

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

CBG and ceruloplasmin are synthesized essentially under the influence of estrogen and are much 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, by far the greatest change from baseline was observed in the EE/DRSP group compared to the E4 treatment group.

[ Example 5]

A multicenter, open label, placebo-controlled, randomised study was conducted to evaluate the benefit of the present method for alleviating the complaint of menstrual pain.

The study population consisted of healthy female subjects aged 12 to 35 years with comprehensive (at screening) primary dysmenorrhea (onset <3 years after menarche).

The product according to the method of the present invention was a combination tablet containing estetrol (15 mg) and drospirenone (3 mg) administered orally once daily continuously or as a 24/4-day regimen (i.e. 24 days of active tablets followed by 4 days of placebo tablets). Different doses of estetrol were included in the supplementary arm as well as the placebo arm.

The efficacy of the method of the present invention was demonstrated by changes between the baseline assessment period and the treatment assessment period, primarily in the number of days with dysmenorrhea pain.

Dysmenorrhea pain was defined as pelvic pain during the menstrual/withdrawal bleeding episode and the 2 days preceding this episode.

Second, after efficacy, daily scores for dysmenorrhea pain were measured using the following scale:

0 - no pain;

1 - Mild pain that does not require painkillers;

2 - Moderate pain requiring pain medication;

3 - Severe pain requiring painkillers.

Additional efficacy evaluations were performed as follows:

1. Change between baseline and end of treatment evaluation period in number of days with pelvic pain, with or without vaginal bleeding;

2. Changes between baseline and treatment assessment periods in the number of days with pelvic pain during unscheduled bleeding;

3. Changes in Rescue Medication Use between baseline and treatment assessment periods. Rescue medication use will be a standardized intake of 200 mg ibuprofen tablets;

4. Percentage of participants with dysmenorrhea pain interfering with work/school and social or other activities;

5. Hours/day and percentage of participants missing time from work due to dysmenorrhea pain at baseline, 3 months and last visit (after 6 months);

6. Percentage of participants satisfied with study treatment;

7. Cost of each treatment for dysmenorrhea pain (Physiotherapy, Alternative Medicine, Acupuncture, Osteopathy, Medical Counselling, Massage, Herbal supplement/Tea itself) assessed by completing the Resource Use Questionnaire (converted to Euro);

8. Patient improvement over the course of the study according to the Clinical Global Impression (CGI) scale completed by the investigator;

9. Rating of patients' assessments and their improvement over the course of the study on the Clinical Global Impression (CGI) scale completed by participants;

10. General health, body pain, physical and social functioning, mental health and vitality measured by the General Health and Well-being Questionnaire SF-36 at baseline, 3 months and last visit using the SF-36 administered questionnaire, a measure of general health status used to assess patient populations and compare health status across different populations.

Clinical studies demonstrate that products according to the method of the present invention are effective in improving symptoms of menstrual cramps.

Claims (17)

A pharmaceutical composition for use in a method of alleviating symptoms of dysmenorrhea in a human, said composition comprising 15 mg of estetrol and 3 mg of drospirenone.
In the first paragraph,
A pharmaceutical composition, wherein the method results in a reduction in one or more of the number, frequency, and severity of treatment-related adverse effects, compared to other dysmenorrhea treatments of similar efficacy.
In the first paragraph,
A pharmaceutical composition, wherein the administration method is a 7-day administration-free interval, or a combined method with a 4-day administration-free interval.
In the first paragraph,
A pharmaceutical composition wherein the above estetrol is estetrol monohydrate.
In the first paragraph,
A pharmaceutical composition, wherein the composition is formulated as an oral dosage unit.
In paragraph 5,
A pharmaceutical composition, wherein the oral dosage unit is formulated to correspond to a daily dosage unit.
In the first paragraph,
A pharmaceutical composition, wherein menstrual pain symptoms are improved after one cycle of administration.
In Article 7,
A pharmaceutical composition, wherein the dysmenorrhea symptoms grade is improved by at least one unit.
In the first paragraph,
A pharmaceutical composition wherein haemostatic changes do not exceed the normal range after one cycle of administration.
In the first paragraph,
A pharmaceutical composition, wherein the following administration pattern is used:
A 24-day interval during which estrogen components and progestogen components are administered; and
Alternately, there is a 4-day interval (days 25 to 28) during which only estrogen is administered.
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