Composition comprising estetrol and drospirenone for relieving or treating pain

Abstract

The present invention relates to a pharmaceutical composition comprising estetrol and drospirenone for use in relieving pain associated with endometriosis in a patient. The pharmaceutical compositions described in the present invention are particularly effective in relieving pain associated with endometriosis in patients having high levels, frequencies and / or intensities of pain, e.g., measured by visual analog scale (VAS) scoring, and / or with other complications such as adenomyosis or hysteromyoma. Uses related to the above and corresponding methods of treatment are also described.

Description

Technical Field

[0001] The present invention relates generally to the field of medicine and, more specifically, to hormonal treatments for female patients experiencing pain associated with endometriosis. Specifically, the present invention relates to a composition comprising estetrol and drospirenone for safely and effectively relieving (i.e., alleviating or treating) pain, particularly pelvic pain, in female patients. The present invention is particularly effective for treating patients with endometriosis who have high visual analog scale (VAS) scores. Background Art

[0002] Endometriosis is a medical condition characterized by the uncontrolled growth of endometrial tissue implants outside the uterine cavity in female patients, which causes pain and sometimes even infertility or (ovarian) cancer. Its exact cause is still under investigation, although there has been increasing evidence recently that endometriosis is caused by multiple factors. It has been documented that the disease is associated with impaired immune function, local hormonal influences, genetic factors, and even environmental pollutants (Zondervan et al., N Engl J Med, 2020). Although a variety of screening tools and tests have been recommended and tested, there is currently no method that is effective for accurately identifying or predicting the individuals or populations most likely to be ill. Therefore, histological and / or laparoscopic confirmation is still necessary to obtain a conclusive diagnosis. Early suspicion of endometriosis is a key factor in achieving early diagnosis, as endometriosis often presents with symptoms similar to other conditions, leading to delayed diagnosis.

[0003] Determining the exact incidence rate is challenging due to the difficulty of diagnosis for medical practitioners. However, some studies suggest that up to 11% of women of childbearing age in the general population may be affected by the condition (Shafrir et al., Best Pract ResClin Obstet Gynaecol, 2018). In 2021, the World Health Organization (WHO) stated that endometriosis has significant social, public health, and economic impacts, and that it reduces quality of life due to severe pain and other symptoms. Currently, there is no curative treatment for the condition. Therefore, symptom control is crucial to improving the quality of life of patients affected by the condition.

[0004] Several symptomatic treatment strategies for managing pain caused by endometriosis have been described in the art, including administration of nonsteroidal anti-inflammatory drugs, analgesics, and surgery to remove endometriotic tissue, adhesions, and scar tissue. However, each of these strategies, as well as their combination, has highly variable success rates, a high risk of (serious) side effects, and questionable long-term safety (Johnson et al., Hum Reprod, 2013).

[0005] Recently, YAZ Flex (containing 20 μg ethinyl estradiol and 3 mg DRSP, intended for use as a flexible extended-cycle oral contraceptive regimen) was studied for endometriosis-associated pelvic pain (clinicaltrials.gov, study identifier NCT03126747) and was shown to be effective in controlling endometriosis-associated pain.

[0006] However, there remains an unmet need for improved innovative strategies for managing the disease, particularly those that can safely and effectively alleviate pain caused by endometriosis to further improve the quality of life of patients afflicted with endometriosis and with fewer side effects than currently available products. Summary of the Invention

[0007] As demonstrated by the examples illustrating certain representative embodiments of the present invention, the inventors have found that a composition comprising 13.5 mg to 16.5 mg of estetrol (E4) and 2.5 mg to 3.5 mg of drospirenone (DRSP) is particularly suitable for relieving pain associated with endometriosis in patients. Unexpectedly, the composition is superior to existing hormonal endometriosis therapies for pain relief, such as compositions comprising ethinylestradiol (EE) and drospirenone (DRSP), particularly in patients who report or are believed to have higher pain levels (i.e., higher visual analog scale scores) caused by the endometriosis. In addition to endometriosis, this improvement can also be observed in patients with adenomyosis and / or uterine fibroids. Therefore, in a more conventional context, the compositions specified herein are particularly suitable for relieving endometriosis and endometriosis symptoms.

[0008] More specifically, similar reductions in the VAS of the most severe endometriosis-related pelvic pain were observed between the treatment group (E4 / DRSP) and the control group (YAZ Flex; EE / DRSP). Unexpectedly, the study showed that the E4 / DRSP regimen was more effective than the control group in suppressing pain during the non-withdrawal bleeding phase, particularly in patients with a baseline VAS value of 70 mm or higher before dosing. Combined with the generally superior safety profile of estetrol compared to other estrogens, which has been documented in the art on numerous occasions, it can be concluded that patients with endometriosis and a baseline VAS of 70 mm or higher should ideally use the experimental E4 / DRSP combination, rather than other hormone combinations used to date, to control endometriosis pain during the non-withdrawal bleeding phase.

[0009] Therefore, the present invention provides the following aspects:

[0010] Aspect 1. A pharmaceutical composition comprising about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and about 2.5 mg to about 3.5 mg of drospirenone for relieving pain associated with endometriosis in a patient and / or for treating endometriosis in the patient.

[0011] Aspect 2. A pharmaceutical composition comprising from about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone for use in treating a patient suffering from pelvic pain and / or for treating endometriosis in said patient.

[0012] Aspect 3. A pharmaceutical composition comprising about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and about 2.5 mg to about 3.5 mg of drospirenone for use in relieving pain associated with endometriosis in a patient and / or for treating endometriosis in the patient, wherein the use comprises the step of determining whether the patient has pelvic pain defined by a visual analog scale (VAS) of greater than about 40 mm, about 50 mm, about 60 mm, or about 70 mm prior to administration.

[0013] Aspect 4. Use of a composition comprising about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and about 2.5 mg to about 3.5 mg of drospirenone for the preparation of a medicament for relieving pain associated with endometriosis in a patient or for the preparation of a medicament for treating endometriosis.

[0014] Aspect 5. Use of a composition comprising about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and about 2.5 mg to about 3.5 mg of drospirenone for the preparation of a medicament for treating a patient suffering from pelvic pain.

[0015] Aspect 6. Use of a composition comprising about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and about 2.5 mg to about 3.5 mg of drospirenone in the manufacture of a medicament for relieving pain associated with endometriosis in a patient or for the manufacture of a medicament for treating endometriosis in said patient, wherein said use comprises the step of determining whether the patient has pelvic pain as defined by a VAS score of greater than about 40 mm, about 50 mm, about 60 mm, or about 70 mm prior to administration.

[0016] Aspect 7. A method of alleviating pain associated with endometriosis in a patient or for treating endometriosis in the patient, the method comprising administering to the patient a composition comprising about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and about 2.5 mg to about 3.5 mg of drospirenone.

[0017] Aspect 8. A method of treating a patient suffering from pelvic pain, the method comprising administering to the patient a composition comprising from about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone.

[0018] Aspect 9. A method of alleviating pain associated with endometriosis in a patient or treating endometriosis in said patient, comprising a first step of determining whether said patient has pelvic pain as defined by a VAS score of greater than about 40 mm, about 50 mm, about 60 mm, or about 70 mm, and comprising the further step of administering to said patient a composition comprising about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone.

[0019] Aspect 10. The composition for use according to any one of aspects 1 to 3, the use according to any one of aspects 4 to 6, or the method according to any one of aspects 7 to 9, wherein the estetrol is estetrol monohydrate.

[0020] Aspect 11. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the pain in the patient is relieved (ie, reduced) during the non-withdrawal bleeding period.

[0021] Aspect 12. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the pain in the patient is relieved in a period unrelated to the withdrawal bleeding period, preferably in a period up to two days before the onset of the withdrawal bleeding.

[0022] Aspect 13. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the pain in the patient is relieved within a period from two days before the withdrawal bleeding episode to the withdrawal bleeding episode, preferably within a period from one day before the withdrawal bleeding episode to the withdrawal bleeding episode.

[0023] Aspect 14. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the pain in the patient is relieved from about 48 hours before the withdrawal bleeding episode until the withdrawal bleeding episode, preferably wherein the patient's pain is relieved from about 36 hours before the withdrawal bleeding episode, more preferably about 24 hours before the withdrawal bleeding episode until the withdrawal bleeding episode.

[0024] Aspect 15. A pharmaceutical composition for use, use or method according to any of the preceding aspects, wherein the pain in the patient is relieved on a hormone-free day marking the end of the dosing cycle of the hormonal contraceptive, preferably wherein the pain in the patient is relieved on a date prior to day 25 (the first day of the hormone-free interval) in a typical hormonal contraceptive treatment regimen.

[0025] Aspect 16. The pharmaceutical composition for use, use or method according to any one of the preceding aspects, wherein the patient is not considered to have or has not been diagnosed as having primary dysmenorrhea, or wherein the patient's past medical history leads to the exclusion of primary dysmenorrhea in the patient, or wherein the patient is a patient whose past medical history excludes primary dysmenorrhea.

[0026] Aspect 17. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the patient has pelvic pain defined by a VAS score of greater than about 40 mm, about 50 mm, about 60 mm or about 70 mm prior to administration.

[0027] Aspect 18. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the patient suffers from pelvic pain associated with endometriosis having a VAS score of greater than about 40 mm, about 50 mm, about 60 mm or about 70 mm before administration.

[0028] Aspect 19. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the patient suffers from endometriosis-induced pelvic pain with a VAS score of greater than about 40 mm, about 50 mm, about 60 mm or about 70 mm prior to administration.

[0029] Aspect 20. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the pain is caused by endometrial tissue implants outside the uterine cavity in the pelvis.

[0030] Aspect 21. The pharmaceutical composition for use, the use or the method according to Aspect 20, wherein the pain is caused by endometrial tissue implants located on the ovaries, fallopian tubes, tissues that hold the uterus in place (ligaments), the outer surface of the uterus, the vagina, the cervix, the vulva, the intestines, the bladder, the rectum or any combination thereof.

[0031] Aspect 22. The pharmaceutical composition for use, the use or the method according to Aspect 20 or 21, wherein the pain is caused by endometrial tissue implants located on the ovary, the fallopian tube, the tissues that hold the uterus in place (ligaments), the outer surface of the uterus, or any combination thereof.

[0032] Aspect 23. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the pain is chronic pelvic pain, pelvic pain such as lower abdominal pain and / or lower back pain, painful defecation and painful intercourse, or pain caused by endometrial adhesions in the pouch of Douglas.

[0033] Aspect 24. The pharmaceutical composition for use, the use or the method according to any of the preceding aspects, wherein the use results in an improvement of the CGI-I scale (Clinical Global Impression - Improvement scale) of at least about 10%, preferably at least about 20%, more preferably about 28.9%.

[0034] Aspect 25. A pharmaceutical composition for use, use or method according to any of the preceding aspects, wherein the use results in an improvement of at least about 10%, preferably at least about 20%, more preferably about 24% in the PGI-I scale (Patient Global Impression - Improvement scale) graded as "markedly satisfactory or above".

[0035] Aspect 26. Pharmaceutical composition for use, use or method according to any one of the preceding aspects, wherein said use results in a responder rate of at least about 40%, preferably at least about 50%, more preferably at least about 60%.

[0036] Aspect 27. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the use results in a decrease in CA125, preferably wherein the use results in a decrease in CA125 serum levels to below 35 U / ml.

[0037] Aspect 28. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the patient is diagnosed with endometriosis by laparotomy / laparoscopy and / or is assessed as having ovarian chocolate cysts by transvaginal ultrasound (TVUS) and / or magnetic resonance imaging (MRI).

[0038] Aspect 29. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the patient suffers from adenomyosis and / or uterine fibroids in addition to endometriosis.

[0039] Aspect 30. A pharmaceutical composition for use, a use or a method according to Aspect 29, wherein the patient has adenomyosis affecting about 25% or less of the uterine corpus (mild adenomyosis), or adenomyosis affecting about 25% to about 50% of the uterine corpus (moderate adenomyosis), or adenomyosis affecting more than about 50% of the uterine corpus (severe adenomyosis).

[0040] Aspect 31. The pharmaceutical composition for use, the use or the method according to Aspect 29, wherein the patient has a uterine fibroid classified as pedunculated, submucosal, intramural, subserosal or any combination thereof.

[0041] Aspect 32. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the composition is used in a cycle of 21 to 28 daily active dosage units of the composition.

[0042] Aspect 33. The pharmaceutical composition for use, use or method according to aspect 32, wherein the composition is used in a cycle of 24 daily active dosage units of the composition.

[0043] Aspect 34. The pharmaceutical composition for use, the use or the method according to Aspect 32 or 33, wherein the cycle comprises a 7-day dose-free interval, preferably a 4-day dose-free interval.

[0044] Aspect 35. The pharmaceutical composition for use, the use or the method according to any one of aspects 32 to 34, wherein use of the composition results in a decrease in VAS score from pre-dose to after the second or third dosing cycle.

[0045] Aspect 36. The pharmaceutical composition for use, use or method according to Aspect 35, wherein use of the composition results in a decrease in VAS score from before administration to after the second or third administration cycle by at least about 10%, preferably at least about 20%, more preferably at least about 30%, more preferably at least about 40%, and most preferably at least about 50%.

[0046] Aspect 37. The pharmaceutical composition for use, the use or the method according to Aspect 36, wherein the reduction remains substantially stable after the second or third dosing cycle.

[0047] Aspect 38. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein use of the composition results in an improvement in the severity of Douglas' induration, an improvement in restricted uterine mobility and / or pelvic tenderness, a reduction in the size and / or number of ovarian chocolate cysts as assessed by TVUS or MRI.

[0048] Aspect 39. The pharmaceutical composition for use, use or method according to Aspect 38, wherein use of the composition results in an improvement in severity of at least about 10%, preferably at least about 20%, more preferably at least about 30%, more preferably at least about 40%, and most preferably at least about 50%.

[0049] Aspect 40. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein use of the composition results in fewer TEAEs than use of the EE 20 g / DRSP 3 mg fixed-dose combination tablet.

[0050] Aspect 41. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the patient has reduced treatment-emergent adverse events (TEAEs) selected from the group consisting of intermenstrual bleeding, headache, nausea and heavy menstrual bleeding.

[0051] Aspect 42. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, for reducing endometriosis-related sleep disturbances.

[0052] In any one aspect defined herein, the dosage unit can exist in the form of a kit comprising a packaging unit (e.g., blister pack), which includes a single daily oral dosage unit comprising estetrol and drospirenone. It is also well known to those skilled in the art that within the scope of the present invention, each packaging unit, such as a blister pack, can be numbered or otherwise marked. In the specific embodiment of the kit, the packaging unit includes 28 containers or a multiple of 28 containers, such as 2 to 12 times of 28 containers. In a preferred embodiment, the packaging unit includes 3 or 6 times of 28 containers. Within the scope of the present invention, each packaging unit can be a sealed blister pack, which has cardboard, paperboard, foil plastic backing and is encapsulated in a suitable lid.

[0053] Any of the aspects defined herein also contemplates a packaging unit, such as a bottle. The material of the bottle is not particularly limited. In a preferred embodiment, the bottle is a glass bottle characterized by a color that reduces or prevents degradation of the bottle contents by, for example, ultraviolet light, while maintaining transparency that allows visual inspection of the bottle contents. Suitable colors include, but are not limited to, amber, cobalt, or vintage green.

[0054] The above and further aspects and preferred embodiments of the present invention are described in the following sections and in the appended claims.The subject matter of the appended claims is hereby specifically incorporated into this description. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 (A) Individual VAS values ​​and spline curves. x-axis: relative number of days to the first treatment day; y-axis: VAS value (mm). (B) Average VAS value. x-axis: number of days; y-axis: VAS value (mm). "FSN-013" corresponds to the 15 mg E4 / 3 mg DRSP group.

[0056] Figure 2Definition of responder: Responder: VAS decreased by more than 70 mm on 80% or more days during the assessment period. Assessment period: Non-withdrawal bleeding period between days 29 and 84.

[0057] Figure 3 Improvements in CGI-I and PGI-I for responders and non-responders (E4 / DRSP + Yaz Flex). Left: CGI-I; Right: PGI-I. Diagonal stripes: responders, right-hand sample group for each histogram. Solid gray fill: non-responders, left-hand sample group for each histogram.

[0058] Figure 4 .The proportion of responders in the E4 / DRSP and Yaz Flex groups. The FSN-013 group corresponds to the 15 mg E4 / 3 mg DRSP group.

[0059] Figure 5 (A) Proportion of patients with improvement, stabilization, or worsening of objective gynecological examination findings after 6 cycles of treatment: cul-de-sac induration (p = 0.002, Fisher's exact value), uterine immobility (p = 0.005, Fisher's exact value), and pelvic tenderness (p = 0.022, Fisher's exact value). (B) Stratified analysis of changes in objective gynecological examination findings after 6 cycles of treatment, based on the presence or absence of adenomyosis.

[0060] Detailed description

[0061] As used herein, the singular forms "a," "an," and "the" include singular and plural referents unless the context clearly dictates otherwise.

[0062] As used herein, the terms "comprising," "comprises," and "comprised of" are synonymous with "including," "includes," or "containing," and are inclusive or open-ended and do not exclude additional, undescribed members, elements, or method steps. The terms also encompass "consisting of" and "consisting essentially of," which have recognized meanings in patent terminology.

[0063] The description of numerical ranges by endpoints includes all numbers and fractions contained in the respective ranges, as well as the endpoints. This applies to numerical ranges regardless of whether they are introduced by the expression "from ... to ..." or the expression "between ... and ..." or other expressions.

[0064] The terms "about" or "approximately" as used herein when referring to a measurable value (such as a parameter, amount, time period, etc.) are intended to encompass variations from the specified value and variations from the specified value, such as variations of + / - 10% or less, preferably + / - 5% or less, more preferably + / - 1% or less, still more preferably + / - 0.1% or less from the specified value, as well as variations of + / - 10% or less, preferably + / - 5% or less, more preferably + / - 1% or less, still more preferably + / - 0.1% or less from the specified value, to the extent such variations are suitable for performing the disclosed invention. It is to be understood that the value to which the modifier "about" or "approximately" refers is itself also specifically and preferably disclosed.

[0065] While the term "one or more" or "at least one", such as one or more members or at least one member of a group of members, is self-explanatory, by way of further illustration, the term specifically encompasses reference to any one of the members, or any two or more of the members, such as, for example, any ≥3, ≥4, ≥5, ≥6, or ≥7 of the members, etc., up to all of the members. In another example, "one or more" or "at least one" may refer to 1, 2, 3, 4, 5, 6, 7 or more.

[0066] The background discussion is included to explain the context of the invention. It should not be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in any country as of the priority date of any claim.

[0067] Throughout this disclosure, various publications, patents, and disclosed patent specifications are referred to by reference as such. All documents cited in this specification are hereby incorporated by reference in their entirety. In particular, the teachings or portions of these documents herein are considered to be specifically incorporated by reference.

[0068] Unless otherwise defined, all terms used in disclosing the present invention, including technical and scientific terms, have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs. By way of further guidance, term definitions are included to better understand the teachings of the present invention. When a particular term is defined in conjunction with a particular aspect of the present invention or a specific embodiment of the present invention, unless otherwise defined, such meaning or interpretation shall apply throughout the specification, i.e., also in the context of other aspects or embodiments of the present invention. For example, references to embodiments for products also apply to corresponding features of methods and uses.

[0069] In the following paragraphs, different aspects or embodiments of the present invention are defined in more detail. Each aspect or embodiment so defined can be combined with any other aspect or embodiment, unless expressly indicated to the contrary. In particular, any feature indicated as preferred or advantageous can be combined with any other feature indicated as preferred or advantageous.

[0070] Throughout this specification, references to "one embodiment," "an embodiment," or "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with that embodiment is included in at least one embodiment of the present invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing throughout this specification do not necessarily all refer to the same embodiment. Furthermore, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner, as will be apparent to those skilled in the art from this disclosure. Furthermore, although some embodiments described herein include other features that are not included in other embodiments, the combination of features from different embodiments is meant to be within the scope of the present invention and to form different embodiments, as will be understood by those skilled in the art. For example, in the appended claims, alternative combinations of the claimed embodiments are encompassed, as will be understood by those skilled in the art.

[0071] Unless otherwise indicated, all methods, steps, techniques and operations not specifically described can be performed and have been performed in a manner known per se, which will be apparent to those skilled in the art, for example, again referring to standard manuals and the general background art mentioned herein and further references cited herein.

[0072] The term "estetrol" as used herein refers to 1,3,5(10)-estratriene-3,15α,16α,17β-tetrol or 15α-hydroxyestetrol and hydrates of estetrol, such as estetrol monohydrate. "Estetrol" or "E4" for short is an estrogenic steroid produced by fetal human liver (PubChem CID: 27125). Estetrol can be described as a 3-hydroxy steroid corresponding to 17β-estradiol, in which the 15α and 16α positions are substituted by two additional hydroxyl groups. Estetrol is known to be an estrogen receptor agonist (Coelingh Bennink et al., Climacteric, 2008). Estetrol can be synthesized by chemical synthesis, synthesis using (mutated) recombinant enzymes, or any combination of the above methods. Therefore, it is obvious that the terms "estetrol" and "estetrol component" also cover estetrol that has been further chemically modified. Estetrol can be identified in the art by its molecular formula: C 18 H 24 O4 or structural formula (I).

[0073]

[0074] It should be understood that when mentioning estetrol in any chapters and sections of this specification, also include any component (i.e. compound) and / or estetrol derivative (such as estetrol ester) containing estetrol. More preferably, in the context of the present disclosure, particularly preferred estetrol (component) is estetrol monohydrate. Those skilled in the art understand that estetrol monohydrate corresponds to the estetrol containing a water molecule, and the core structural formula of estetrol is not different from formula (I). As an illustration and not as a limitation, the structural formula of estetrol monohydrate is as shown in formula (II):

[0075]

[0076] The compositions, uses, and methods described throughout this disclosure are generally compared with a fixed-dose combination tablet containing ethinylestradiol and drospirenone in terms of safety and efficacy. 20 H 24 Estradiol (E2) refers to an estrogen different from estratetol and estratetol monohydrate, which is widely used in combination with progestogens in contraceptives. Ethinylestradiol is a synthetic derivative of estradiol (estradiol is a natural estrogen). The popularity of ethinylestradiol is due to its favorable properties compared to estradiol, including improved bioavailability and increased resistance to metabolism. By way of illustration and not limitation, the structural formula of ethinylestradiol is shown in Formula (III):

[0077]

[0078] "Drospirenone" (abbreviated as DRSP, PubChem CID: 68873) is a progestogen component that is widely used in combined oral contraceptives (commonly abbreviated as COCs) due to its anti-mineralocorticoid and anti-androgenic activities and generally low off-target activity. Generally, COCs containing drospirenone are referred to as fourth-generation COCs. A non-limiting example of a commercially available COC containing drospirenone is called "Yaz TM ” and Yasmin TM An illustrative example of a progestogen-only pill containing drospirenone is "Slynd TM ”, which is also commercially available. In addition, hormone replacement therapy compositions containing estrogens such as estradiol and drospirenone are available, such as “Angeliq TM Drospirenone is alternatively known in the art by its molecular formula C 24 H 30 O3, or represented by structural formula (IV):

[0079]

[0080] It should be understood that when the term "drospirenone" is used herein, any drospirenone derivative is also contemplated. The terms "progestogen," "gestagen," or "gestogen," and their derivatives, "progestogenic component," as used herein and in the art, refer to any molecule that produces an effect similar to the natural female sex hormone progesterone in a patient's body. Progestogens are considered to be agonists of the progesterone receptor, a function that has been thoroughly validated in the art (see, in particular, the discussion in Kuhl, Menopause, 2005). Progestogens are a subgroup of progestogens, including synthetic progestogens. Although the above terms are used interchangeably in the art, it is generally understood that when referring to a progestogen, a synthetic progestogen is intended.

[0081] Surprisingly, the present inventors have discovered that administering a composition comprising estradiol and drospirenone represents a highly effective and safe approach to treating endometriosis-induced and / or endometriosis-associated pain in patients. Furthermore, the combination offers significant advantages over other hormonal treatment strategies commonly recommended for this indication, such as, but not limited to, compositions comprising ethinylestradiol and drospirenone, in that it can be administered with a flexible, extended-cycle oral contraceptive regimen. These improvements were particularly observed in patients characterized by high (i.e., intense and / or frequent) endometriosis-induced pain. This was unexpected, as one skilled in the art would have expected that the combination of estrogen and drospirenone would generally result in similar therapeutic outcomes. The more potent effects of estradiol compared to ethinylestradiol are all the more significant, particularly given that estradiol is generally considered a "weak" estrogen (Gérard et al., J Endocrinol, 2015). The general safety of combined oral contraceptives with estetrol as the estrogen component reported in the art can be confirmed by the minimal effects of the estetrol / drospirenone combination on the blood coagulation and fibrinolysis systems and the limited treatment-emergent adverse events (TEAEs). No significant deviations from baseline were observed for a large number of clinical markers, such as hematological parameters, biochemical tests, urine tests, electrocardiograms (ECGs), and QT intervals.

[0082] Thus, in a first aspect, the present invention relates to a pharmaceutical composition comprising estetrol and drospirenone for use in relieving pain associated with, caused by, and / or induced by endometriosis. Estetrol and drospirenone are typically included in the pharmaceutical composition in pharmaceutically effective amounts, for example, from about 13.5 mg to about 16.5 mg of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone. In other words, the present invention contemplates the use of a composition comprising from about 13.5 mg to about 16.5 mg of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone in the preparation of a medicament for relieving pain associated with endometriosis in a patient. Still in other words, the present invention contemplates a method for relieving pain associated with endometriosis in a patient, wherein the method comprises administering to the patient a composition comprising from about 13.5 mg to about 16.5 mg of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone. Use of the pharmaceutical composition described herein is contemplated for relieving pain associated with endometriosis. Optionally, use of the pharmaceutical compositions described herein is envisaged for the relief of pain induced by endometriosis.

[0083] As used herein, "endometriosis" refers to a benign (i.e., non-malignant) proliferative disease in which functional endometrial tissue is present in locations other than the endometrium, i.e., outside the uterine cavity. As will be appreciated by those skilled in the art, endometriosis is a condition distinct from endometrial cancer. As used herein, the term "endometriosis" does not include endometrial cancer. Endometriosis may occur when cells from the endometrium implant in distal sites, which may include the pelvic region, peritoneal surfaces, ovaries, ligaments, intestines, and bladder. Thus, the term "endometriosis" includes any form or specific classification of the condition, including, but not limited to, exometriotic endometriosis, endometriomas, endometriotic nodules outside the uterosacral ligaments, autoimmune endometriosis, mild endometriosis, moderate endometriosis, severe endometriosis, superficial (peritoneal) endometriosis, deep (invasive) endometriosis, and ovarian endometriosis. Unless otherwise specified, the term endometriosis is therefore used herein to describe any of these conditions. It will further be apparent to those skilled in the art that the efficacy of the compositions subject of the present disclosure for treating pain associated with endometriosis also essentially means that the compositions are effective for treating endometriosis itself. Optionally, relieving pain associated with endometriosis as described herein may therefore equally mean treating endometriosis itself.

[0084] "Adenomyosis" occurs when tissue similar to the lining of the uterus (endometrium) begins to grow into the muscular wall of the uterus (myometrium), meaning endometrial-like tissue grows into the uterine muscle. It causes the uterus to thicken and enlarge—sometimes to double or triple its normal size. Adenomyosis can cause painful periods, heavy or prolonged menstrual bleeding with clotting, and abdominal / pelvic pain. Adenomyosis can cause painful menstrual cramps (dysmenorrhea), heavy menstrual bleeding (menorrhagia), menstrual abnormalities, pelvic pain with or without severe cramping, painful intercourse (dyspareunia), infertility, an enlarged uterus, and abdominal bloating or distension (adenomyosis abdomen). Adenomyosis can be diagnosed through a pelvic exam, transvaginal ultrasound, and imaging scans such as magnetic resonance imaging (MRI) scans. Adenomyosis is usually classified as mild, moderate, or severe, depending on the area of ​​the uterine corpus that is affected. By way of illustration and not limitation, mild adenomyosis corresponds to about 25% or less of the portion of the uterine body affected, moderate adenomyosis corresponds to about 25% to about 50% of the portion of the uterine body affected, and severe adenomyosis corresponds to greater than about 50% of the portion of the uterine body affected.

[0085] Uterine fibroids are noncancerous growths of the uterus that often appear during the reproductive years. Also known as leiomyomas or myomas, uterine fibroids are not associated with an increased risk of uterine cancer and almost never develop into cancer. Fibroids can range in size from tiny, undetectable embryos to large masses that can distort and enlarge the uterus. There may be one fibroid or multiple fibroids. In extreme cases, multiple fibroids can enlarge the uterus so much that it reaches the rib cage and adds weight.

[0086] Fibroids can be diagnosed during a pelvic exam or prenatal ultrasound. The most common symptoms of uterine fibroids are heavy menstrual bleeding, menstrual periods lasting more than a week, pelvic pressure or pain, frequent urination, difficulty emptying the bladder, constipation, and back or leg pain. Fibroids are generally classified by their location. Intramural fibroids grow within the muscular uterine wall. Submucosal fibroids expand into the uterine cavity. Subserosal fibroids protrude outside the uterus. In addition, pedunculated uterine fibroids have been described, which are characterized by attachment to the uterine wall by a stalk-like structure. Those skilled in the art can obtain more specific classification methods for uterine fibroids through publications on uterine fibroids, such as the FIGO (International Federation of Gynecology and Obstetrics) classification system (Munro et al., Int J Gynaecol Obstet, 2018). Each of these different types of uterine fibroids is contemplated in the context of the present invention. Those skilled in the art also recognize that endometriosis is a medical condition that is significantly different from dysmenorrhea, particularly primary dysmenorrhea. It is important to note that there are no physical signs associated with primary dysmenorrhea, and primary dysmenorrhea is not associated with any laboratory abnormalities or abnormal findings on imaging studies. Therefore, healthcare practitioners can easily distinguish endometriosis from primary dysmenorrhea because endometrial tissue is present outside the uterine cavity in endometriosis but not in primary dysmenorrhea (e.g., Harada, Dysmenorrhea and endometriosis in young women, Yonago Acta Med, 2013).

[0087] Endometriosis can be classified according to severity, extent, location, or any combination thereof. Different stages of endometriosis (i.e., stages I-IV) can be specified, and its location is important in determining an appropriate treatment plan, which may include surgical removal of the endometriotic tissue and hormonal therapy (including progestins, oral contraceptives, and GnRH antagonists). Thus, as contemplated by the present disclosure, an individual may have been identified as having stage 1 or stage 2 endometriosis. Stage 1 (or minimal) endometriosis is a stage of the disease in which the patient is characterized by a small number of (relatively small) implants, small wounds, and / or lesions. The implants may be found on or in organs or tissues lining the pelvis or abdomen, with little or no scar tissue. Compared to stage 1, stage 2 (or mild) endometriosis is generally characterized by more implants, which may be located deeper in the tissue, and optionally, scar tissue may be present. Alternatively, the individual may have been identified as having stage 3 or stage 4 endometriosis. Stage 3 (or moderate) endometriosis is typically characterized by numerous, deep implants, optionally including small cysts on one or both ovaries, and thick bands of scar tissue (i.e., adhesions). Stage 4 (or severe) endometriosis is typically characterized by numerous, deep implants and thick adhesions, with additional large cysts on one or both ovaries. Thus, a patient may optionally be characterized by stage 1, 2, 3, or 4 endometriosis, or any combination thereof.

[0088] Alternatively, endometriosis may be grouped according to any other classification method or classification system reported in the art. Suitable systems include, by way of illustration and not limitation, the rASRM classification system (American Society for Reproductive Medicine, FertilSteril, 1997), the Endometriosis Fertility Index (EFI) (Adamson and Pasta, FertilSteril, 2010), and the ENZIAN score (Haas et al., FertilSteril, 2011).

[0089] Pain is a submodality of somatic sensation that is caused by a complex constellation of unpleasant sensations, emotions, and cognitive experiences that are triggered by real or perceived tissue damage and manifest as certain autonomic, psychological, and behavioral responses (Terman and Bonica, Bonica's management of pain, 2003). The term "pain" used in the context of the present disclosure refers to physical pain. However, it should be understood that physical pain may also lead to secondary unwanted emotional states associated with non-physical pain (i.e., mental pain). Therefore, although the inventors envision the broad applicability of the compositions and methods presented herein, as described in further detail herein, they may additionally improve the patient's emotional state. In this context, it is particularly relevant to alleviate chronic pain, which is known to be detrimental to the patient's mental health and is often detrimental to health (Sheng et al., Neural Plasticity, 2017).

[0090] The phrase "alleviate" may be used interchangeably with any synonym known in the art. Non-limiting examples of synonyms include "relieve," "treat," "alleviate," "comfort," "diminish," "relieve," "relax," "reduce," "diminish," and "reduce." Each of these terms should be interpreted as referring to therapeutic treatment of pain associated with endometriosis that has already developed and resulted in (clinical) manifestations, as well as prophylactic or preventative measures, wherein the goal of treatment is to prevent, diminish, or reduce the likelihood of the occurrence of unwanted distress, such as preventing the onset, development, and progression of pain associated with endometriosis. Beneficial or desired clinical outcomes may include, but are not limited to, reducing the extent of pain associated with or induced by endometriosis (i.e., reducing severity), stabilizing (i.e., not worsening) the pain, delaying or slowing the onset of pain associated with endometriosis, and the like. "Prevention" or "prevent," as used in the context of the present invention, refers to avoiding the development of a condition or disease symptom in a patient, i.e., the establishment of a prophylactic or preventative measure. Prophylactic treatment refers to treatment in which, in the context of endometriosis-related pain, the goal is to avoid symptoms of (worsening) undesirable physiological or psychological changes in the patient's body or part thereof. As used herein, the terms "therapeutic treatment" or "therapy" and the like refer to treatment in which the goal is to change the perception of pain associated with endometriosis to a more desirable state, e.g., a less severe state (e.g., to improve, or even return to its normal, healthy state (i.e., no pain perception)), to maintain it (i.e., not make the pain worse) in the undesirable physiological state (e.g., stabilize), or to slow the progression to more severe or worse pain. In a specific embodiment, a measurable reduction includes any statistically significant decrease in a measurable marker or symptom. Statistically significant, as used herein, refers to a p-value of less than 0.05, which is a generally accepted cut-off score in statistical analysis as understood by those skilled in the art.

[0091] The terms "pharmaceutical formulation", "pharmaceutical composition" or "pharmaceutical product" are used interchangeably herein. Likewise, the terms "formulation", "composition" or "product" are used interchangeably herein. Throughout the specification, unless expressly stated otherwise, the absolute amounts referred to herein correspond to the amounts present in one administered dose. Optionally, estetrol and drospirenone are the sole (i.e., single, only) pharmaceutically active ingredient portion of the composition. The term "pharmaceutically active ingredient", which may be used interchangeably with "pharmaceutically active agent" throughout this disclosure, should be interpreted according to the World Health Organization's definition of that term: "a substance used in a finished pharmaceutical product (FPP) that is intended to exhibit pharmacological activity or otherwise have a direct effect in the diagnosis, cure, alleviation, treatment or prevention of disease, or in restoring, correcting or modifying a physiological function in the human body".

[0092] As used herein, the term "subject" or "patient" refers to a female human patient, preferably a female patient of childbearing age. Alternatively, perimenopausal and / or postmenopausal female patients are also contemplated. The female patients contemplated herein can be patients who are in need of, or believed to be in need of, treatment to relieve pain associated with endometriosis, or who are predicted to need such treatment at a foreseeable future time point, optionally due to entering a particular life stage, such as childbearing age, or in view of endometriosis in a close family member, such as a mother, grandmother, or sibling. Optionally, the patient is a female patient of about 12 to about 95 years of age, preferably about 14 to about 80 years of age, more preferably about 16 to about 70 years of age, and most preferably about 18 to about 60 years of age. Optionally, the female patient is a patient of about 60 years of age or younger, preferably a patient of about 55 years of age or younger, preferably a patient of about 50 years of age or younger, preferably a patient of about 45 years of age or younger, preferably a patient of about 40 years of age or younger, preferably a patient of about 35 years of age or younger, preferably a patient of about 30 years of age or younger, preferably a patient of about 25 years of age or younger, preferably a patient of about 20 years of age or younger. Most preferably, the female patient is a patient of about 16 to about 25 years of age.

[0093] Another aspect of the present invention relates to a pharmaceutical composition comprising about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone for treating a patient suffering from pelvic pain. As used herein, "pelvic pain" refers to pain in the pelvic region. In other words, the present invention relates to the use of a composition comprising about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone in the preparation of a medicament for treating a patient suffering from pelvic pain. In other words, the present invention relates to a method for treating a patient suffering from pelvic pain, comprising administering to the patient a composition comprising about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone. Optionally, the pelvic pain is characterized by a severity that limits the patient's normal (i.e., healthy) function in society (e.g., missing school and / or work). Optionally, the pelvic pain is diagnosed as or is considered to be chronic pelvic syndrome (i.e., pelvic pain that persists for more than six months and whose severity limits the patient's function).

[0094] In yet another aspect, the present invention relates to a pharmaceutical composition comprising about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone for use in relieving pain associated with endometriosis in a patient, wherein the use comprises the step of determining whether the patient has pelvic pain as defined by a VAS score of greater than about 40 mm prior to administration. Alternatively, the present invention relates to the use of a composition comprising about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone in the preparation of a medicament for relieving pain associated with endometriosis in a patient, wherein the use comprises the step of determining whether the patient has pelvic pain as defined by a VAS score of greater than about 40 mm prior to administration. Preferably, pelvic pain is defined by a VAS score of greater than 50 mm. More preferably, pelvic pain is defined by a VAS score of greater than about 70 mm, even more preferably greater than about 80 mm, and most preferably greater than about 90 mm. Alternatively, pelvic pain may be defined by a VAS score of 40 mm to 100 mm, 50 mm to 80 mm, 60 mm to 80 mm, 40 mm to 70 mm, or 60 mm to 90 mm.

[0095] The term "visual analog scale score", abbreviated as "VAS score", refers to a widely accepted pain rating scale (originally described by Hayes and Patterson in 1921). In a typical VAS, the pain score is determined by measuring the distance (mm) between the "no pain" anchor and the patient's mark on a 10 cm line, providing a score range of 0–100. The higher the score, the greater the pain intensity. The following pain intensity groups have generally been formed: no pain (0-4 mm), mild pain (5-44 mm), moderate pain (45-74 mm), severe pain (75-100 mm). Different VAS structures, configurations, directions and response schemes have been described and are within the knowledge of those skilled in the art (see, for example, Byrom et al., Ther Innov Regul Sci, 2022). Therefore, the specific VAS scoring system used does not particularly limit the present invention. By way of illustration and not limitation, the VAS can be presented as a numerical rating scale with a center point, graduations, and / or numbers; a curved analog scale, a box scale consisting of circles equidistant from one another, and a graphic rating scale. All orientations of the scale on a table or electronic display are contemplated. The present disclosure also contemplates alternative pain rating scales. By way of illustration and not limitation, these scales include a numerical rating scale (NRS-11), the Stanford Pain Rating Scale, a visual rating scale (VRS), or a visual numerical scale. The broader concepts of pain measurement instruments and methods have been described in detail in the art (e.g., in Younger et al., Current Pain And Headache Reports, 2010), with the values ​​on the corresponding scales representing the patient's equivalent pain level. Alternatively, the patient can be a patient characterized by an NRS-11 score of 1 to 10, 2 to 9, 3 to 7, or 4 to 6. Alternatively, the patient may be characterized by a Stanford Pain Scale score of 1 to 3 (i.e., mild pain), 4 to 6 (i.e., moderate pain), or 7 to 10 (i.e., severe pain). In the context of the present disclosure, endometriosis-related pain is preferably represented by a VAS scale, as has been evaluated and recommended in the art (e.g., Bourdel et al., Hum Reprod Update, 2015). One skilled in the art will be able to compare the reported pain levels between different pain scales. By way of illustration and not limitation, it is generally accepted in the art that, in the context of endometriosis, an NRS value of 0 corresponds to a VRS index of "no pain," an NRS value of 1 to 3 corresponds to a VRS index of "mild pain," an NRS value of 4 to 6 corresponds to a VRS index of "severe pain," and an NRS value of 7 to 10 corresponds to a VRS index of "severe pain."Likewise, a VAS score of approximately 0 mm corresponds to a VRS index of “no pain,” and a VAS score of approximately 100 mm corresponds to a VRS index of “worst possible pain” (Bourdel et al., Hum Reprod Update, 2015).

[0096] The patient's pain can be measured using a VAS pain score during the non-withdrawal bleeding phase. In such an embodiment, the patient's pain is measured within a time window characterized by the absence of withdrawal bleeding (i.e., predetermined bleeding (bleeding) / spotting (spotting) outbreak) using a VAS pain score. Alternatively, the patient's pain is measured at a time point of at least one week, at least two weeks, or at least three weeks after withdrawal bleeding stops using a VAS pain score. Optionally, the patient has pain defined by a VAS score greater than about 40mm, about 50mm, about 60mm, about 70mm, about 80mm, or about 90mm before administration. Alternatively, the patient suffers from pelvic pain defined by a VAS score greater than about 40mm, about 50mm, about 60mm, about 70mm, about 80mm, or about 90mm before administration. Alternatively, the patient may suffer from pelvic pain associated with endometriosis with a VAS score greater than about 40mm, about 50mm, about 60mm, about 70mm, about 80mm, or about 90mm before administration.

[0097] As used herein, "withdrawal bleeding" refers to vaginal bleeding that occurs during the hormone-free interval of a typical dosing regimen for hormonal contraceptives. The compositions according to the present invention are particularly suitable for relieving pain in patients during the non-withdrawal bleeding period. In some embodiments, the pain is unrelated to the withdrawal bleeding period, or in other words, the pain involved occurs before day 25 (wherein day 25 corresponds to the first day of the hormone-free interval in a typical hormonal contraceptive regimen). Withdrawal bleeding typically begins on about day 26. In preferred embodiments, the pain involved occurs on any of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24.

[0098] For the withdrawal bleeding period or scheduled bleeding, it refers to bleeding / spotting from day 25 (the first day of the hormone interval) to day 4 of the next cycle, including any bleeding / spotting that starts before day 25 and continues to the scheduled bleeding period, or bleeding / spotting that starts during the scheduled bleeding period but continues after day 4. Vice versa, the non-withdrawal bleeding period refers to the days in the cycle that are different from the withdrawal bleeding period or scheduled bleeding. Spotting refers to vaginal bleeding that is very small and does not require the use of sanitary protection, including sanitary napkins, and / or bleeding refers to vaginal bleeding that requires the use of sanitary protection, including tampons, pads or sanitary napkins, which may also occur during the non-withdrawal bleeding period. Even bleeding / spotting episodes may also occur during the non-withdrawal bleeding period, i.e. one or more consecutive bleeding / spotting days separated by two no bleeding / spotting days at either end. Unplanned bleeding / spotting refers to any bleeding / spotting that does not meet the criteria for planned bleeding. Even if bleeding and / or spotting occurs outside of the withdrawal or scheduled bleeding period, the time outside of the scheduled bleeding period is still referred to herein as a non-withdrawal bleeding period, even if bleeding and / or spotting occurs in an infrequent event.

[0099] Definitions used to analyze bleeding patterns:

[0100]

[0101] Thus, a patient may be one who has been diagnosed with endometriosis, is believed to have endometriosis, or is predicted to develop endometriosis (related pain). Alternatively, a patient may be diagnosed with, is believed to have, or is predicted to develop adenomyosis and / or uterine fibroids. A patient may be predicted to develop pain associated with and / or induced by endometriosis. "Diagnosed with," "diagnosing," and "diagnosis" refer to the process of identifying, determining, or concluding a disease, condition, or (adverse side effect) in a patient based on symptoms and signs and / or from the results of various diagnostic procedures. "Diagnosing" endometriosis and / or pain associated with endometriosis may particularly mean that a skilled medical practitioner has a high, or even definite, probability that the patient suffers from endometriosis or pain associated with endometriosis, respectively. A patient may be diagnosed as not having such symptoms despite exhibiting one or more conventional symptoms or signs suggestive of such symptoms. "Prediction" in the context of the present invention refers to an anticipation of the progression of pain associated with and / or induced by endometriosis in a patient, as well as the prospects (e.g., probability, duration, and / or extent) of recovery in a patient, and / or the severity or improvement of the pain associated with and / or induced by endometriosis. The term may include an expectation that the condition will not worsen or worsen, preferably within a given timeframe.

[0102] Optionally, the patient is a patient diagnosed with endometriosis by laparotomy or laparoscopy, and optionally with adenomyosis and / or uterine fibroids. Those skilled in the art are familiar with the terms "laparotomy" and "laparoscopy", which refer to the process of forming a surgical incision of considerable size in the abdominal cavity and the process of forming a small incision (also referred to as "keyhole incision" and "minimally invasive surgery" in the art), respectively. The patient may be a patient diagnosed with ovarian chocolate cysts. It is generally believed that the term "ovarian chocolate cyst", which is interchangeably represented by the term "ovarian endometrioma" in the art, refers to a fluid-filled ovarian sac or sac present in the inner layer of the uterus (i.e., the endometrium). Ovarian chocolate cysts can be detected by transvaginal ultrasound (TVUS) and / or magnetic resonance imaging (MRI), as described in detail in the art (e.g., et al., Diagnostics (Basel), 2022).

[0103] In connection with the foregoing, "predicting" or "prediction" generally refers to a statement, declaration, indication or prediction of a disease or condition in a patient that does not (or has not yet) show any or limited clinical manifestations of pain associated with endometriosis and / or induced by endometriosis. The prediction of the development of the pain in a patient can indicate the probability, chance or risk that the patient will develop the clinical manifestation, for example, within a specific time period after the diagnosis of one or more endometriosis-related symptoms. The probability, chance or risk can be expressed as any suitable qualitative or quantitative expression, wherein non-limiting examples of quantitative expressions include absolute values, ranges or statistics. Alternatively, the probability, chance or risk can be indicated relative to a suitable control patient or a group of control patients (i.e., a control patient population (e.g., relative to a typical, normal or healthy patient or patient population)). Thus, any probability, chance or risk can advantageously be expressed as an increase or decrease, an upward or downward adjustment, a multiplication or reduction relative to a suitable control patient or patient population, or relative to a baseline value that can be derived from a control patient (population) or a textbook reference value. It is clear that when a patient population is used to define a baseline value, the baseline value should be the central dimension of one or more values ​​(parameters) of the population, such as the mean or median of the values. It will also be understood by those skilled in the art that monitoring, such as those described in the present disclosure, can be implemented during the patient's medical treatment. Such monitoring can be included in decisions, such as whether a patient can be discharged from a controlled clinical or health care environment, whether a change in treatment or therapy is required, or whether hospitalization is required.

[0104] The pharmaceutical compositions of the present disclosure comprise from about 13.5 mg to about 16.5 mg of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone. It will be understood that these ranges represent pharmaceutically effective amounts of estetrol and drospirenone. The skilled artisan will appreciate that terms such as "amount," "amount," and "level" are synonymous and have well-defined meanings in the art. Optionally, the pharmaceutical compositions of the present disclosure comprise from about 14 mg to about 16 mg of estetrol and from about 2 mg to about 3 mg of drospirenone. Optionally, the pharmaceutical compositions of the present disclosure comprise from about 14.5 mg to about 15.5 mg of estetrol and from about 2 mg to about 3 mg of drospirenone. Optionally, the pharmaceutical compositions of the present disclosure comprise from about 15 mg of estetrol and from about 3 mg of drospirenone. Preferably, the pharmaceutical compositions of the present disclosure comprise from about 15 mg of estetrol monohydrate and from about 3 mg of drospirenone.

[0105] Alternatively, each of the compositions described herein is described in terms of the daily amount of estetrol (monohydrate) and drospirenone ultimately administered to a patient. Thus, any composition expressed as comprising from about 13.5 mg to about 16.5 mg of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone may be equivalent to a composition administered in an amount corresponding to a daily dose equivalent to from about 13.5 mg to about 16.5 mg of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone. Thus, the expression "administered in an amount equivalent to..." indicates that a substance (in the context of the present invention, estetrol and drospirenone) is administered that achieves the same physiological and / or psychological effects as if the patient had been administered the amount of estetrol and drospirenone. Furthermore, the term "daily" indicates that the amount recited is the cumulative amount administered to the patient each day. One skilled in the art will understand that if a patient is administered the composition of the present disclosure only once a day (i.e., every day), the amount of estrogen administered in that single administration will be the daily dose. Alternatively, it will be understood by those skilled in the art that if the composition is administered more than once a day (e.g., 2 or 3 times), the daily amount will correspond to the (independent) sum of all estetrol and all drospirenone administered during each administration event within the total time window of 24 hours. It is within the skill of the art to verify the daily dosage of estetrol and drospirenone.

[0106] The pharmaceutical compositions described herein can be formulated into one or more dosage units. Optionally, the dosage unit is a daily dosage unit. Optionally, the dosage unit is an oral dosage unit. In another embodiment, the dosage unit is a daily oral dosage unit. Obviously, any composition and dosage unit may contain one or more pharmaceutically acceptable excipients as appropriate. The term "pharmaceutically acceptable" as used herein is consistent with the art and means compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0107] The compositions of the present invention are particularly suited for formulation as oral dosage units. However, also contemplated are dosage units formulated for alternative methods of administration, such as, but not limited to, sublingual, buccal, or sublabial dosage units.

[0108] "Dosage unit", used interchangeably with "dosage form" herein, refers to a physical formulation suitable for administration to a patient without the need to adjust the formulation prior to administration, i.e., the final beneficial product. Thus, a dosage unit refers to a composition that is ready to be taken. The term does not limit any other details of the treatment, such as the frequency of administration and / or any characteristics of the dosage unit (flavor, appearance, size, etc.). In the context of the present invention, each dosage unit preferably contains estetrol and drospirenone in an amount equivalent to about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone as pharmaceutically acceptable ingredients. The presence of estetrol and drospirenone as pharmaceutically acceptable ingredients does not exclude the presence of one or more other pharmaceutically active ingredients. As an illustration and not limitation, other pharmaceutically acceptable ingredients may be analgesics, i.e., ingredients that are capable of achieving pain relief in a patient. The term "analgesic" may be used interchangeably with synonyms such as "analgesic" or "analgesic". Optionally, the analgesic agent may be selected from the group consisting of: acetaminophen (ie paracetamol), nonsteroidal-inflammatory drugs (NSAIDs), opioids, muscle relaxants, anxiolytics, antidepressants, anticonvulsants, and corticosteroids.

[0109] The term "pharmaceutically acceptable" as used herein is consistent with the art and means compatible with the other ingredients of the pharmaceutical composition and harmless to the recipient thereof. Non-limiting suitable excipients are further described throughout the disclosure. In this regard, the term "oral dosage unit" includes any dosage unit used and / or suitable for administration to a patient via the oral cavity. The (immediate or near-immediate) administration of the dosage unit is contemplated as an embodiment of the present invention, but is not intended to limit the scope of the invention.

[0110] The oral dosage units described herein can be solid or semisolid dosage units, such as tablets, capsules, cachets, pellets, pills, powders, or granules, or any combination thereof. For example, the oral dosage units of the subject matter of the present invention can be tablets comprising estetrol-containing particles and drospirenone, or capsules comprising estetrol-containing particles and drospirenone. Optionally, drospirenone can be contained in estetrol-containing particles. Alternatively, drospirenone can be contained in different particles, i.e., particles that do not contain estetrol. The term "solid or semisolid dosage unit" also includes capsules containing a liquid (e.g., oil) in which estetrol and drospirenone are dissolved or dispersed.

[0111] Tablets and equivalent solid and semisolid dosage units may contain materials such as binders (e.g., hydroxypropylmethylcellulose, polyvinylpyrrolidone (povidone, PVP), other cellulosic materials, and starches), diluents (e.g., lactose (monohydrate) and other sugars, starches (e.g., corn starch), dicalcium phosphate, and cellulosic materials), disintegrants (e.g., starch polymers and cellulosic materials (e.g., sodium starch glycolate)), and lubricants (e.g., stearic acid (magnesium) and talc), as appropriate. These tablets and equivalent solid dosage units may be prepared by any suitable method well described in the art (e.g., Kaur, Int Res J Pharm, 2012). Non-limiting examples of methods for processing estetrol and drospirenone when preparing dosage units include wet granulation, e.g., using aqueous or organic solutions, direct compression, 3D printing, or coating estetrol and, optionally, drospirenone (on the same carrier particles or on separate particles) on carrier particles using organic or inorganic solvents.

[0112] Optionally, the excipient can be an active pharmaceutical ingredient excipient, a binder excipient, a carrier excipient, a co-processing excipient, a coating system excipient, a controlled release excipient, a diluent excipient, a disintegrant excipient, a dry powder inhalation excipient, an effervescent system excipient, an emulsifier excipient, a lipid excipient, a lubricant excipient, a controlled release excipient, a penetration enhancer excipient, a permeation enhancer excipient, a pH adjuster excipient, a plasticizer excipient, a preservative excipient, or a pharmaceutical composition. In some embodiments, the present invention relates to a pharmaceutical composition comprising a pharmaceutically active ingredient, such as a sachet, a solubilizing agent, a solvent, a sustained release agent, a sweetener, a flavoring agent, a thickener, a viscosity modifier, a filler, a compression agent, a dry granulation agent, a hot melt extrusion agent, a wet granulation agent, a rapid release agent, a bioavailability increasing agent, a dispersing agent, a solubility enhancing agent, a stabilizer, a capsule filling agent, or any combination thereof. It is known to those skilled in the art that it is common practice to use these media and reagents for pharmaceutically active substances, and therefore the incorporation of these excipients is well known in the art. It is obvious that the concentrations of all ingredients used in the final pharmaceutical composition or dosage unit should be nontoxic and should not negatively interfere with the activity of one or more pharmaceutically active ingredients, in this context at least estetrol and drospirenone.

[0113] As described above, the composition and (oral) dosage unit may comprise one or more suitable excipients. The term "excipient" may be a "carrier" and refers to any solvent, diluent, buffer (including but not limited to neutral buffered saline, phosphate buffered saline, or optionally tris-HCl, acetate or phosphate buffer), solubilizer (including but not limited to Tween 80 or polysorbate 80), colloid, dispersion medium, vehicle, filler, chelating agent (including but not limited to EDTA or glutathione), amino acid, protein, disintegrant, binder, lubricant, wetting agent, stabilizer, emulsifier, sweetener, colorant, flavoring, fragrance, thickener, any agent suitable for achieving a storage effect, coating agent, antifungal agent, any preservative (including but not limited to thimerosal, benzalkonium chloride or benzyl alcohol), antioxidant (including but not limited to ascorbic acid, sodium metabisulfite), tonicity control agent, absorption delaying agent, adjuvant, filler (including but not limited to lactose, mannitol) and any other ingredient that may affect any parameter or characteristic of the oral dosage unit of the present invention. Those skilled in the art understand that one or more excipients may be used in the composition or oral dosage unit, provided that the one or more excipients are compatible with the pharmaceutical ingredients (i.e., at least estetrol and drospirenone in the context of the present disclosure) and a pharmaceutically acceptable formulation is obtained.

[0114] Optionally, the composition is contained in a tablet, and the tablet, in addition to comprising estetrol and drospirenone, also comprises a filler, a super disintegrant, a binder and a disintegrant, another binder and a lubricant. In a preferred embodiment, the composition is contained in a tablet, and the tablet comprises estetrol and drospirenone, lactose, sodium starch glycolate, corn / corn starch, povidone and magnesium stearate. Preferably, the composition is contained in a tablet, and the tablet comprises estetrol monohydrate, drospirenone, lactose monohydrate, sodium starch glycolate type A, corn starch, povidone K30 and magnesium stearate. Optionally, the tablet is coated with a coating agent. In a further optional embodiment, the coating agent comprises hypromellose, hydroxypropyl cellulose, titanium dioxide, red iron oxide, hydrogenated cottonseed oil and talc. As an illustration and not limitation, a suitable coating agent is AquaPolishPink 044.08MS. It will also be understood by those skilled in the art that any excipients present in any dosage unit (eg, oral dosage unit) should conform to pharmaceutical grade industry quality standards such as Ph. Eur. and USP-NF.

[0115] The (solid) oral dosage unit may be suitable for, or even specifically formulated for, sublingual, buccal, and / or sublabial administration. The dosage unit may be capable of rapidly releasing estetrol and drospirenone upon contact with an aqueous solvent, such as saliva. Thus, in such an embodiment, the solid dosage unit is an orally dispersible dosage unit that releases at least about 50%, preferably at least about 60%, more preferably at least about 70%, even more preferably at least about 80%, and most preferably greater than about 80% of the estetrol and / or drospirenone within about 5 minutes, preferably within about 3 minutes, more preferably within about 2.5 minutes, more preferably within about 90 seconds, and most preferably within about 90 seconds. The dosage unit may be an orally dispersible dosage unit. In such an embodiment, when the dosage unit comes into contact with saliva, it rapidly disintegrates in the oral cavity and disperses the estetrol and / or drospirenone into the saliva, whereupon it can be absorbed through the mucosal lining of the oral cavity. Methods for determining the release rate of pharmaceutically active ingredients (e.g., estetrol and drospirenone) from a dosage unit are known to those skilled in the art. Non-limiting standardized tests generally accepted in the art include those according to Ph. Eur 2.9.1 ("Disintegration of Tablets and Capsules") and USP <701> ("Disintegration") is a disintegration test performed, for example, using water as the disintegration medium.

[0116] As used herein, the term "sublingual" refers to a pharmacological route of administration whereby estetrol and / or drospirenone (contained in a dosage unit) diffuses into the bloodstream through the tissues beneath the tongue.

[0117] As used herein, the term "buccally" refers to a pharmacological route of administration whereby estetrol and / or drospirenone (contained in a dosage unit) diffuses into the bloodstream through the tissues of the oral vestibule, the area between the buccal lining (oral mucosa) and the teeth / gums within the mouth.

[0118] As used herein, the term "sublabial" refers to a pharmacological route of administration in which estetrol and / or drospirenone (contained in the dosage unit) is placed between the lip and the gum.

[0119] In certain embodiments, estetrol and drospirenone are formulated into solid dosage units, including but not limited to hard capsules, soft capsules, tablets, coated tablets such as enameled tablets or sugar-coated tablets, granules, aqueous or oily solutions, syrups, emulsions, suspensions, ointments, pastes, lotions, gels, inhalants, or suppositories. In embodiments where an effective amount of estetrol and drospirenone is administered orally, the oral dosage units according to the present invention are preferably solid or semisolid dosage units, such as tablets, capsules, cachets, pellets, pills, powders, and granules. The term "solid or semisolid dosage unit" also includes capsules containing a liquid (e.g., oil) in which the estetrol and drospirenone of the present invention are dissolved or dispersed. Tablets and equivalent solid and semisolid dosage units may suitably contain materials such as binders (e.g., hydroxypropylmethylcellulose, polyvinylpyrrolidone, other cellulosic materials, and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate, and cellulosic materials), disintegrants (e.g., starch polymers and cellulosic materials), and lubricants (e.g., stearates or salts and talc). These tablets and equivalent solid dosage units may be prepared by any suitable method described in detail in the art (e.g., Kaur, Int Res J Pharm, 2012). Non-limiting examples of processing estetrol and drospirenone when preparing dosage units include wet granulation, e.g., using aqueous or organic solutions, direct compression, 3D printing, or coating estetrol and drospirenone on carrier particles using organic or inorganic solvents.

[0120] As an illustration and not limitation, oral dosage units comprising the composition themes of the present disclosure can be prepared by methods involving wet granulation. It will be appreciated by those skilled in the art that the wet granulation method can suitably include the following successive steps: distribution and screening of the active ingredient and excipients, mixing the screened material in a processor, granulation, screening of the particles (i.e., further screening), and one or more mixing steps of the screened particles with one or more additional excipients. The particles can then be compressed into, for example, tablets, optionally including a coating step for the tablets, with a view to the final dosage unit.

[0121] Estetrol can be included in the composition and the final dosage unit as granules. Optionally, the estetrol granules have a D(10) of about 0.5 μm to about 10 μm, preferably about 1 μm to about 5 μm, more preferably about 1.5 μm to about 2.5 μm. Optionally, the estetrol granules have a D(50) of less than 20 μm or preferably less than 12 μm, more preferably about 5 μm to about 15 μm, preferably about 6 μm to about 12 μm, more preferably about 7 μm to about 11 μm, most preferably about 8 μm to about 12 μm. Optionally, the estetrol granules have a D(90) of about 15 μm to about 50 μm, preferably about 20 μm to about 30 μm, more preferably about 22 μm to about 28 μm. Optionally, the estetrol granules are further granulated into larger granules. In certain embodiments, estetrol is included in the composition as a plurality of larger particles having a volume median diameter of about 100 μm to about 4000 μm, preferably about 200 μm to about 1000 μm, more preferably about 200 μm to about 600 μm.

[0122] There are a variety of measurement techniques that can be used to determine particle size distribution values, including sieve analysis, air elutriation analysis, photo analysis, optical counting, resistance counting, sedimentation, laser diffraction, laser obscuration, transition time, acoustic spectroscopy, ultrasonic attenuation microscopy, using a cascade impactor, or any combination thereof. Unless otherwise explicitly mentioned, the particle size distribution values ​​disclosed herein are obtained by laser diffraction analysis. Laser diffraction analysis, which can be interchangeably annotated in the art by laser diffraction spectroscopy, is a particle measurement technique based on the interpretation of laser diffraction patterns passing through an object. Laser diffraction can measure the geometric dimensions of particles. Laser diffraction protocols have been described in detail many times in the art (e.g., reviewed in detail in the context of particle analysis in Eshel et al., Soil Science Society of America Journal, 2004).

[0123] Endometriosis-related or endometriosis-induced pain may be the result of endometrial tissue implants outside the uterine cavity in the pelvis, optionally accompanied by adenomyosis and uterine fibroids. As used herein, "pelvis" should be interpreted according to the definition generally accepted in the art, i.e., the lower part of the torso between the abdomen and the thighs. The pelvis contains embedded bones, commonly annotated as pelvic bones. Similarly, the skilled artisan readily understands that the uterine cavity is associated with the interior of the uterus. The uterine cavity is formed by the interior of the uterine body and is flanked by the fallopian tubes (the top of the endometrial hole that communicates with the cervical canal). Optionally, pain is caused by endometriosis in distal (extraperitoneal) sites, including but not limited to the colon, kidneys, liver, pancreas, and lungs. Optionally, endometrial tissue implants can result in ovarian lesions, peritoneal lesions, rectovaginal lesions, or any combination thereof, as further described below. Optionally, the pain is caused by implants of endometrial tissue located on the ovaries, fallopian tubes, tissues that hold the uterus in place (ligaments), the outer surface of the uterus, vagina, cervix, vulva, intestines, bladder, rectum, or any combination thereof.

[0124] Optionally, the pain is selected from the group consisting of chronic pelvic pain, pelvic pain such as lower abdominal pain and / or lower back pain, pain with defecation and pain with sexual intercourse, or pain caused by adhesions of the endometrium in the pouch of Douglas. As used herein, "chronic pelvic pain" is defined as pain in the pelvic region that persists for six months or longer. Chronic pelvic pain can be continuous or cyclical, optionally cyclical, and this does not limit the scope of the invention. As used herein, "Douglas pouch," interchangeably referred to as "rectouterine pouch," "rectovaginal pouch," or "cul-de-sac," refers to the extension of the peritoneum between the rectum and the posterior wall of the uterus. As is well known, the pouch of Douglas is the deepest point in the peritoneal cavity.

[0125] The compositions, uses and methods of use described herein each result in a significant improvement in pain associated with or induced by endometriosis, particularly in patients characterized by a VAS score of at least about 40 mm, at least about 50 mm, at least about 60 mm, at least about 70 mm, wherein a significant improvement is observed when compared to hormonal treatment strategies described in the art. The method of assessing such pain improvement does not limit the present invention. Optionally, the improvement is measured by the Clinical Global Impression - Improvement scale (CGI-I scale), which has been described in detail in the art and is therefore well known to those skilled in the art (e.g., Busner and Targum, Psychiatry, 2007). The CGI-Improvement (CGI-I) is assessed at each visit to the patient after starting the medication, by the clinician comparing the patient's overall clinical condition with the condition one week before starting the medication (i.e., the so-called baseline visit). The following query is scored on a seven-point scale: "Compared to the patient's condition at the time of program admission [before starting medication], the patient's condition is:

[0126] 1 = marked improvement since the start of treatment;

[0127] 2 = markedly improved;

[0128] 3 = minimal improvement;

[0129] 4 = no change from baseline (start of treatment);

[0130] 5 = minimal deterioration;

[0131] 6 = marked deterioration;

[0132] 7 = Severe deterioration since start of treatment.

[0133] In a preferred embodiment, at least about 10%, preferably at least about 15%, more preferably at least about 20%, more preferably at least about 28%, or most preferably at least about 28.9%, or about 28.9% of patients show improvement compared to their condition before the start of administration of the composition. Alternatively, the improvement in pain since the start of treatment can be "minimal improvement" corresponding to a CGI-I score of 3, preferably "much improved" corresponding to a CGI-I score of 2, and most preferably "significantly improved" corresponding to a CGI-I score of 1. The CGI-I scale score is significantly improved compared to known treatment strategies, including but not limited to a fixed-dose combination tablet containing ethinylestradiol and drospirenone, more particularly a formulation of 20 μg ethinylestradiol and 3 mg drospirenone, administered in a flexible extended-cycle oral contraceptive regimen. Optionally, an improvement in the CGI-I scale corresponding to "minimal improvement or greater" (CGI-I score of 1 to 3) is achieved in at least about 75% of patients, preferably in at least about 77.5% of patients, more preferably in at least about 80% of patients, and most preferably in at least about 82% of patients.

[0134] Alternatively, the improvement can be measured using the Patient Global Impression - Improvement scale (PGI-I scale) known to those skilled in the art (e.g., Viktrup et al., BMC Urol, 2012). The improvement can result in at least about 30%, preferably at least about 40%, more preferably at least about 50%, more preferably at least about 60%, more preferably at least about 70%, even more preferably at least about 75%, and most preferably at least about 75.5% of patients being rated as "slightly satisfactory or higher" (PGI-I scores of 1 to 3) compared to the situation before the start of administration of the composition. The improvement can result in at least about 10%, preferably at least about 20%, and more preferably at least about 24% of patients being rated as "much satisfactory or higher" (PGI-I scores of 1 and 2). Alternatively, the improvement in pain since the start of treatment can be "slightly better" corresponding to a PGI-I of 3, preferably "much better" corresponding to a PGI-I of 2, and most preferably "much better" corresponding to a PGI-I of 1. The PGI-I scale score is significantly improved compared to known treatment strategies (e.g., but not limited to, a formulation containing ethinylestradiol and drospirenone in the form of a fixed-dose combination tablet administered as a flexible extended-cycle oral contraceptive regimen, more particularly a formulation of 20 μg ethinylestradiol and 3 mg drospirenone). Optionally, an improvement in the PGI-I scale corresponding to "mildly satisfactory or higher" (PGI-I score 1 to 3) is achieved in at least about 67.5% of patients, preferably in at least about 70% of patients, more preferably in about 72.5% of patients, and most preferably in at least about 75% of patients.

[0135] Optionally, use of the compositions and methods described herein can result in a significant improvement in the patient's quality of life compared to the time point before the start of use (i.e., treatment). Various assays for assessing the patient's quality of life have been described in the art, such as the Quality of Life Scale (QOLS) (Burckhardt and Anderson, Health Qual Life Outcomes, 2003). Thus, the quality of life measured by the patient's QOLS can be improved by at least 10%, preferably by at least 20%, preferably by at least 30%, preferably by at least 40%, preferably by at least 50%, compared to the patient's QOLS score before the start of administration of the composition.

[0136] The compositions, uses, and methods of use described herein are characterized by a high responder rate (across the general population). Optionally, the compositions, uses, and methods of use result in a responder rate of at least about 40%, preferably at least about 50%, more preferably at least about 60% or about 70%. The responder rate is significantly improved compared to known treatment strategies, including but not limited to a fixed-dose combination tablet containing ethinylestradiol and drospirenone, more particularly a formulation of 20 μg ethinylestradiol and 3 mg drospirenone, administered in a flexible extended-cycle oral contraceptive regimen.

[0137] Optionally, the dosage unit is administered to the patient via a continuous dosing regimen. The terms "continuously" and "continuously" as used herein refer to dosage units being administered at relatively regular intervals without significant (therapeutic) interruptions. Naturally, slight interruptions that do not affect the overall effectiveness of the method may occur, and in fact such deviations are encompassed by the present invention. Preferably, and more mathematically, a dosage regimen is considered continuous if the longest interval between two subsequent administrations is no more than 3.5 times the average interval. Even more preferably, the longest interval is no more than 2.5 times the average interval, and most preferably no more than 1.5 times the average interval. By way of illustration and not limitation, the therapeutic strategies and methods described herein preferably employ continuous administration of estetrol and drospirenone over a period of at least 10 days, preferably at least 20 days.

[0138] Preferably, the pharmaceutical compositions described herein are used in 21 to 28 daily dosing cycles (i.e., cyclical dosing regimens), for example, 21 to 28 daily active dosage units. The pharmaceutical compositions described herein can be used in 21, 22, 23, 24, 25, 26, 27, or 28 daily dosing cycles by administering a corresponding amount of daily active dosage units. The cycle preferably also includes a 7, 6, 5, or 4 day dosing-free interval. Preferably, the cycle includes a 4 day dosing-free interval.

[0139] As described above and supported by the following examples, use of the composition results in a significant reduction in VAS score from pre-dose to after the third dosing cycle, preferably from pre-dose to after the second dosing cycle. It should be understood that one dosing cycle corresponds to a daily dosing cycle as described above, supplemented with a dosing-free interval as described above. Optionally, from pre-dose to after the third dosing cycle, the use reduces the VAS score by at least 10%, preferably at least 20%, more preferably at least 30%, more preferably at least 40%, more preferably at least 50%, more preferably at least 60%, more preferably at least 70%, more preferably at least 80%, more preferably at least 90%. Preferably, from pre-dose to after the second dosing cycle, the use reduces the VAS score by at least 10%, preferably at least 20%, more preferably at least 30%, more preferably at least 40%, more preferably at least 50%, more preferably at least 60%, more preferably at least 70%, more preferably at least 80%, more preferably at least 90%. Optionally, the use reduces the VAS score to such an extent that a VAS score of less than about 40 mm is obtained after the second dosing cycle, and even after the third dosing cycle, preferably less than about 30 mm, preferably less than about 20 mm, most preferably less than about 15 mm, or even less than about 10 mm. Optionally, the use reduces the VAS score from pre-dosing to after the third dosing cycle by at least about 10 mm, preferably at least about 20 mm, preferably at least about 30 mm, preferably at least about 40 mm, preferably at least about 50 mm, preferably at least about 60 mm, preferably at least about 70 mm.

[0140] In further administration cycles, such as after the second administration cycle or after the third administration cycle, the reduction in VAS score as described above is maintained (i.e., maintained at a stable score or a substantially constant reduced score). Therefore, the pain relief and pain suppression effects of the composition are long-term effects without decreasing in efficacy over time.

[0141] Optionally, use of the composition results in an improvement in at least one parameter selected from the group consisting of severity of Douglas' induration, limited uterine mobility, pelvic tenderness, reduction in size of ovarian cysts assessed by TVUS or MRI, and number of ovarian cysts. In preferred embodiments, each of these parameters is improved by use of the composition. Preferably, the severity of Douglas' induration improves by at least about 10%, preferably at least about 20%, preferably at least about 30%, preferably at least about 40%, preferably at least about 50%, preferably at least about 60%, preferably at least about 70%, preferably at least about 80%, preferably at least about 90%. As used herein, "induration" refers to thickening and / or hardening of soft tissues of the body, and in the context of the present invention, refers to Douglas' pouch. Preferably, the major axis of the ovarian cyst is reduced by at least about 10 mm, preferably at least about 20 mm, preferably at least about 24.88 mm. Preferably, the minor axis of the ovarian cyst is reduced by at least about 10 mm, preferably at least about 20 mm, preferably at least about 26.24 mm. Preferably, the volume of the ovarian chocolate cyst is reduced by at least about 10 cm 3 , preferably at least about 20 cm 3 , preferably at least about 30 cm 3 , preferably at least about 39.56 cm 3 .

[0142] In a preferred embodiment, use of the composition results in a reduction in cancer antigen 125 (CA125). Preferably, CA125 serum levels are reduced to below 35 U / ml. "CA125" is interchangeably referred to in the art as "MUC-16" or "mucin-16" and is encoded in humans by the MUC16 gene.

[0143] The compositions, uses and methods of use described herein are characterized by a low incidence of treatment-emergent adverse events (TEAEs) compared to treatment strategies known in the art, which rely on the administration of estrogen and drospirenone, more particularly 20 μg ethinylestradiol and 3 mg drospirenone, in the form of a fixed-dose combination tablet administered in a flexible extended-cycle oral contraceptive regimen. It should be understood that a TEAE is an adverse event caused by the use of a certain pharmaceutical active ingredient, composition or dosage unit in a patient, which adverse event was not present before administration to the patient. Optionally, the TEAE is selected from intermenstrual bleeding, headache, nausea, heavy menstrual bleeding, including any combination thereof. Preferably, the sum of all TEAEs is at least 10% lower, preferably at least 20% lower, preferably at least 30% lower, preferably at least 40% lower, preferably at least 50% lower, compared to known treatment strategies (e.g., treatments relying on the administration of estrogen and drospirenone, more particularly 20 μg ethinylestradiol and 3 mg drospirenone, in a fixed-dose combination tablet administered in a flexible extended-cycle oral contraceptive regimen).

[0144] While drospirenone, particularly 2.5 mg to 3.5 mg of drospirenone, and more particularly about 3 mg of drospirenone, is highly preferred in the context of the present invention, other progestogen components are also contemplated as alternatives. Examples include, but are not limited to, levonorgestrel, norgestimate, norethisterone, demegestone, 3-β-hydroxydesogestrel, 3-ketodesogestrel, 17-deacetylnorgestimate, 19-norprogesterone, acetyloxypregnenolone, allylestrenol, amgestone, chlormadinone acetate, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, fluorogestone, and chlormadinone acetate. acetate), gastrienone, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol, mecirogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone, norethynodrel, norgestrel (including dextrorotatory (d)-norgestrel and left-right optically active (dl)-norgestrel), norgestrienone, normethisterone, progesterone, quingestanol, (17α)-17-hydroxy-11-methylene-19-norgestrel-4,15-Dien-20-yn-3-one, tibolone, trimegestone, algestone-acetophenide, nestorone, promegestone, 17-hydroxyprogesterone ester, 19-nor-17-hydroxyprogesterone, 17α-ethynyltestosterone, 17α-ethynyl-19-nortestosterone, d-17β-acetoxy-13β-ethyl-17α-ethynylpregn-4-en-3-one oxime, 6β,7β;15β,16β-dimethylene-3-oxo-17-pregn-4,9(11)-diene-21,17β-lactone or tanaproget, and precursors of these compounds capable of releasing these progestogens in vivo.

[0145] Another aspect of the present invention relates to a packaging unit containing the dosage units described herein. The packaging unit may include at least 14, preferably at least 21, and even more preferably at least 28 containers for supporting individually packaged and removable dosage units, wherein each container contains at least one dosage unit comprising from about 13.5 to about 16.5 mg of estetrol or estetrol monohydrate, preferably from about 15 mg of estetrol monohydrate, and from about 2.5 mg to about 3.5 mg of drospirenone, preferably from about 3 mg of drospirenone. Preferably, the individually packaged and individually removable dosage units are oral dosage units. More preferably, each individually packaged and individually removable dosage unit contains from about 13.5 mg to about 16.5 mg of estetrol or estetrol monohydrate, preferably from about 15 mg of estetrol monohydrate, and from about 2.5 mg to about 3.5 mg of drospirenone. Optionally, each of the additional containers for supporting the dosage units containing estetrol and drospirenone is individually visually arranged to present a recommended order of administration.

[0146] It will be appreciated by those skilled in the art that within the scope of the present invention, each packaging unit, such as a blister pack, may be numbered or otherwise labeled. The packaging unit may be provided in any suitable packaging known in the art, non-limiting examples being lozenges, sachets, pouches, bottles, films, sprays, microcapsules, implants, sticks, or blister packs.

[0147] By way of illustration and not limitation, each packaging unit can be a sealed blister pack having a cardboard, paperboard, or foil plastic backing, enclosed in a suitable lid. Also contemplated within any aspect of this definition are packaging units such as bottles. The material of the bottle is not particularly limited. In a preferred embodiment, the bottle is a glass bottle characterized by a color that reduces or prevents degradation of the bottle contents by, for example, ultraviolet light, while maintaining a transparency that permits visual inspection of the bottle contents. Suitable colors include, but are not limited to, amber, cobalt blue, or vintage green.

[0148] In a particular embodiment of the invention, the packaging unit comprises 28 containers or a multiple of 28 containers, such as 2 to 12 times 28 containers.

[0149] The packaging unit of the contraceptive kit disclosed herein can be a "compliance packaging". As known in the art, "compliance packaging" is a packaging unit of variable size and form, which, in addition to providing a suitable storage device for one or more drugs, is also intended to provide help and / or guidance to the patient to comply with the expected regular administration (Peck Gossel, Packaging the Pill, Manifesting Medicine: Bodies and Machines, New York: Taylor & Francis, 1999). As a non-limiting example, the packaging unit may be provided with a digital indication and / or symbol that allows the patient to track, for example, the patient's menstrual cycle. In a selectable non-limiting example, the packaging unit may include a device that sends an electronic signal to the patient when the scheduled administration time (i.e., a certain day) is reached, and the dosage unit for this time point is still contained in the packaging unit. In those instances, the electronic signal can be sent to a data storage device and / or to a user-defined electronic device, wherein a smartphone and smart wear are illustrative examples thereof. In certain embodiments, different parts of the packaging unit provide different sensory triggers to the patient, and non-limiting examples are different colors or roughness.

[0150] Although the present invention has been described in conjunction with specific embodiments thereof, it will be apparent that many substitutions, modifications, and variations will be apparent to those skilled in the art based on the foregoing description. Therefore, the present invention is intended to include all such substitutions, modifications, and variations within the spirit and broad scope of the appended claims. The aspects and embodiments of the present invention disclosed herein are further supported by the following non-limiting examples. The following specific experimental examples are provided to support the claimed invention, but should not be construed as limiting the scope of the invention. Example

[0151] Example 1. An open-label, parallel-group study to explore the pharmacodynamics, pharmacokinetics, and safety during 3-cycle treatment with 15 mg E4 monohydrate / 3 mg DRSP tablets in Japanese patients with endometriosis.

[0152] Study Objectives

[0153] The aim of this study was to explore the pain relief effects, pharmacodynamics, pharmacokinetics, and safety of a 15 mg E4 monohydrate / 3 mg DRSP tablet (hereinafter referred to as "E4 / DRSP") tablet administered daily for 24 days, followed by a 4-day placebo period, for a total of 28 days in three treatment cycles for patients with endometriosis.

[0154] Study Design

[0155] Multicenter, open-label, randomized, parallel group

[0156] Phase, research type

[0157] Phase II, Clinical Pharmacology

[0158] Eligibility Criteria

[0159] Inclusion criteria

[0160] 1. Endometriosis diagnosed by laparotomy / laparoscopy, and / or ovarian chocolate cyst diagnosed by TVUS or MRI

[0161] 2. Age ≥ 20 years and < 50 years

[0162] 3. Pelvic pain during the baseline observation period (defined as VAS score ≥40mm)

[0163] 4. Regular menstrual cycle during baseline observation period (25-38 days)

[0164] 5. Body mass index (BMI) < 30 kg / m2

[0165] 6. Fully understand the content of this trial and agree in writing to participate in this study

[0166] Exclusion criteria

[0167] 1. Undiagnosed abnormal vaginal bleeding in the 6 months prior to the screening test

[0168] 2. Endometrioma aged ≥40 years with a maximum diameter >10 cm

[0169] 3. Endometrioma containing solid components

[0170] 4. Surgical treatment of endometriosis by cyst aspiration (such as transvaginal alcohol fixation), laparotomy, or laparoscopy (laparoscopy) within 2 months before the screening test

[0171] 5. Oral contraceptives or hormonal preparations containing progestin have not improved endometriosis symptoms (moderate or severe pelvic pain)

[0172] 6. The researcher determines that surgical treatment of organic diseases should be prioritized.

[0173] 7. The presence or history of malignant tumors (such as cervical intraepithelial neoplasia, cervical cancer, breast cancer). Non-melanoma skin cancer is acceptable

[0174] 8. The presence or history of deep vein thrombosis, thrombophlebitis (excluding superficial), pulmonary embolism, cerebrovascular disease, coronary artery disease, etc.

[0175] 9. Aged ≥35 years and smoking ≥15 cigarettes per day

[0176] 10. Migraine with aura (flash, dark spots, star-shaped flashes, etc.)

[0177] 11. Valvular heart disease associated with pulmonary hypertension or atrial fibrillation, or valvular heart disease with a history of subacute bacterial endocarditis

[0178] 12. Diabetes associated with vascular disease, such as diabetic nephropathy and diabetic retinopathy

[0179] 13. Thrombotic tendency (such as antithrombin, protein S and protein C deficiency)

[0180] 14. Phospholipid antibody syndrome (such as antiphospholipid antibody positive or unknown systemic lupus erythematosus)

[0181] 15. Planned surgery within 4 weeks after obtaining consent or surgery within 2 weeks before obtaining consent

[0182] 16. Severe liver damage (such as acute viral hepatitis, severe cirrhosis, etc.)

[0183] 17. Presence of liver tumor

[0184] 18. Severe (GFR < 60 mL / min / 1.73 m2) or acute renal damage

[0185] 19. History of heart disease, such as uncomplicated valvular heart disease

[0186] 20. Hypertension [systolic blood pressure ≥140 mmHg and / or diastolic blood pressure ≥90 mmHg]

[0187] 21. People with otosclerosis

[0188] 22. History of jaundice, persistent itching, or herpes during pregnancy

[0189] 23. Pregnant women or women who may become pregnant

[0190] 24. Delivery within 6 weeks before recruitment or miscarriage in mid-pregnancy

[0191] 25. Breastfeeding women

[0192] 26. Hypersensitivity reaction to the active ingredient of the study drug

[0193] 27.Yaz Flex combination tablets are banned

[0194] 28. History of discontinuation of sex hormone therapy due to adverse events or hypersensitivity reactions

[0195] 29. Have been taking drugs or their derivatives that are believed to affect the secretion of sex hormones

[0196] 30. Have you taken the following medications in the month before screening?

[0197] - Hormonal preparations containing progestogens, estrogens, low-dose contraceptive pills, fixed-dose combinations of progestogens and estrogens

[0198] -GnRH agonists / antagonists, testosterone derivatives

[0199] - Estrogen antagonists, aromatase inhibitors

[0200] - Herbal medicine for dysmenorrhea, endometritis, and menstrual pain

[0201] -Anticoagulants

[0202] - Medications for hypercholesterolemia, antidiabetic medications (including insulin), medications that affect serum potassium levels (ACE inhibitors, ARBs, potassium-sparing diuretics, aldosterone antagonists)

[0203] - Weak tranquilizers, antispasmodics

[0204] 31. Currently using or currently using the following drugs within 1 month before registration

[0205] -CYP3A4 inducers (such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John's wort, etc.)

[0206] -CYP3A4 inhibitors (such as cobicistat, indinavir, itraconazole, ritonavir, telaprevir, voriconazole, clarithromycin, nelfinavir, saquinavir, grapefruit juice, etc.)

[0207] -HIV protease inhibitors, HCV protease inhibitors, non-nucleoside reverse transcriptase inhibitors

[0208] 32. Regular use of analgesics for medical reasons other than relief of endometrial pain during the study period (occasional use is permitted; prophylaxis is not permitted)

[0209] 33. Participated in other trials within 1 month before the screening test, or took other research drugs within 3 months before the screening test. Participated in other clinical trials of oral contraceptives containing approved active ingredients in Japan and completed these trials within 2 months before the screening test

[0210] 34. Patients who wish to become pregnant or do not agree to abstain from sexual intercourse or contraception

[0211] *) During the study period

[0212] *) Use a barrier contraceptive device (male latex condom or contraceptive vaginal ring) approved or certified in Japan

[0213] 35. Deemed unqualified by the researcher.

[0214] Number of patients

[0215] A total of 80 patients were enrolled: 40 patients each in the E4 / DRSP or Yaz Flex group.

[0216] [Note] Because this trial was an exploratory clinical pharmacology study, its design was based on the results of previous clinical studies. Based on the results of the Phase III study of Yaz Flex combination tablets in patients with endometriosis (change in VAS for pelvic pain, lower abdominal pain, and lower back pain at the most advanced stage - change in VAS from the previous observation period), the number of cases required to maintain 80% efficacy was estimated, assuming an effect size (effect size) of 0.5 and a dropout rate of 15%.

[0217] Dosage, route of administration, and duration of treatment

[0218] Research Group:

[0219] -E4 monohydrate 15 mg / DRSP 3 mg, fixed-dose combination tablet

[0220] The drug was administered orally for 24 days, followed by 4 days of placebo administration, for a total of 28 days, divided into 3 cycles (84 days).

[0221] Reference Group:

[0222] -Yaz Flex (EE 20 μg / DRSP 3 mg, fixed-dose combination tablet)

[0223] Continue dosing until day 24, regardless of bleeding. If bleeding (including spotting) is observed for three consecutive days after day 25, discontinue the drug for four days. Continue dosing, regardless of whether bleeding has stopped or is continuing. The drug administration cycle lasts for 84 days.

[0224] Excluded medications and dietary products

[0225] Criteria for banning drugs

[0226] - Hormonal preparations containing progestogens and / or estrogens, low-dose OCs, fixed-dose combinations of progestogens and estrogens

[0227] -GnRH agonists / antagonists, testosterone derivatives, estrogen antagonists, aromatase inhibitors

[0228] - Drugs or their derivatives that are believed to affect the secretion of sex hormones

[0229] - Weak tranquilizers, antispasmodics

[0230] -CYP3A4 inducers (such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, etc.)

[0231] -CYP3A4 inhibitors (such as cobicistat, indinavir, itraconazole, ritonavir, telaprevir, voriconazole, clarithromycin, nelfinavir, saquinavir, grapefruit juice, etc.)

[0232] Herbal remedies for dysmenorrhea, endometritis, and menstrual pain

[0233] -Anticoagulants

[0234] - Medications for hypercholesterolemia, antidiabetic medications (including insulin), medications that affect serum potassium levels (ACE inhibitors, ARBs, potassium-sparing diuretics, aldosterone antagonists)

[0235] -HIV protease inhibitors

[0236] -HCV protease inhibitors

[0237] - Non-nucleoside reverse transcriptase inhibitors

[0238] - Other study drugs other than those used in this trial

[0239] Criteria for prohibiting treatment

[0240] - Cyst aspiration (eg, vaginal alcohol fixation), laparotomy, or laparoscopy for treatment or investigation

[0241] Use of analgesics

[0242] - Occasional use of analgesics for medical reasons (unbearable pain related to endometriosis and adverse events) is allowed during the study: loxoprofen tablets or granules (60 mg / time, ≤3 times a day), ibuprofen tablets or granules (200 mg / time, ≤3 times a day)

[0243] - No NSAID use is allowed during the study except loxoprofen and ibuprofen, which should be discontinued before the first follow-up visit if applicable

[0244] Main criteria for evaluation and analysis

[0245] 1. Worst pelvic pain

[0246] Visual Analog Scale (VAS) collected from patient diaries

[0247] 2. Gynecological examination

[0248] Douglas' induration, restricted uterine mobility, and pelvic tenderness

[0249] 3. Hemostasis and related parameters

[0250] Protein S (total activity, antigen (total), specific activity, antigen (free)), free TFPI antigen, antithrombin activity, APC sensitivity ratio (based on APTT, based on ETP), D-dimer, fibrinogen, factor V / VII / X, prothrombin time, protein C, plasminogen, tPA-PAI-1 complex, prothrombin fragments 1+2, soluble fibrin monomer complex, APTT, SHBG

[0251] 4. Endocrine parameters

[0252] Estradiol, progesterone, LH, FSH

[0253] 5. Security

[0254] Adverse events, clinical laboratory tests, weight, vital signs (blood pressure, pulse, temperature), 12-lead ECG, physical examination

[0255] 6. Pharmacokinetics

[0256] Plasma concentrations of E4, EE, and DRSP

[0257] Key statistical considerations

[0258] 1. Worst pelvic pain (VAS): according to the protocol group

[0259] Descriptive statistics (number of patients, arithmetic mean, standard deviation, % coefficient of variation, quartiles, minimum and maximum values) were used to summarize the change from baseline in VAS by stratification factor, visit, and group. Analytic variance analysis (ANOVA) was performed using the stratification factor as a fixed effect. Within the ANOVA framework, the LS mean and two-sided 95% confidence intervals for the change from baseline were extrapolated by follow-up and group.

[0260] 2. Pain scores related to endometriosis and dysmenorrhea scores: According to the protocol group

[0261] Descriptive statistics were used to calculate the changes from baseline in the "endometriosis pain score and dysmenorrhea score" during treatment by group and follow-up.

[0262] 3. Gynecological examination

[0263] Descriptive statistics for continuous variables and frequencies for categorical data were estimated separately.

[0264] 4. Endocrine-related parameters

[0265] Descriptive statistics were used to calculate the absolute and relative changes from baseline by group and follow-up.

[0266] 5. Hemostasis and related parameters: according to the protocol group population

[0267] Adopt descriptive statistics, by grouping and follow up the variation (observed and relative %) of each parameter from baseline.By follow up and grouping, carry out ANOVA to estimate the LS mean value and two-sided 95% confidence interval (relative %) of variation from baseline.Use the model that has considered visit treatment interaction term, the difference of LS mean value (E4 / DRSP-Yaz) and two-sided 95% confidence interval has been carried out identical ANOVA analysis.

[0268] 6. Safety: Safe people

[0269] Descriptive statistics were used to summarize continuous variables (clinical laboratory tests, blood pressure, pulse, temperature, weight, and 12-lead electrocardiogram) by follow-up and group. Categorical (AE) variables were summarized using frequency tables giving the number and percentage of patients in each category. The latest version of MedDRA was used.

[0270] 7. Pharmacokinetics: Safety Population

[0271] Descriptive statistics were used to summarize serum or plasma concentrations of E4, EE, and DRSP by group and by follow-up. In addition, nonlinear mixed-effects models were used to explore exposure-response relationships, where applicable.

[0272] Summary of Results

[0273] 1. Efficacy for endometriosis-related pain

[0274] In both the per-protocol analysis set (PPS) and full analysis set (FAS) populations, E4 / DRSP and Yaz Flex were found to similarly reduce the VAS values ​​for grading the most severe pelvic pain (lower abdominal and back pain). The change from baseline in VAS values ​​remained largely stable after cycle 2, or 56 days of flexible dosing, and during the efficacy assessment period (EAP), cycle 3, or 84 days of flexible dosing, resulted in -32.48±19.575 (mean±SD, as above) mm in the E4 / DRSP and -33.93±27.024 mm in the Yaz Flex groups, respectively.

[0275] The numerical rating scale (NRS) also showed that any type of pain related to endometriosis was relatively improved between the E4 / DRSP and Yaz Flexible groups throughout the treatment period.

[0276] In both groups, the dysmenorrhea score, which consists of dysmenorrhea symptom severity and analgesic use, also decreased after dosing in cycles 2 and 3, or on days 56 and 84, but slightly greater improvements were observed in the Yaz Flexible group. Dysmenorrhea symptom severity and analgesic use showed a similar pattern to the dysmenorrhea score. Analgesic use decreased at visits 5 and 6 in both the E4 / DRSP and Yaz Flexible groups, but the magnitude of improvement was slightly greater in the Yaz Flexible group.

[0277] Gynecological examination revealed slight improvement in the severity of Douglas' induration, limited uterine mobility and pelvic tenderness, and the size and number of ovarian chocolate cysts.

[0278] In the Clinical Global Impression - Improvement (measured on the CGI-I scale) after 3 cycles or 84 days of flexible dosing, the frequency of "improved or greater" (CGI-I scores of 1 and 2) was 28.9% (13 / 45 patients) in the E4 / DRSP group and 40% (16 / 40 patients) in the Yaz flexible group. Similarly, the frequency of "slightly improved or greater" (CGI-I scores of 1 to 3) was rated 82.2% (37 / 45 patients) and 72.5% (29 / 40 patients) in the E4 / DRSP and Yaz flexible groups, respectively. In addition, the Patient Global Impression of Improvement (PGI-I) study found that 24% of patients (11 / 45) and 75.5% (34 / 45) of patients in the E4 / DRSP group were rated as "significantly satisfied or greater" (PGI-I scores of 1 and 2) and "slightly satisfied or greater" (PGI-I scores of 1 to 3), respectively. Scores were similar in the Yaz Flexible group, with an estimated 32.5% (13 / 40 patients) being "very satisfied or higher" (PGI-I scores 1 and 2) and 65.0% (26 / 40 patients) being "slightly satisfied or higher" (PGI-I scores 1 to 3).

[0279] 2. Effects on the blood coagulation-fibrinolysis system

[0280] Both the forest plot and ANOVA indicated that E4 / DRSP had very limited effects on the blood coagulation-fibrinolysis system, especially on the baseline variability of hemostatic parameters, compared with the Yaz flexible group. The collection or results can be summarized as shown in Tables 1 to 3 below;

[0281] Table 1. Hemostatic parameters that were statistically significant only in the Yaz Flexible group (change from baseline, %)

[0282] factor E4 / DRSP Yaz is flexible D-dimer 16.457％ 75.927％ PT (seconds) -1.59％ -4.91％ PT-INR -1.561％ -4.779％ Soluble fibrin monomer 1.06％ 8.84％ Protein S, antigen 0.163％ -16.554％ Factor V -1.7％ -8.9％ Protein C 3.0％ 13.7％ Prothrombin fragment F1+2 1.3％ 47.6％

[0283] (p<0.05)

[0284] Table 2. Statistically significant hemostatic parameters in the E4 / DRSP and Yaz flexible groups (change from baseline, %)

[0285] factor E4 / DRSP Yaz is flexible Fibrinogen 11.2％ 15.2％ APTT (sec) -8.00％ -11.21％ APTT (controlled) -0.63％ -0.73％ Protein S (total activity) 8.707％ -10.992％ Protein S (specific activity) 8.987％ 6.728％ Protein S (free antigen) 7.8％ -13.6％ Free TFPI (antigen) -21.1％ -47.2％ APCsr (based on APTT) -1.650％ -3.462％ APCsr (based on ETP) 41.544％ 155.624％ Factor VII 14.2％ 53.0％ Factor X 17.4％ 32.1％ Plasminogen 14.1％ 36.0％ SHBG 63.12％ 210.40％

[0286] (p<0.05)

[0287] Table 3. Statistically significant group differences in hemostatic parameters in change from baseline (%) between the E4 / DRSP and Yaz flexible groups.

[0288]

[0289]

[0290] 3. Pharmacokinetics

[0291] Higher drug concentrations were observed for E4 (E4 / DRSP group), EE (Yaz flexible group), and DRSP (E4 / DRSP and Yaz flexible groups) measured 2 hours after dosing, followed by a gradual decrease over time. Nonlinear mixed model analysis was performed, with two-compartment models of first-order absorption and elimination for E4 and DRSP. A marginal relationship appeared between the CL on E4 and body dimensions, such as BMI, but statistical significance was not confirmed and is unlikely to be indicative of potential patient covariates, including DRSP. No nonlinear mixed model was developed for EE.

[0292] 4. Security

[0293] Treatment-emergent adverse events (TEAEs) were reported in 88.9% (40 / 45 patients) of the E4 / DRSP group and 92.7% (38 / 41 patients) of the Yaz Flexible group. Causality could not be excluded for TEAEs in 77.8% (35 / 45 patients) of the E4 / DRSP group and 90.2% (37 / 41 patients) of the Yaz Flexible group. No serious adverse events (SAEs) were reported in the E4 / DRSP group, but one SAE, deep vein thrombosis, was reported in the Yaz Flexible group. One serious TEAE, thrombosed hemorrhoid, was observed in the Yaz Flexible group but not in the E4 / DRSP group. No serious TEAEs with a causal relationship were reported in either treatment group. One patient in the Yaz Flexible group discontinued the study prematurely due to fatigue and loss of appetite. In contrast, there were no TEAEs leading to premature discontinuation in the E4 / DRSP group.

[0294] In the E4 / DRSP group, the most frequently reported TEAEs were intermenstrual bleeding (68.9%, 31 / 45 patients), headache (17.8%, 8 / 45 patients), and abdominal discomfort / nausea / heavy menstrual bleeding (6.7%, 3 / 45 patients each). Causally related TEAEs were intermenstrual bleeding (68.9%, 31 / 45 patients), headache (6.7%, 3 / 45 patients), and heavy menstrual bleeding (6.7%, 3 / 45 patients). In the Yaz Flexible group, intermenstrual bleeding, headache, nausea, and heavy menstrual bleeding were reported by 73.2% (30 / 41 patients), 26.8% (11 / 41 patients), 22.0% (9 / 41 patients), and 12.2% (5 / 41 patients), respectively, as highly reported TEAEs. Fatigue, edema, and nasopharyngitis occurred in 3 / 41 patients (7.3%). Among them, the causally related TEAEs were intermenstrual bleeding in 73.2%, nausea in 22.0%, headache and heavy menstrual bleeding in 9.8% each, and edema in 7.3%.

[0295] After three cyclical or flexible administrations, the endometrial thickness in the E4 / DRSP group was 4.35±2.340 mm (mean / standard deviation, same as above), and that in the Yaz flexible group was 3.73±1.666 mm, both of which were relatively thinner.

[0296] The number of bleeding days was calculated as 30.4 ± 14.58 days in the E4 / DRSP group and 27.4 ± 14.29 days in the Yaz Flexible group. Bleeding events occurred similarly in both groups, with an assessment of 4.5 ± 1.19 days in the E4 / DRSP group and 3.4 ± 1.39 days in the Yaz Flexible group. Bleeding events lasted for 7.32 ± 4.750 days in the E4 / DRSP group and 8.65 ± 5.137 days in the Yaz Flexible group. In the E4 / DRSP group, spotting was reported in 23.3% (251 / 1076 days), 15.1% (159 / 1056 days), and 10.4% (110 / 1056 days) of treatment cycles 1, 2, and 3 (excluding the placebo period), respectively. In contrast, event rates in the Yaz Flexible group were 22.9% (255 / 1113 days), 10.6% (105 / 991 days), and 8.8% (74 / 840 days) during the 28, 56, and 84-day flexible treatment periods, respectively. Similar results were obtained for bleeding events: E4 / DRSP - 29.0% (312 / 1076 days) in the first cycle, 8.0% (85 / 1056 days) in the second cycle, and 10.0% (106 / 1056 days) in the third cycle. Yaz Flexible - 27.9% (310 / 1113 days) in the 28-day flexible dosing, 7.6% (75 / 991 days) in the 56-day flexible dosing, and 4.5% (38 / 840 days) in the 84-day flexible dosing. During the hormone-free interval, the number of genital bleeding events with Yaz flexible was less than that with E4 / DRSP, and most of them were spotting events.

[0297] No significant findings were found in clinical laboratory tests (including hematological tests, biochemical tests, urine tests, physical examinations, and body mass (height, weight, and BMI)) in either group.

[0298] No abnormal ECG changes were observed after the second follow-up in DRSP / E4. In contrast, the second follow-up ECG examination revealed three events (ECG abnormality, right bundle branch block, and first-degree atrioventricular block) in two patients in the Yaz flexible group, all of which were diagnosed as complications.

[0299] No abnormal shifts in the QTc interval were observed in either the E4 / DRSP or Yaz Flexible groups. In the E4 / DRSP group, QTcB (Bazett-type correction) and QTcF (Fredericia-type correction) were assessed at visit 6 / EOS, respectively, at 409.7±42.29 msec and 406.6±42.92 msec. Similar values ​​were observed in the Yaz Flexible group, at 419.3±21.99 msec (QTcB) and 415.0±20.04 msec (QTcF), respectively.

[0300] Special analysis results after database lock

[0301] This analysis aimed to characterize the patient population in Japanese endometriosis patients for whom E4 / DRSP FDC (fixed-dose combination) tablets provide clinical benefit and compare it with EE / DRSP FDC (Yaz flexible).

[0302] The worst pelvic pain in two different menstrual cycles (before treatment) was estimated to be approximately 70 mm VAS value as the median value for the E4 / DRSP and Yaz flexible groups, meaning that 50% of the randomized patients suffered from pain intensity corresponding to 70 mm or greater.

[0303] This set of analyses consisted of three distinct parts. First, individual pain intensity (VAS) distributions over time were plotted based on daily VAS values, and spline functions were applied to elucidate the VAS distributions over time for each medication (i.e., E4 / DRSP and Yaz Flexible groups). Figure 1 As shown, the spline curve profiles indicate that pain intensity was suppressed to varying degrees during the non-withdrawal bleeding period between the two drugs, with E4 / DRSP achieving a more suppressive VAS reduction during the active dosing period compared to Yaz Flexible. As a second part, the significant VAS curve over time was quantified according to the following definition - the proportion of days with a VAS reduction of 70 mm or more from baseline in 80% or more of the assessment period ( Figure 2 ). In this analysis, patients who met the criteria are tentatively referred to as "responders". Ultimately, the key question is what clinical advantage is conferred to responders, and the CGI-I and PGI-I scores are investigated to correlate with the criteria. To this end, the primary focus is on the observation of higher CGI-I and / or PGI-I scores in responders. The Cochran-Armitage test indicated a statistically significant trend in responders (p = 0.009), but not in non-responders, leading to a statistically significant trend in clinical investigators and patients compared to non-responders (solid grey fill, Figure 3 ) compared to the control group, marked significantly improved / satisfactory or higher ratings among responders (diagonal stripes, Figure 3Finally, the responder rates were compared between E4 / DRSP and Yaz Flexible. The E4 / DRSP group resulted in a responder rate of approximately 60%, whereas the Yaz Flexible group had a responder rate of approximately half, approximately 30%. Figure 4 Statistical significance was observed using the chi-square test (p=0.033).

[0304] In conclusion, it is suggested that E4 / DRSP can reduce non-menstrual pelvic pain more flexibly and effectively than Yaz, thereby improving CGI-I and PGI-I.

[0305] Example 2. Efficacy and safety of estratetol monohydrate 15 mg / drospirenone 3 mg combination (E4 / DRSP) in a cyclical regimen for the treatment of endometriosis-associated pain and objective gynecological outcomes: a multicenter, placebo-controlled, double-blind, randomized study

[0306] Materials and methods

[0307] Study Design

[0308] A multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in Japanese patients with endometriosis to investigate the potential of E4 / DRSP for the treatment of endometriosis-associated pelvic pain (EAPP) after six 24-week cycles of E4 / DRSP (24 days per cycle followed by a 4-day hormone-free interval).

[0309] patient

[0310] Patients aged 20 years or older with a diagnosis of endometriosis were enrolled. Clinical diagnosis was confirmed by laparotomy / laparoscopy, transvaginal ultrasound (TVUS), magnetic resonance imaging (MRI) (for the presence of ovarian endometrioma), or gynecologic examination. Another key eligibility criterion was an EAPP ≥40 mm on a visual analog scale (VAS) during the baseline observation period. Demographic and baseline characteristics are shown in Table 4.

[0311] Table 4: Demographics and baseline characteristics (FAS).

[0312]

[0313] 1) Mean ± standard deviation, 2) Range (minimum - maximum)

[0314] Other inclusion and exclusion criteria

[0315] The patients had regular menstrual cycles (25-38 days) and BMI < 30 kg / m2 in the last two menstrual cycles before randomization. 2 Japanese patients were included. Patients who signed informed consent based on their full understanding of the trial were included.

[0316] Additional exclusion criteria were patients with undiagnosed abnormal vaginal bleeding within 6 months before the screening test; patients aged ≥40 years with ovarian endometriomas >10 cm in greatest diameter; patients with ovarian endometriomas containing solid components; patients who had surgical treatment for endometriosis, adenomyosis, and uterine fibroids by cyst aspiration (e.g., transvaginal alcohol fixation), laparotomy, or laparoscopy within 2 months before the screening test; patients whose endometriosis symptoms (moderate or severe pelvic pain) did not improve with the use of combined oral contraceptives or hormonal preparations containing progestins; patients who used analgesics regularly during the study for medical reasons other than relief of endometriosis pain (occasional use was allowed; prophylaxis was not allowed); patients who were diagnosed with Patients undergoing surgery; patients with a history of hormone-related malignancies (non-melanoma skin cancers are permitted); patients with a history of deep vein thrombosis, thrombophlebitis (except superficial), pulmonary embolism, cerebrovascular disease, and coronary artery disease; patients aged ≥35 years who smoke ≥15 cigarettes per day; patients with a history of migraine with aura; patients with valvular heart disease with pulmonary hypertension or atrial fibrillation and a history of subacute bacterial endocarditis; patients with diabetes associated with vascular disease (e.g., diabetic nephropathy, diabetic retinopathy); patients with known thrombotic mutations (e.g., factor V; prothrombin mutations; protein S, protein C, and antithrombin deficiencies); and patients with antiphospholipid antibody syndrome. Patients with leukemia (such as antiphospholipid antibody positive or unknown systemic lupus erythematosus); patients scheduled to undergo surgery within 4 weeks after signing the informed consent, patients who underwent surgery within 2 weeks before signing the informed consent, or patients who were in a long-term rest state when signing the informed consent; patients with severe liver damage (such as acute viral hepatitis, severe cirrhosis); patients with liver tumors, patients with severe or acute kidney damage; patients with a history of heart disease (such as uncomplicated valvular heart disease) or complications; patients with hypertension (except mild hypertension), severe dyslipidemia (such as severe familial dysbetalipoproteinemia), otosclerosis, uncontrolled thyroid disease; patients with clinical diagnosis of severe depression before screening or in the past year; pregnant women Patients with a history of jaundice, persistent itching or herpes; patients who are pregnant or may be pregnant; patients who have given birth or had a miscarriage in the second trimester within 6 weeks before screening; breastfeeding women; patients with a tendency to be allergic to the components of the study drugs; patients with a history of side effects or hypersensitivity reactions that require discontinuation of medication during sex steroid hormone therapy; patients taking drugs and derivatives that are believed to affect sex hormone secretion; patients who have taken hormonal preparations containing progestogens, estrogens, low-dose oral contraceptives, combinations of progestogens and estrogens, testosterone derivatives, estrogen antagonists, aromatase inhibitors, herbal medicines for dysmenorrhea, endometritis and menstrual pain, anxiolytics or antispasmodics within one month before screening, or patients who have taken GnRH analogs within 2 months before screening;Patients who are currently using or have used drugs that may trigger interactions with combined oral contraceptives within 1 month before randomization. This includes but is not limited to: CYP3A4 inducers, CYP3A4 inhibitors, HIV and / or HCV protease inhibitors, non-nucleoside reverse transcriptase inhibitors; patients who participated in other clinical trials within one month before screening or took other research drugs within three months before screening; patients who wish to become pregnant or do not agree to abstain from sexual intercourse or contraception (using barrier contraceptive devices approved or certified in Japan (male condoms or contraceptive vaginal suppositories)) during this study; patients who are deemed ineligible by the investigator or assistant investigator for other reasons.

[0317] deal with

[0318] Eligible patients were randomly assigned to the E4 / DRSP group or the placebo group in equivalent proportions balanced for baseline VAS (<60 mm or ≥60 mm) and comorbidities (uterine fibroids and adenomyosis). After randomization, patients took one tablet daily starting on the first day of their menstrual period. In the E4 / DRSP group, patients received E4 / DRSP treatment according to a cyclical regimen for six consecutive cycles of 24 weeks. The placebo group received oral placebo tablets daily for 28 days per cycle for a total of six cycles. The stratified randomization code was developed using a permuted group design using an interactive web-response system and controlled by an office independent of the clinical investigators and other study stakeholders to ensure the blinding of the study.

[0319] Assessment endpoint

[0320] The primary endpoint was the change from baseline in the VAS score in the most severe EAPP after six treatment cycles (Bourdel N, Alves J, Pickering G, Ramilo I, Roman H, Canis M. Systematic Review of Endometriosis Pain Assessment: How to Choose a Scale? Hum Reprod Update. 2015; 21:136; Gerlinger C, Schumacher U, Faustmann T, Colligs A, Schmitz F, Seitz C. 2010. Defining a Minimal Clinically Important Difference for Endometriosis-Associated Pelvic Pain Measured on a Visual Analog Scale: Analyses of Two Placebo-Controlled, Randomized Trials. Health Qual Life Outcomes. 2010; 8:138). During baseline observation and treatment, patients were asked to grade their most severe EAPP (lower abdominal pain / back pain) using an electronic diary device equipped with a VAS. Baseline was the most severe EAPP during the observation period before randomization. Secondary endpoints included: 1) Numerical Rating Scales (NRS) for pelvic, chronic, acute, and defecation pain, and dyspareunia; 2) responder rate achieving a ≥30% or ≥50% reduction in the worst EAPP VAS or mean NRS from baseline to cycle 5 and 6; 3) gynecological examination: induration, pelvic tenderness, and uterine mobility restriction; 4) number and size of ovarian endometriomas (two-dimensional measurements) and endometrial thickness measured by TVUS; 5) intervention on daily activities and sleep using a five-point scale; 6) a seven-point scale rated by investigators (Clinical Global Impression of Improvement-I: CGI-I) and patients (Patient Global Satisfaction Impression-I: PGI-I); and 7) serum E2, P4, FSH, LH, and CA125. All secondary variables were collected using patient electronic diaries and interviewed or examined by investigators at the clinical study sites.

[0321] Throughout the study, treatment-emergent adverse events (TEAEs) were monitored as safety endpoints, with severity and causality judged by the investigator. Patients recorded bleeding events using an electronic diary device.

[0322] Statistical analysis

[0323] The primary analysis was performed using a mixed effects model with repeated measures to assess the point estimate of the group difference (E4 / DRSP-placebo) with a two-sided 95% confidence interval (CI) for the change in VAS of the most severe EAPP from baseline to the sixth treatment cycle. Secondary endpoints were assessed using the Wilcoxon test, Fisher's exact test, and two-sided 95% CI. Any efficacy analysis was performed on the full analysis set (FAS): patients who received one or more study drugs and obtained a VAS score for the EAPP. Safety analyses included the frequency of any TEAE, drug-related TEAEs, and severity and causality. This was performed using a safety analysis set of patients who took at least one study tablet. All descriptive statistics are presented as mean ± standard deviation. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., NC, USA).

[0324] result

[0325] patient

[0326] This study included 162 patients from 25 clinical research sites in Japan.

[0327] The FAS consisted of 79 patients in the E4 / DRSP group and 83 patients in the placebo group. The demographic characteristics were comparable between the groups (Table 4). The mean age was 34.7 years, and the body mass index was 21.4 kg / m 2 Of the 162 patients, 44 (27.2%) and 26 (16.0%) developed adenomyosis and uterine fibroids, respectively, and both complications were observed in 13 patients (8.0%).

[0328] effect

[0329] On average, after six treatment cycles, E4 / DRSP reduced the VAS score of the most severe EAPP by -33.2 mm from baseline. A mean reduction in pain intensity of -22.2 mm was observed in the placebo group. As shown in Table 5, after 24 weeks of treatment, the point estimate of the group difference was -8.5 mm (two-sided 95% CI: -16.1 to -0.9 mm), which was significant (p = 0.028).

[0330] Table 5: Change from baseline in VAS of the most severe EAPP after 24 weeks of treatment.

[0331]

[0332]

[0333] 1) Least squares mean, 2) Mean ± standard deviation, 3) Two-sided 95% confidence interval

[0334] During the fifth or sixth cycle, the response rates of patients in the E4 / DRSP group with a ≥30% and ≥50% reduction in VAS from baseline for the most severe EAPP were 53.2% and 36.4%, respectively, which were significantly higher than those in the placebo group.

[0335] The NRS grading showed that E4 / DRSP significantly reduced pain intensity, but did not relieve dyspareunia and defecation. In the E4 / DRSP group, the mean NRS response rates were 55.8% and 36.4%, respectively, with reductions of ≥30% and ≥50% from baseline, which were statistically significant compared with the placebo group.

[0336] After six treatment cycles, gynecological examinations showed objective improvement in the E4 / DRSP group (Table 6). No worsening of induration was diagnosed, and 23.1% of patients in the E4 / DRSP group showed significant improvement. Similar results were obtained for uterine mobility restriction. E4 / DRSP also prevented the progression of pelvic tenderness (E4 / DRSP 1.3%, placebo 12.0%) compared with the proportion of patients who worsened in the placebo group ( Figure 5 A). Substantial improvements were also observed in patients with adenomyosis ( Figure 5 B) Compared with the placebo group, the volume of the largest ovarian endometrioma in the E4 / DRSP group decreased by approximately 45.0%. Ovarian endometriomas also resolved in 7.7% of patients in the E4 / DRSP group. Serum CA125 levels returned to normal (<35 U / mL) in 19.2% of patients in the E4 / DRSP group and only in 2.4% of patients in the placebo group.

[0337]

[0338] In the E4 / DRSP group, there was no significant improvement in daily activities. However, six cycles of E4 / DRSP treatment did not result in patients rating themselves as "extremely disturbed" and reduced the proportion who rated themselves as "quite disturbed" by 9.0%, unlike the placebo group. Sleep disturbances were significantly improved in the E4 / DRSP group, with a 52.6% increase in the proportion of patients who rated themselves as "not disturbed at all." A significant improvement in overall impression was observed, with approximately 45% of patients in the E4 / DRSP group. Serum endocrine hormone levels decreased throughout the study period in the E4 / DRSP group. In the E4 / DRSP group, endometrial thickness changed from 9.81±3.66 mm at baseline to 4.83±2.48 mm at week 24.

[0339] Safety

[0340] TEAEs were reported by 77 of 79 patients (97.5%) in the E4 / DRSP group and 72 of 83 patients (86.7%) in the placebo group. In the E4 / DRSP group, intermenstrual bleeding events generally occurred and decreased over the course of treatment: 51.9% in the first cycle and 24.7% thereafter. Spotting was the primary event after the third treatment cycle, accounting for approximately 50% of bleeding events. Intermenstrual bleeding / spotting occurred less than 1 day after the second treatment cycle. TEAEs related to study drug were similar to those commonly reported with OCP and included nausea (6.3%), abdominal pain (2.5%), diarrhea (2.5%), somnolence (6.3%), and headache (6.3%) in the E4 / DRSP group. One patient in the placebo group discontinued treatment due to an elevated D-dimer level. Notably, fewer differences were observed in the proportion of patients with hemostatic parameters outside the reference range between the E4 / DRSP and placebo groups. No deaths or other serious AEs occurred during the treatment period. No clinically relevant changes were observed in other safety endpoints.

[0341] discuss

[0342] In this study, E4 / DRSP improved the most severe EAPP pain in a cyclic regimen, similar to EE / DRSP in a flexible extended regimen (Harada T, Kosaka S, Elliesen J, Yasuda M, Ito M, Momoeda M. Ethinylestradiol 20 μg / drospirenone 3 mg in a flexible extended regimen for the management of endometriosis-associated pelvic pain: a randomized controlled trial. Fertil Steril 2017;108:798–805), and demonstrated superiority to placebo. The responder rate also showed a more robust finding of EAPP relief (Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9–19), indicating that approximately 40% of patients achieved a ≥50% reduction in pain intensity from baseline. In addition, pain intensity was reduced by <40 mm, a goal for chronic pain management, in ≥50% of patients who received E4 / DRSP for 24 weeks (Carol S. Burckhardt and Kim D. Jones. Adult measures of pain the McGill Pain Questionnaire (MPQ), Rheumatoid Arthritis Pain Scale (RAPS), Short-Form McGill Pain Questionnaire (SF-MPQ), Verbal Descriptive Scale (VDS), Visual Analog Scale (VAS), and West Haven-Yale Multidisciplinary Pain Inventory (WHYMPI). Arthritis Care Res 2003;49:S96–S104).

[0343] Objective results of gynecological examination showed that the E4 / DRSP group had significantly improved pelvic tenderness, uterine mobility restriction and induration. In the E4 / DRSP group, the volume of ovarian endometriomas was significantly reduced, similar to that in the EE / DRSP and EE / norethindrone groups (Taniguchi F, Enatsu A, Ota I, Toda T, Arata K, Harada T. Effects of low-dose oral contraceptive pill containing drospirenone / ethinylestradiolin patients with endometrioma. Eur J Obstet Gynecol Reprod Biol 2015;191:116–20.; Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial. Fertil Steril 2008;90:1583–8). These treatment benefits were best demonstrated by the significant superiority of the E4 / DRSP group in QoL-related questionnaires and global impression scores.

[0344] Safety assessments revealed that intermenstrual bleeding events were the most frequently reported TEAEs associated with E4 / DRSP. The frequency decreased with increasing cycle number, consistent with a previous Phase III study involving 2,234 participants outside of Japan (Kaunitz AM, Achilles SL, Zatik J, Weyers S, Piltonen T, Suturina L, et al. Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol / drospirenone on bleeding patterns in healthy women. Contraception 2022;116:29–36). Other reported TEAEs are known to occur with OCPs, such as nausea and headache. No ventricular embolism (VTE) was reported, and the proportion of patients with D-dimer levels exceeding the upper limit was comparable to that in the placebo group, suggesting that E4 / DRSP has a minimal effect on hemostatic parameters.

[0345] E4 / DRSP meets the following requirements for the treatment of endometriosis: relief of EAPP, improvement in objective gynecological examination findings, and restoration of QoL and global impression. No safety concerns were raised, including hemostasis and bleeding pattern.

[0346] in conclusion

[0347] Conclusions: This study demonstrates that E4 / DRSP is clinically effective in treating EAPP, improving objective gynecological examination findings, QoL, and global impression in patients with endometriosis. Therefore, E4 / DRSP should be considered as a first-line treatment option for endometriosis.

Claims

1. A pharmaceutical composition comprising from about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone for use in relieving pain associated with endometriosis in a patient.

2. A pharmaceutical composition comprising from about 13.5 mg to about 16.5 mg of estetrol or a hydrate of estetrol and from about 2.5 mg to about 3.5 mg of drospirenone for use in treating a patient suffering from pelvic pain.

3. The pharmaceutical composition for use according to claim 1 or 2, wherein the pain in the patient is pain during the non-withdrawal bleeding phase.

4. The composition for use according to any one of claims 1 to 3, wherein the patient's pain is measured by a visual analog scale (VAS), preferably wherein the patient has pelvic pain determined by a VAS score of greater than about 40 mm, about 50 mm, about 60 mm or about 70 mm before administration.

5. The composition for use according to any one of claims 1 to 3, wherein the patient suffers from pelvic pain associated with endometriosis prior to administration, the pelvic pain having a VAS score of greater than about 40 mm, about 50 mm, about 60 mm or about 70 mm, preferably wherein the patient suffers from pelvic pain associated with endometriosis prior to administration, the pelvic pain having a VAS score of greater than about 40 mm, about 50 mm, about 60 mm or about 70 mm.

6. The composition for use according to any one of the preceding claims, wherein the pain is caused by migration of endometrial tissue outside the uterine cavity in the pelvis.

7. The composition for use according to any one of the preceding claims, wherein the pain is chronic pelvic pain, pelvic pain such as lower abdominal pain and / or lower back pain, pain during defecation and pain during sexual intercourse, or pain caused by adhesions of the endometrium in the pouch of Douglas.

8. The composition for use according to any one of the preceding claims, wherein said use results in an improvement in the CGI-I scale (Clinical Global Impression - Improvement scale), preferably wherein said use results in an improvement of about 28.9% in the CGI-I scale.

9. The composition for use according to any one of the preceding claims, wherein said use results in an improvement of the PGI-I scale (Patient Global Impression - Improvement scale) graded as "Much Satisfactory or More", preferably wherein said use results in an improvement of about 24% of the PGI-I scale graded as "Much Satisfactory or More".

10. The composition for use according to any one of the preceding claims, wherein the use results in a responder rate of about 60%.

11. The composition for use according to any one of the preceding claims, wherein the patient is diagnosed with endometriosis by laparotomy / laparoscopy and / or is assessed as having ovarian chocolate cysts by transvaginal ultrasound (TVUS) and / or magnetic resonance imaging (MRI).

12. Composition for use according to any one of the preceding claims, wherein the composition is used in a cycle of 21 to 28 daily active dosage units of the composition, preferably in a cycle of 24 active dosage units of the composition.

13. Composition for use according to claim 12, wherein the cycle comprises a 7-day, preferably a 4-day, dose-free interval.

14. The composition for use according to claim 12 or 13, wherein the use of the composition results in a decrease in VAS score after the second or third administration cycle compared to before administration, preferably wherein the decrease remains substantially stable after the second or third administration cycle.

15. The composition for use according to any one of the preceding claims, wherein use of the composition results in an improvement in the severity of Douglas' induration, an improvement in uterine mobility restriction and / or pelvic tenderness, and a reduction in the size and / or number of ovarian chocolate cysts as assessed by TVUS or MRI.

16. The composition for use according to any one of the preceding claims, wherein use of the composition results in fewer TEAEs than use of the EE 20 μg / DRSP 3 mg fixed dose combination tablet, preferably wherein the TEAEs are selected from the group consisting of: intermenstrual bleeding, headache, nausea and heavy menstrual bleeding.

17. The composition for use according to any one of the preceding claims, wherein the patient suffers from adenomyosis and / or uterine fibroids in addition to endometriosis.

18. A pharmaceutical composition comprising from about 13.5 mg to about 16.5 mg of estetrol or estetrol monohydrate and from about 2.5 mg to about 3.5 mg of drospirenone for relieving pain associated with endometriosis in a patient, wherein use comprises determining, prior to administration, whether the patient has pelvic pain as defined by a VAS score of greater than about 40 mm, about 50 mm, about 60 mm, or about 70 mm.

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