Compositions for treating pain associated with endometriosis

Abstract

To provide compositions for treating pain associated with endometriosis.SOLUTION: The present invention relates to a pharmaceutical composition containing estetrol and drospirenone for use in alleviating pain associated with endometriosis in a subject. The pharmaceutical composition described herein is effective in alleviating pain associated with endometriosis, particularly in subjects who report high levels, frequency and / or intensity of pain, such as measured by visual analogue scale (VAS) scores, and / or have additional co-morbidities, such as adenomyosis or uterine fibroids. The above and corresponding uses for methods of treatment are also described herein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates generally to the field of medicine, and more particularly to hormonal treatment of female subjects characterized by pain associated with endometriosis. Specifically, the present invention relates to a composition comprising estetrol and drospirenone for use in safely and effectively alleviating (i.e., reducing or treating) pain, particularly pelvic pain, in female subjects. The present invention is particularly effective in treating endometriosis subjects with high visual analog scale (VAS) scores. [Background technology]

[0002] Endometriosis is a medical condition characterized by the uncontrolled growth of endometrial tissue excluding the uterine cavity in female subjects, causing pain and sometimes even infertility or (ovarian) cancer. Recently, there has been increasing evidence that endometriosis is caused by multiple factors, but the exact cause is still under investigation. Associations with immune disorders, local hormonal influences, genetic predisposition, and even environmental pollutants have been described (Non-Patent Document 1). Several screening tools and tests have been proposed and tested, but none have been validated to accurately identify or predict individuals or populations most likely to have the disease. Therefore, histological and / or laparoscopic confirmation remains necessary to reach a definitive diagnosis. Early suspicion of endometriosis is a key factor for early diagnosis, as endometriosis can often present with symptoms similar to other conditions, contributing to delayed diagnosis.

[0003] Because diagnosis is difficult for doctors, it remains difficult to determine the exact incidence rate. However, one study suggests that up to 11% of reproductive-age women in the general population may be affected by this condition (Non-Patent Document 2). In 2021, the WHO stated that endometriosis has a significant social, public health, and economic impact, and reduces quality of life due to severe pain and other symptoms. At present, there is no therapeutic treatment available for this condition. Symptom management is therefore crucial to improving the quality of life of subjects affected by this condition.

[0004] Some symptomatic treatment strategies for managing endometriosis-induced pain have been described in the art, including the administration of nonsteroidal anti-inflammatory drugs, analgesics, and surgery to remove endometriotic tissue, adhesions, and scar tissue. However, each of these strategies is characterized by highly variable success rates, a significant risk of (severe) side effects, long-term safety concerns, and a combination thereof (Non-Patent Document 3).

[0005] Recently, the use of YAZ Flex (containing 20 μg ethinyl estradiol and 3 mg DRSP intended for use in a flexible extended-cycle oral contraceptive regimen) for pelvic pain associated with endometriosis has been studied (clinicaltrials.gov, trial identification number NCT03126747) and proven effective in managing pain associated with endometriosis. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Zondervan et al.,N Engl J Med,2020 [Non-patent document 2] Shafrir et al.,Best Pract Res Clin Obstet Gynaecol,2018 [Non-patent document 3] Johnson et al.,Hum Reprod,2013

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[0007] Nevertheless, there remains an unmet need for improved and innovative strategies for the management of this disease, particularly strategies that provide safe and effective reduction of endometriosis-induced pain, further improving the quality of life of subjects suffering from endometriosis and with fewer side effects than existing products. [Means for solving the problem]

[0008] As evidenced by the examples illustrating certain representative embodiments of the present invention, the inventors have discovered 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 alleviating pain associated with endometriosis in subjects. Unexpectedly, this composition was found to be superior to existing hormonal endometriosis therapies for pain relief, such as compositions comprising ethinylestradiol (EE) and drospirenone (DRSP), particularly in subjects who reported or believed to have high levels of pain caused by said endometriosis (i.e., high visual analog scale scores). This improvement was also observed in subjects suffering from adenomyosis and / or uterine fibroids in addition to endometriosis. Therefore, in a more general context, the compositions described herein are particularly suitable for alleviating endometriosis and endometriosis symptoms.

[0009] More specifically, the VAS of the most severe endometriosis-related pelvic pain is found to be similarly reduced between treatment group (E4 / DRSP) and control group (YAZ Flex; EE / DRSP).Surprisingly, E4 / DRSP is shown to be significantly more effective than control group in suppressing pain during non-withdrawal bleeding, especially in patients with pre-administration baseline VAS value of 70mm or more.Compared with other estrogens, combined with the generally good safety profile of estetrol that has been described many times throughout the art, it can therefore be concluded that endometriosis subjects with baseline VAS of 70mm or more should ideally use the E4 / DRSP composition tested, rather than other hormone compositions currently used to manage endometriosis pain during non-withdrawal bleeding.

[0010] Therefore, the present invention provides the following aspects. Aspect 1. A pharmaceutical composition comprising about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and about 2.5 mg to about 3.5 mg of drospirenone for use in alleviating pain associated with endometriosis in a subject and / or for use in treating endometriosis in said subject. Aspect 2. A pharmaceutical composition comprising about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and about 2.5 mg to about 3.5 mg of drospirenone for use in treating a subject suffering from pelvic pain and / or for use in treating endometriosis in said subject. Aspect 3. A pharmaceutical composition comprising about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and about 2.5 mg to about 3.5 mg of drospirenone for use in alleviating pain associated with endometriosis in a subject and / or for use in treating endometriosis in said subject, wherein the use comprises the step of determining whether the patient has pre-administration pelvic pain as defined by a visual analog scale (VAS) score of greater than about 40 mm, about 50 mm, about 60 mm, or about 70 mm. Aspect 4. Use of a composition comprising about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and about 2.5 mg to about 3.5 mg of drospirenone for the manufacture of a medicament for alleviating pain associated with endometriosis in a subject or for the manufacture of a medicament for treating endometriosis. Aspect 5. Use of a composition comprising about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and about 2.5 mg to about 3.5 mg of drospirenone for the manufacture of a medicament for treating a subject suffering from pelvic pain. Aspect 6. Use of a composition comprising about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and about 2.5 mg to about 3.5 mg of drospirenone for the manufacture of a medicament for alleviating pain associated with endometriosis in a subject or for the manufacture of a medicament for treating endometriosis in said subject, the use comprising the step of determining whether the patient has pelvic pain prior to administration as defined by a VAS score of greater than about 40 mm, about 50 mm, about 60 mm, or about 70 mm. Aspect 7. A method for alleviating pain associated with endometriosis in a subject or for treating endometriosis in said subject, comprising administering to said subject a composition comprising from about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and from about 2.5 mg to about 3.5 mg of drospirenone. Aspect 8. A method for treating a subject suffering from pelvic pain, comprising administering to the subject a composition comprising from about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and from about 2.5 mg to about 3.5 mg of drospirenone. Aspect 9. A method for alleviating pain associated with endometriosis in a subject or for treating endometriosis in said subject, comprising a first 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, and comprising the further step of administering to said subject a composition comprising between about 13.5 mg and about 16.5 mg of estetrol and between about 2.5 mg and about 3.5 mg of drospirenone. Aspect 10. A pharmaceutical composition for use according to any one of aspects 1 to 3, a use according to any one of aspects 4 to 6, or a method according to any one of aspects 7 to 9, wherein estetrol is estetrol monohydrate. Aspect 11. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein pain in the subject is alleviated (i.e., reduced) during the non-withdrawal bleeding phase. 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 subject is alleviated during a period not related to the withdrawal bleeding phase, preferably during a period up to 2 days before the onset of withdrawal bleeding. 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 subject is alleviated during the period from 2 days before the onset of withdrawal bleed to the onset of withdrawal bleed, preferably during the period from 1 day before the onset of withdrawal bleed to the onset of withdrawal bleed. 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 subject is alleviated from about 48 hours prior to the onset of withdrawal bleed until the onset of withdrawal bleed, preferably the pain in the subject is alleviated from about 36 hours, more preferably about 24 hours prior to the onset of withdrawal bleed until the onset of withdrawal bleed. Aspect 15. The pharmaceutical composition for use, the use, or the method of any one of the preceding aspects, wherein the pain in the subject is alleviated on a hormone-free day that corresponds to the end of a hormonal contraceptive administration cycle, preferably the pain in the subject is alleviated on a day prior to day 25 (day 1 of the hormone-free holiday) in a typical hormonal contraceptive treatment schedule. Aspect 16. The pharmaceutical composition for use, the use, or the method of any one of the preceding aspects, wherein the subject is not thought to have or has not been diagnosed as having primary dysmenorrhea, or the subject's medical history has ruled out primary dysmenorrhea in said subject, or the subject is one in which primary dysmenorrhea is ruled out by said subject's medical history. Aspect 17. The pharmaceutical composition for use, the use, or the method according to any one of the preceding aspects, wherein the subject 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. Aspect 18. The pharmaceutical composition for use, use, or method according to any one of the preceding aspects, wherein the subject is suffering 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 prior to administration. Aspect 19. The pharmaceutical composition for use, use, or method according to any one of the preceding aspects, wherein the subject is suffering 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. Aspect 20. The pharmaceutical composition for use, use or method according to any one of the preceding aspects, wherein the pain is due to engraftment of endometrial tissue outside the uterine cavity in the pelvis. Aspect 21. A pharmaceutical composition for use, a use or a method according to aspect 20, wherein the pain is caused by endometrial tissue engraftment located in the ovaries, fallopian tubes, tissues holding the uterus in place (ligaments), the outer surface of the uterus, vagina, cervix, vulva, bowel, bladder, rectum or any combination thereof. Aspect 22. A pharmaceutical composition for use, use or method according to aspect 20 or 21, wherein said pain is caused by endometrial tissue engraftment located in the ovaries, fallopian tubes, tissues holding the uterus in place (ligaments), the outer surface of the uterus, or any combination thereof. Aspect 23. The pharmaceutical composition for use, the use, or the method according to any one of the preceding aspects, wherein the pain is pelvic pain such as chronic pelvic pain, lower abdominal pain and / or lower back pain, pain during defecation and pain during sexual intercourse, or pain caused by endometrial adhesions in the pouch of Douglas. Aspect 24. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the use results in an improvement in the CGI-I scale (Clinician Global Impressions-Improvement Scale) of at least about 10%, preferably at least about 20%, more preferably about 28.9%. Aspect 25. A pharmaceutical composition for use, a use or a method according to any one of the preceding aspects, wherein the use results in an improvement in the PGI-I scale (Patient Global Impressions-Improvement Scale) of at least about 10%, preferably at least about 20%, more preferably about 24%, as graded as "markedly satisfied or better". Aspect 26. A pharmaceutical composition for use, a use or a method according to any one of the preceding aspects, wherein the use results in a responder rate of at least about 40%, preferably at least 50%, more preferably at least about 60%. Aspect 27. A pharmaceutical composition for use, a use or a method according to any one of the preceding aspects, wherein the use results in a reduction of CA125, preferably wherein the use results in a reduction of CA125 serum levels to less than 35 U / ml. Aspect 28. The pharmaceutical composition for use, the use, or the method according to any one of the preceding aspects, wherein the subject is diagnosed as having endometriosis by laparotomy / laparoscopy and / or as having ovarian chocolate cysts as assessed by transvaginal ultrasound (TVUS) and / or magnetic resonance imaging (MRI). Aspect 29. The pharmaceutical composition for use, the use or the method according to any one of the preceding aspects, wherein the subject has adenomyosis and / or uterine fibroids in addition to endometriosis. Aspect 30. A pharmaceutical composition for use, use or method according to aspect 29, wherein the subject has adenomyosis affecting about 25% or less of the uterine corpus (mild adenomyosis), or about 25% to about 50% of the uterine corpus (moderate adenomyosis), or more than about 50% of the uterine corpus (severe adenomyosis). Aspect 31. A pharmaceutical composition for use, a use, or a method according to aspect 29, wherein the subject has uterine fibroids classified as pedunculated, submucosal, intramuscular, subserosal, or any combination thereof. Aspect 32. The pharmaceutical composition, use, or method of use according to any one of the preceding aspects, wherein the composition is used in a cycle of 21 to 28 day daily active dosage units of said composition. Aspect 33. A pharmaceutical composition, use or method for use according to aspect 32, wherein the composition is used in a cycle of 24 daily active dosage units of said composition. Aspect 34. A pharmaceutical composition for use, a use or a method according to aspect 32 or 33, wherein said cycle comprises a 7-day dosing-free period, preferably a 4-day dosing-free period. Aspect 35. A pharmaceutical composition for use, use or method according to any one of aspects 32 to 34, wherein use of the composition results in a reduction in VAS score from before administration to after the second or third administration cycle. Aspect 36. A pharmaceutical composition for use, a use or a method according to aspect 35, wherein use of the composition results in a reduction in VAS score 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%, from pre-administration to after the second or third administration cycle. Aspect 37. A pharmaceutical composition for use, a use or a method according to aspect 36, wherein said reduction remains substantially stable after a second or third administration cycle. Aspect 38. A pharmaceutical composition for use, a use or a method according to any one of the preceding aspects, wherein use of the composition results in an improvement in the severity of Douglas induration, restriction of uterine mobility and / or pelvic tenderness, a reduction in the size and / or number of ovarian chocolate cysts as assessed by TVUS or MRI. Aspect 39. A 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%. Aspect 40. The pharmaceutical composition, use, or method for use according to any one of the preceding aspects, wherein use of the composition results in fewer TEAEs than use of a 20 μg EE / 3 mg DRSP fixed-dose combination tablet. Aspect 41. The pharmaceutical composition for use, the use, or the method of any one of the preceding aspects, wherein said subject has a reduction in a treatment-emergent adverse event (TEAE) selected from the group consisting of: intermenstrual bleeding, headache, nausea, and heavy menstrual bleeding. Aspect 42. A pharmaceutical composition, use or method for use according to any one of the preceding aspects for reducing sleep disturbances associated with endometriosis.

[0011] In any one of the aspects defined herein, the dosage units may be presented as a kit of parts containing a packaging unit, e.g., a blister pack containing daily oral dosage units comprising estetrol and drospirenone. Those skilled in the art will additionally recognize that, within the scope of the present invention, each packaging unit, e.g., a blister pack, may be numbered or marked. In a specific embodiment of the kit of parts, the packaging unit contains 28 containers or a number of 28 containers, such as 2-12 x 28 containers. In a preferred embodiment, the packaging unit contains 3 or 6 x 28 containers. Within the scope of the present invention, each packaging unit may be a sealed blister pack with a cardboard, paperboard, or foil plastic backing, or may be enclosed in a suitable bag.

[0012] Packaging units such as bottles are also contemplated in any one of the aspects defined herein. The material of the bottle is not particularly limited. In a preferred embodiment, the bottle is a glass bottle characterized by a color that can reduce or prevent degradation of the contents of the bottle, for example, by UV light, while maintaining transparency that allows visual inspection of the contents of the bottle. Suitable colors include, but are not limited to, amber, cobalt, or vintage green.

[0013] The above and further aspects and preferred embodiments of the present invention are described in the following paragraphs and in the appended claims, the subject matter of which is hereby specifically incorporated into this specification. [Brief explanation of the drawings]

[0014] [Figure 1] (A) Individual VAS values ​​and spline curves. X-axis: day relative to the first treatment day; Y-axis: VAS value (mm). (B) Mean VAS values. X-axis: day; Y-axis: VAS value (mm). "FSN-013" corresponds to the 15 mg E4 / 3 mg DRSP group. [Figure 2]Figure 2 shows the definition of responders. Responders: VAS reduction of more than 70 mm for 80% or more days of the evaluation period. Evaluation period: non-withdrawal bleeding period between days 29 and 84. [Figure 3] Figure 3 shows the improvement of CGI-I and PGI-I in responders and non-responders (E4 / DRSP+Yaz Flex). Left panel: CGI-I; Right panel: PGI-I. Diagonal stripes: responders, cases on the right of each histogram. Solid gray fill: non-responders, cases on the left of each histogram. [Figure 4] Figure 4 shows the proportion of responders in the E4 / DRSP group and the Yaz Flex group. The FSN-013 group corresponds to the 15 mg E4 / 3 mg DRSP group. [Figure 5] (A) Percentage of subjects with improved, stable, or worsened gynecological findings after 6 cycles of treatment: cul-de-sac induration (p=0.002, Fisher's exact test), restricted uterine mobility (p=0.005, Fisher's exact test), and pelvic tenderness (p=0.022, Fisher's exact test). (B) Stratified analysis of changes in gynecological objective findings after 6 cycles of treatment by those with or without adenomyosis. DETAILED DESCRIPTION OF THE INVENTION

[0015] As used herein, the singular forms "a," "an," and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0016] 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, unrecited components, elements, or method steps. These terms also encompass "consisting of" and "consisting essentially of," which have well-established meanings in patent language.

[0017] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within each range and the recited endpoints. This applies to numerical ranges whether the numerical range is introduced by the phrase "to" or the phrase "between" or otherwise.

[0018] As used herein, the term "about" or "approximately," when referring to a measurable value such as a parameter, amount, time period, and the like, is meant to encompass variations at and from the specified value, such as variations of + / - 10% or less, preferably + / - 5% or less, more preferably + / - 1% or less, and even more preferably + / - 0.1% or less, insofar as such variations are appropriate to the practice of the disclosed invention. It should be understood that the value to which the modifier "about" or "approximately" refers is itself also specifically and preferably disclosed.

[0019] The terms "one or more" or "at least one," such as one or more components or at least one component of a group of components, will become clear with further example, but the terms specifically encompass reference to any one of said components or any two or more of said components, such as any >3, >4, >5, >6, or >7 of said components, etc., and even up to all of said components. In alternative examples, "one or more" or "at least one" may refer to 1, 2, 3, 4, 5, 6, 7, or more.

[0020] The discussion of the background to the invention herein is included to explain the context of the invention and should not be taken as an admission that any of the documents referenced were published, known, or part of the common general knowledge in any country as of the priority date of any of the claims.

[0021] Throughout this disclosure, various publications, patents, and published patent specifications are referenced by an identifying citation. All documents cited herein are hereby incorporated by reference in their entirety. In particular, the teachings or passages of such documents specifically referenced herein are incorporated by reference.

[0022] Unless otherwise defined, all terms used in disclosing the present invention, including technical and scientific terms, have meanings as commonly understood by those skilled in the art. For further guidance, term definitions are included to better appreciate the teachings of the present invention. When a particular term is defined in relation to a particular aspect of the present invention or a particular embodiment of the present invention, such connotation or meaning is meant to apply throughout this specification, i.e., with respect to other aspects or embodiments of the present invention, unless otherwise defined. For example, an embodiment relating to a product is also applicable to the corresponding features of the method and use.

[0023] In the following paragraphs, various aspects or embodiments of the invention are defined in further detail. Each aspect or embodiment so defined may be combined with any other aspect or embodiment, unless expressly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature indicated as being preferred or advantageous.

[0024] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as would be apparent to one of ordinary skill in the art from this disclosure. Furthermore, although some embodiments described herein include some features and not other features included in other embodiments, combinations of features from various embodiments form various embodiments that are intended to be within the scope of the present invention and will be understood by one of ordinary skill in the art. For example, the appended claims encompass alternative combinations of the claimed embodiments, as would be understood by one of ordinary skill in the art.

[0025] Unless otherwise indicated, all methods, steps, techniques and operations not specifically described in detail can be and have been carried out in a manner known per se, as would be apparent to one skilled in the art, reference being made here, for example, to the standard textbooks and the general background art mentioned herein and further references cited therein.

[0026] The term "estetrol" as used herein refers to 1,3,5(10)-estratriene-3,15alpha,16alpha,17beta-tetrol or 15alpha-hydroxyestriol and hydrates of estetrol, such as estetrol monohydrate. "Estetrol" or abbreviated "E4" is an estrogenic steroid produced by fetal human liver (PubChem CID: 27125). Estetrol may be described as a 3-hydroxysteroid equivalent to 17beta-estradiol, in which the 15alpha and 16alpha positions are substituted with two additional hydroxy groups. It is known that estetrol is an estrogen receptor agonist (Non-Patent Document 4). Estetrol may be chemically synthesized, synthesized by the use of (mutated) recombinant enzymes, or any combination thereof. Therefore, it is clear that the terms "estetrol" and "estetrol moiety" also encompass further chemically modified estetrol. Estetrol is known in the art to have the molecular formula: C 18 H 24 O4 or by structural formula (I). Formula (I) [ka]

[0027] When estetrol is mentioned throughout any section of this specification, it is understood that any estetrol-containing component (i.e., compound) and / or estetrol derivative (such as estetrol ester) is also envisioned.More preferably, in the context of the present disclosure, the particularly preferred estetrol (component) is estetrol monohydrate.Those skilled in the art will recognize that estetrol monohydrate corresponds to estetrol containing one molecule of water, and the core structural formula of estetrol is not different from formula (I).By way of example and not limitation, the structural formula of estetrol monohydrate is shown by formula (II): Formula (II) [ka]

[0028] 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 O2) refers to an estrogen distinct from estetrol and estetrol monohydrate, which are widely used in contraceptive pills in combination with a progestogen component. Ethinylestradiol is a synthetic derivative of estradiol (the latter being a natural estrogen). The popularity of ethinylestradiol is due in part to its favorable properties, including improved bioavailability and increased resistance to metabolism compared to estradiol. By way of example and not limitation, the structural formula of ethinylestradiol is shown by formula (III): Formula (III) [ka]

[0029] "Drospirenone" (abbreviated as DRSP, PubChem CID: 68873) is an example of a progestogen component, which has found widespread use in combined oral contraceptives (commonly abbreviated as COCs) due to its antimineralocorticoid and antiandrogenic activity combined with low overall off-target activity. Drospirenone-containing COCs are generally referred to as fourth-generation COCs. Non-limiting examples of commercially available COCs containing drospirenone are known as "Yaz™" and Yasmin™. An ​​illustrative example of a drospirenone-only progestogen pill is "Slynd™," which is also commercially available. Additionally, hormone replacement therapy compositions containing estrogen, such as estradiol, and drospirenone are available, such as "Angeliq™." Drospirenone can alternatively be expressed by its molecular formula C24 H 30 It may be represented in the art by O3 or by structural formula (IV). Formula (IV) [ka]

[0030] When the term "drospirenone" is used herein, it is understood that any drospirenone derivative is also contemplated. The terms "progestogen," "gestagen," or "progestin," and the resulting "progestogenic component," as used both herein and in the art, refer to any molecule that produces an effect in a subject similar to that of the natural female hormone progesterone. Progestogens are thought to be agonists of the progesterone receptor, and their function has been thoroughly reviewed in the art (discussed, inter alia, in (Non-Patent Document 5)). Progestins are a subgroup of progestogens, including synthetic progestogens. While the above terms may be used interchangeably in the art, it is generally understood that when progestins are mentioned, synthetic progestogens are meant.

[0031] Unexpectedly, the inventors have found that administering a composition comprising estetrol and drospirenone represents a highly effective yet safe means for treating endometriosis-induced and / or endometriosis-associated pain in subjects. Furthermore, the combination offers undeniable advantages over other hormonal treatment strategies typically recommended for this indication, such as compositions comprising ethinyl estradiol and drospirenone, which may be administered in a flexible extended-cycle oral contraceptive regimen. Improvement is particularly evident in subjects characterized by high levels of endometriosis-induced pain (i.e., severe and / or frequent). This is unexpected, since those skilled in the art would normally assume that estrogen combined with drospirenone would typically achieve similar therapeutic results. The stronger effect of estetrol compared to ethinyl estradiol is particularly noteworthy, especially given the fact that estetrol is typically considered a "weak" estrogen (Non-Patent Document 6). The general safety reported throughout the art for combined oral contraceptives with estetrol as the estrogen component was confirmed by the minor effects of the estetrol / drospirenone combination on the blood coagulation and fibrinolysis systems and the limited number of treatment-emergent adverse events (TEAEs). No significant deviations from baseline were observed for many clinical markers, such as hematological parameters, biochemistry, urinalysis, electrocardiogram (ECG) and QT interval.

[0032] Therefore, in a first aspect, the present invention relates to a pharmaceutical composition comprising estetrol and drospirenone for use in alleviating pain associated with, caused by, and / or induced by endometriosis. Estetrol and drospirenone are typically present in the pharmaceutical composition in pharmaceutically effective amounts, such as about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone. In other words, the present invention contemplates 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 for the manufacture of a medicament for alleviating pain associated with endometriosis in a subject. In yet another aspect, the present invention contemplates a method for alleviating pain associated with endometriosis in a subject, the method comprising the step of administering to the subject 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. It is contemplated that the use of the pharmaceutical compositions described herein will alleviate pain associated with endometriosis. Optionally, it is contemplated that the use of the pharmaceutical compositions described herein will alleviate pain induced by endometriosis.

[0033] As used herein, "endometriosis" refers to a benign (i.e., non-malignant) proliferative disorder in which normally functioning endometrial tissue is present in locations within the body other than the endometrium of the uterus, i.e., outside the uterine cavity. Therefore, as those skilled in the art will recognize, endometriosis is a distinct medical condition from endometrial cancer, which is not encompassed by the term "endometriosis" as used herein. Endometriosis may develop when cells lining the uterus implant in distal locations, which may include the pelvic region, peritoneal surfaces, ovaries, ligaments, bowel, and bladder. Therefore, the term "endometriosis" encompasses any form or specific classification of the condition, including, but not limited to, endometriosis externa, endometriomas, endometriotic nodules other than those in the uterosacral ligaments, autoimmune endometriosis, mild endometriosis, moderate endometriosis, severe endometriosis, superficial (peritoneal) endometriosis, deep (invasive) endometriosis, and ovarian endometriosis. Unless otherwise clearly stated, the term endometriosis is therefore used herein to describe any of these conditions.It is further clear to those skilled in the art that the effectiveness of the composition of the present disclosure's subject matter for treating the pain associated with endometriosis also essentially implies that the composition is effective for treating endometriosis itself.Optionally, the alleviation of the pain associated with endometriosis described herein can therefore also mean the treatment of endometriosis itself.

[0034] "Adenomyosis" is when tissue similar to the lining of the uterus (endometrium) begins to grow into the muscular wall of the uterus (myometrium), i.e., endometrial-like tissue growing into the uterine muscle. Adenomyosis causes the uterus to thicken and enlarge, sometimes doubling or tripling its normal size. Adenomyosis can cause heavy or prolonged menstrual bleeding with painful periods, blood clots, and abdominal / pelvic pain. Adenomyosis may cause painful menstrual cramps (dysmenorrhea), heavy menstrual bleeding (menorrhagia), menstrual irregularities, pelvic pain with or without severe cramps, pain during intercourse (dyspareunia), infertility, uterine enlargement, and abdominal bloating or distension (adenomyosis abdomen). Adenomyosis may be diagnosed by imaging scans such as a pelvic exam, transvaginal ultrasound, and magnetic resonance imaging (MRI) scan. Adenomyosis is typically classified as mild, moderate, or severe based on the portion of the uterine body affected. By way of example and not limitation, mild adenomyosis corresponds to about 25% or less of the uterine body being affected, moderate adenomyosis corresponds to about 25% to about 50% of the uterine body being affected, and severe adenomyosis corresponds to more than about 50% of the uterine body being affected.

[0035] "Uterine fibroids" are noncancerous growths of the uterus that often occur during the childbearing years. Also called leiomyomas or myomas, uterine fibroids are not associated with an increased risk of uterine cancer and rarely develop into cancer. Fibroids range in size from tiny seedlings undetectable by the human eye to giant masses that can distort and enlarge the uterus. A woman may have a single fibroid or multiple fibroids. In extreme cases, multiple fibroids can enlarge the uterus to the point where it reaches the rib cage, causing weight gain.

[0036] 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 usually classified by their location. Intramural fibroids develop within the muscle of the uterine wall. Submucosal fibroids protrude into the uterine cavity. Subserosal fibroids protrude outside the uterus. Additionally, pedunculated fibroids, characterized by attachment to the uterine wall by a stalk-like structure, have been described. More specific classifications for uterine fibroids are available to those skilled in the art through publications in the field, such as the FIGO (International Federation of Gynecology and Obstetrics) classification system (Non-Patent Document 7). Each of these various types of uterine fibroids is contemplated in the context of the present invention. Those skilled in the art will further recognize that endometriosis is a medical condition that can be clearly distinguished from dysmenorrhea, particularly primary dysmenorrhea. It is important to emphasize that there are no physical findings associated with primary dysmenorrhea and that primary dysmenorrhea is not associated with any abnormal laboratory values ​​or abnormal imaging findings. Therefore, physicians can easily distinguish endometriosis from primary dysmenorrhea by the presence of endometrial tissue outside the uterine cavity of subjects with endometriosis, which is absent in primary dysmenorrhea (e.g., (Non-Patent Document 8)).

[0037] Endometriosis may be classified according to severity, extent, location, or any combination thereof. Various stages of endometriosis may be designated (i.e., stages I-IV), and their location is important in determining appropriate treatment regimens, which may include surgical removal of endometriotic tissue and hormonal therapy, including progestins, oral contraceptives, and GnRH antagonists. Therefore, as contemplated by the present disclosure, individuals may be identified as having stage 1 or stage 2 endometriosis. Stage 1 (or minimal) endometriosis refers to a stage of the disease in which a subject is characterized by few (relatively small) implantations, small wounds, and / or lesions. The implantations may be found on or in the tissue lining the organs or the pelvis or abdomen, with little or no scar tissue. Stage 2 (or minimal) endometriosis is typically characterized by more implantations compared to stage 1, which may be located deeper in the tissue, and optionally, scar tissue may be present. Alternatively, an individual may be identified as having stage 3 or 4 endometriosis. Stage 3 (or moderate) endometriosis is typically characterized by numerous deep implantations, optionally including small cysts and thick bands of scar tissue (i.e., adhesions) on one or both ovaries. Stage 4 (or severe) endometriosis is typically characterized by numerous deep implantations and thick adhesions, as well as large cysts on one or both ovaries. Thus, a subject may optionally be characterized by stage 1, stage 2, stage 3, or stage 4 endometriosis, or any combination thereof.

[0038] Alternatively, endometriosis may be grouped according to any other classification method or classification system reported in the art. By way of example and not limitation, suitable systems include the rASRM classification system (Non-Patent Document 9), the endometriosis fertility index (EFI) (Non-Patent Document 10), and the ENZIAN score (Non-Patent Document 11).

[0039] Pain is a somatosensory submodality resulting from a complex array of unpleasant sensory, emotional, and cognitive experiences caused by real or perceived tissue damage and manifested by certain autonomic, psychological, and behavioral responses (Non-Patent Document 12). The term "pain" as used within the context of this disclosure refers to physical pain. However, it should be understood that physical pain may also cause secondary, undesirable emotional states associated with non-physical, i.e., psychological, pain. Therefore, while the inventors envision broad applicability of the compositions and methods presented herein, the inventors may also seek to improve a subject's emotional state, as described in more detail herein. Specifically, this relates to the alleviation of chronic pain, which is known to be harmful and often detrimental to a subject's psychological well-being (Non-Patent Document 13).

[0040] The expression "alleviate" may be used interchangeably with any synonym as known in the art. Non-limiting examples of synonyms include "alleviate," "treat," "sedate," "pacify," "relieve," "relieve," "attenuate," "reduce," "diminish," and "diminish." Each of these terms should be construed as both a therapeutic treatment and a prophylactic or preventative measure for pain associated with endometriosis that has already developed and progressed to clinical manifestations, where the goal of treatment is to prevent, diminish, or reduce the likelihood of the occurrence of unwanted suffering, such as preventing the onset, development, and progression of pain associated with endometriosis. Beneficial or desired clinical results may include, but are not limited to, a reduction in the degree (i.e., reduction in severity) of pain associated with or induced by endometriosis, stabilization (i.e., not worsening) of said pain, a delay or slowing of pain associated with endometriosis, and the like. "Prevention" or "preventing" as used in the present invention refers to the avoidance of the manifestation of a condition or disease in a subject, i.e., the establishment of a preventative or prophylactic measure. Preventative treatment refers to treatment whose purpose is to prevent the subject's body or elements thereof from exhibiting (worsening of) symptoms, such as unwanted physiological or psychological changes, related to pain associated with endometriosis as disclosed herein. As used herein, the terms "therapeutic treatment" or "therapy" and the like refer to treatment whose purpose is to alter the perception of pain associated with endometriosis to a less severe state (e.g., a more desirable state such as remission) or even to its normal, healthy state (i.e., no sensation of pain), to maintain the undesired physiological state (i.e., pain does not worsen) (e.g., stabilization), or to slow the progression of pain to a more severe or worse perception. In certain embodiments, measurably reducing includes any statistically significant attenuation in a measurable marker or symptom. Statistically significant, as used herein, refers to a p-value of less than 0.05, which is a commonly accepted cutoff score in statistical analysis as will be recognized by those skilled in the art.

[0041] The terms "pharmaceutical formulation", "pharmaceutical composition" or "pharmaceutical preparation" may be used interchangeably herein. Likewise, the terms "formulation", "composition" or "preparation" may be used interchangeably herein. Throughout this specification, absolute quantities referred to herein correspond to the amounts present in a single administered dose, unless expressly stated otherwise. Optionally, estetrol and drospirenone are part of the only (i.e., single, sole) pharmaceutically active component of the composition. The term "pharmaceutically active component", which is used interchangeably with "pharmaceutically active agent" throughout this disclosure, should be interpreted according to the definition of the term by the World Health Organization: "A substance used in a finished pharmaceutical product (FPP) is intended to exhibit pharmacological activity or to have a direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have a direct effect in repairing, modifying or regulating physiological function in humans."

[0042] As used herein, the term "subject" or "patient" refers to a female human subject, preferably a female subject of reproductive age. Alternatively, perimenopausal and / or postmenopausal female subjects are also contemplated. A female subject contemplated herein may be one who is in need of, or is considered to be in need of, treatment to alleviate pain associated with endometriosis, or who is predicted to be in need of such treatment at some point in the not-too-distant future, optionally in light of entering a particular stage of life, such as reproductive age, or endometriosis in a close relative, such as a mother, grandmother, or sibling. Optionally, the subject is a female subject between about 12 and about 95 years of age, preferably between about 14 and about 80 years of age, more preferably between about 16 and about 70 years of age, and most preferably between about 18 and about 60 years of age. Optionally, the female subject is about 60 years old or younger, preferably about 55 years old or younger, preferably about 50 years old or younger, preferably about 45 years old or younger, preferably about 40 years old or younger, preferably about 35 years old or younger, preferably about 30 years old or younger, preferably about 25 years old or younger, preferably about 20 years old or younger. Most preferably, the female subject is about 16 to about 25 years old.

[0043] A further 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 use in treating a subject 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 for the manufacture of a medicament for treating a subject suffering from pelvic pain. In yet another aspect, the present invention relates to a method for treating a subject suffering from pelvic pain, comprising administering to the subject 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 subject's normal (i.e., healthy) function in society (e.g., absenteeism from school and / or work). Optionally, the pelvic pain is diagnosed or considered to be a chronic pelvic syndrome (ie, pelvic pain that lasts for more than six months and is of a severity that limits the subject's function).

[0044] In a further 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 alleviating pain associated with endometriosis in a subject, the use comprising a step of determining whether the patient has pre-administration pelvic pain as defined by a VAS score of greater than about 40 mm. In other words, the present invention relates to 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 for the manufacture of a medicament for alleviating pain associated with endometriosis in a subject, the use comprising a step of determining whether the patient has pre-administration pelvic pain as defined by a VAS score of greater than about 40 mm. Preferably, the pelvic pain is defined by a VAS score of greater than 50 mm. More preferably, the 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 40mm to 100mm, 50mm to 80mm, 60mm to 80mm, 40mm to 70mm, or 60mm to 90mm.

[0045] The term "visual analog scale score," abbreviated as "VAS score," refers to a widely accepted pain scoring scale (first described by Hayes and Patterson in 1921). In a typical VAS, pain scores are determined by measuring the distance (in mm) on a 10-cm line between the "no pain" endpoint and the patient's mark, providing a score range of 0 to 100. Higher scores indicate greater pain intensity. Typically, the following groups of pain intensity are formed: no pain (0-4 mm), mild pain (5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm). Various VAS structures, configurations, orientations, and response options have been described and are within the knowledge of one of ordinary skill in the art (e.g., as reviewed in (Non-Patent Document 14)). The particular VAS scoring system used is therefore not particularly limiting for the present invention. By way of example and not limitation, the VAS can be presented as a numeric rating scale with a center point, tick marks, and / or numbers; a curvilinear analog scale, a box scale consisting of circles spaced at equal distances from one another, and a graphic rating scale. Any orientation of the scale on paper or electronic display is contemplated. Alternative pain rating scales are also contemplated by the present disclosure. By way of example and not limitation, these include the numeric rating scale (NR-11), the Stanford pain scale, the visual rating scale (VRS), or the visual numeric scale. The broader concept of pain measurement instruments and techniques has been described in detail in the art (e.g., in (Non-Patent Document 15)), each with a value on the respective scale corresponding to an equivalent level of pain in the subject. Optionally, the subject may be characterized by an NR-11 score of 1-10, 2-9, 3-7, or 4-6. Alternatively, the subject may be characterized by a Stanford Pain Scale score of 1-3 (ie, mild pain), 4-6 (ie, moderate pain), or 7-10 (ie, severe pain).For the present disclosure, pain associated with endometriosis is preferably expressed by a VAS scale, as determined and recommended in the art (e.g., Non-Patent Document 16). Those skilled in the art can compare the degree of pain reported among various pain scales. By way of example and not limitation, with respect to endometriosis, it is generally accepted in the art that an NRS value of 0 corresponds to a VRS index of "no pain," an NRS value of 1-3 corresponds to a VRS index of "mild pain," an NRS value of 4-6 corresponds to a VRS index of "severe pain," and an NRS value of 7-10 corresponds to a VRS index of "severe pain." Similarly, 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 imaginable pain" (Non-Patent Document 16).

[0046] Pain in the subject may be measured using a VAS pain score during the non-withdrawal bleeding phase. In such embodiments, pain in the subject is measured using a VAS pain score during a time frame characterized by the absence of withdrawal bleeding (i.e., scheduled bleeding / spotting episodes). Optionally, pain in the subject is measured using a VAS pain score at least 1 week, at least 2 weeks, or at least 3 weeks after the cessation of withdrawal bleeding. Optionally, the subject has pain as defined by a VAS score of greater than about 40 mm, about 50 mm, about 60 mm, about 70 mm, about 80 mm, or about 90 mm prior to administration. Alternatively, the subject has pelvic pain as defined by a VAS score of greater than about 40 mm, about 50 mm, about 60 mm, about 70 mm, about 80 mm, or about 90 mm prior to administration. Further alternatively, the subject may be suffering from pelvic pain associated with endometriosis with a VAS score of greater than about 40 mm, about 50 mm, about 60 mm, about 70 mm, about 80 mm, or about 90 mm prior to administration.

[0047] As used herein, "withdrawal bleeding" refers to vaginal bleeding that occurs during a portion of the hormone-free rest period in a typical hormonal contraceptive treatment schedule. The compositions of the present invention are particularly suitable for alleviating pain in a subject during the non-withdrawal bleeding period. In some embodiments, the pain is not associated with the withdrawal bleeding period, or in other words, pain that occurs before day 25 (day 25 corresponds to the first day of the hormone-free rest period in a typical hormonal contraceptive treatment schedule). Withdrawal bleeding usually begins around day 26. In a preferred embodiment, the pain 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, or 24.

[0048] By withdrawal bleeding phase or scheduled bleeding, we mean bleeding / spotting from day 25 (day 1 of the hormone-free rest period) through day 4 of the subsequent cycle, including any bleeding / spotting that began before day 25 and continued until the scheduled bleeding phase, or bleeding / spotting that began during the scheduled bleeding phase but continued after day 4. Conversely, non-withdrawal bleeding phase refers to days of the cycle that are different from the withdrawal bleeding phase or scheduled bleeding. Spotting, referred to as light vaginal bleeding that did not require the use of new sanitary products, including panty liners, and / or bleeding that required the use of tampons, pads, or panty liners, may also occur during the non-withdrawal bleeding phase. Even bleeding / spotting episodes, meaning one or more consecutive bleeding / spotting days bounded on either end by two bleeding / spotting-free days, may occur during the non-withdrawal bleeding phase. Unscheduled bleeding / spotting refers to any bleeding / spotting that does not meet the criteria for scheduled bleeding. Even if bleeding and / or spotting occurs outside of the withdrawal bleeding period or the scheduled bleeding period, the period outside of the scheduled bleeding period is still referred to herein as the non-withdrawal bleeding period, even if bleeding and / or spotting occurs in an episode.

[0049] Definitions used for the analysis of bleeding patterns:

[0050] [Table 1]

[0051] Thus, the subject may be a subject diagnosed with endometriosis, thought to have endometriosis, or predicted to develop (pain associated with) endometriosis. Optionally, the subject may be diagnosed with, thought to have, or predicted to develop adenomyosis and / or uterine fibroids. The subject may be predicted to develop pain associated with and / or caused 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 subject based on symptoms and signs and / or the results of various diagnostic methods. A "diagnosis" of endometriosis and / or endometriosis-associated pain may specifically mean that the subject has a high or even certain likelihood, as determined by a skilled physician, of experiencing endometriosis or endometriosis-associated pain, respectively. A subject may also be diagnosed as not having endometriosis despite exhibiting one or more conventional symptoms or signs that mimic such. "Predicting" in the context of the present invention refers to the prediction of the progression of pain associated with and / or caused by endometriosis in a subject and the outlook (e.g., likelihood, duration, and / or extent) for recovery from and / or the severity of experiencing or remission of said pain associated with and / or caused by endometriosis in a subject. The term may also preferably encompass the prediction of not further worsening or aggravating such within a given time period.

[0052] Optionally, the subject is a subject diagnosed with endometriosis and, optionally, adenomyosis and / or uterine fibroids by laparotomy or laparoscopy. Those skilled in the art are familiar with the terms "laparotomy" and "laparoscopy," which refer to procedures involving the placement of a substantial surgical incision in the abdominal cavity and a small incision (also referred to in the art as "keyhole incision" and "minimally invasive surgery"). The subject may also be a subject diagnosed with an ovarian chocolate cyst. The term "ovarian chocolate cyst," interchangeably referred to throughout the art as "ovarian endometrioma," is generally recognized to refer to fluid-filled ovarian sacs or pouches present in the lining of the uterus (i.e., the endometrium). Ovarian chocolate cysts may be detected by transvaginal ultrasound (TVUS) and / or magnetic resonance imaging (MRI), as described in detail in the art (e.g., (Non-Patent Document 17)).

[0053] In the foregoing, "predicting" or "prediction" generally refers to the statement, declaration, indication, or forecast of a disease or condition in a subject who will not (yet) exhibit or will exhibit limited clinical manifestations of pain associated with and / or caused by endometriosis. A prediction of the onset of said pain in a subject may indicate a likelihood, probability, or risk that said subject will develop said clinical manifestation, for example, within a certain time period after diagnosis of one or more endometriosis-related symptoms. The likelihood, likelihood, or risk may be expressed as any suitable qualitative or quantitative expression; non-limiting examples of quantitative expressions include absolute values, ranges, or statistics. Alternatively, the likelihood, likelihood, or risk may be expressed relative to a suitable control subject or group of control subjects (i.e., a control subject population (e.g., compared to a general, normal, or healthy subject or subject population)). Therefore, any likelihood, probability, or risk may advantageously be expressed as increased or decreased, up-regulated or down-regulated, fold increased or decreased, compared to a suitable control subject or subject population, or compared to a baseline value, which may be derived from a control subject (population) or textual reference value. When a population of subjects is used to establish a baseline value, the baseline value will obviously be the median size of one or more values ​​(parameters) of the population, the mean or median of said values, etc. Those skilled in the art will further recognize that monitoring may be applied during the course of medical treatment of a subject, such as that described by the present disclosure. Such monitoring may be involved, for example, in decision-making as to whether a patient may leave a controlled clinical or health care environment, whether a change in treatment or therapy is necessary, or whether hospitalization is required.

[0054] The pharmaceutical composition of the present disclosure contains about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone. It should be recognized that these ranges correspond to pharmaceutically effective amounts of both estetrol and drospirenone. Those skilled in the art will recognize that terms such as "amount," "quantity," and "level" are synonymous and have well-defined meanings in the art. Optionally, the pharmaceutical composition of the present disclosure contains about 14 mg to about 16 mg of estetrol and about 2 mg to about 3 mg of drospirenone. Optionally, the pharmaceutical composition of the present disclosure contains about 14.5 mg to about 15.5 mg of estetrol and about 2 mg to about 3 mg of drospirenone. Optionally, the pharmaceutical composition of the present disclosure contains about 15 mg of estetrol and about 3 mg of drospirenone. Preferably, the pharmaceutical composition that is the subject of the present disclosure comprises about 15 mg of estetrol monohydrate and about 3 mg of drospirenone.

[0055] Each of the compositions described herein may alternatively be described in terms of the daily amount of estetrol (monohydrate) and drospirenone ultimately administered to a subject. Thus, any composition described as containing about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone may similarly be a composition administered in an amount equivalent to a daily amount of about 13.5 mg to about 16.5 mg of estetrol and about 2.5 mg to about 3.5 mg of drospirenone. Thus, the phrase "administered in a daily amount equivalent to..." refers to the administration of estetrol and drospirenone, in the context of the present invention, to achieve the same physiological and / or psychological effects as would be achieved by administering the aforementioned amounts of estetrol and drospirenone to a subject. Additionally, the term "daily" indicates that the recited amount is a cumulative amount administered to a subject per day. Those skilled in the art will understand that when the composition of the presently disclosed subject matter is administered only once per day (i.e., every day), the amount of estrogen administered in that single administration is the daily dose.Instead, those skilled in the art will recognize that when the composition is administered more than once per day (for example, twice or three times), the daily amount corresponds to the (independent) sum of all estetrol and all drospirenone administered during each administration event within a total time frame of 24 hours.It is within the ability of those skilled in the art to establish the daily amounts of estetrol and drospirenone.

[0056] The pharmaceutical compositions described herein may 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 a further embodiment, the dosage unit is a daily oral dosage unit. It is clear that both the composition and the dosage unit may suitably contain one or more pharmaceutically acceptable additives. The term "pharmaceutically acceptable" as used herein is consistent in the art and means compatible with other components of the pharmaceutical composition and not toxic to the recipient thereof.

[0057] The subject compositions of the present invention are particularly suitable for formulation as oral dosage units, however dosage units formulated for alternative methods of administration, such as, but not limited to, sublingual, buccal, or sublabial dosage units, are also envisioned.

[0058] The term "dosage unit" is used interchangeably herein with "dosage form" and refers to a physical preparation suitable for administration to a subject, without the need for adaptation of the preparation prior to administration, i.e., the final beneficial product. A dosage unit thus refers to a composition that can be administered as is. The term is not limited with respect to any other details of treatment, such as the frequency of administration, and / or any characteristics of the dosage unit (taste, appearance, size, etc.). In the context of the present invention, each dosage unit preferably contains, as pharmaceutically acceptable components, amounts of estetrol and drospirenone 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. The presence of estetrol and drospirenone as pharmaceutically acceptable components does not preclude the presence of one or more additional pharmaceutically active components. By way of example and not limitation, the additional pharmaceutically acceptable component may be an analgesic, i.e., a component capable of achieving analgesia in a subject. The term "analgesic" may be used interchangeably with synonyms such as "pain reliever" or "analgesic." Optionally, the analgesic may be selected from the group consisting of acetaminophen (i.e., paracetamol), a nonsteroidal inflammatory drug (NSAID), an opioid, a muscle relaxant, an anxiolytic, an antidepressant, an anticonvulsant, and a corticosteroid.

[0059] The term "pharmaceutically acceptable," as used herein, is consistent in the art and means compatible with the other ingredients of the pharmaceutical composition and not toxic to the recipient thereof. Non-limiting suitable excipients are further described throughout this disclosure.

[0060] For purposes of this specification, the term "oral dosage unit" encompasses any dosage unit intended for and / or suitable for administration to a subject via the oral cavity. Immediate or near-immediate ingestion of a dosage unit is envisioned as an embodiment of the present invention, but does not in any way limit the scope of the present invention.

[0061] The oral dosage units described herein may be solid or semi-solid dosage units such as tablets, capsules, cachets, pellets, pills, powders or granules, or any combination thereof. For example, the oral dosage unit of the present invention may be a tablet containing estetrol-containing granules and drospirenone, or a capsule containing estetrol-containing granules and drospirenone. Optionally, drospirenone may be contained in the estetrol-containing granules. Alternatively, drospirenone may be contained in separate granules, i.e., granules that do not contain estetrol. The term "solid or semi-solid dosage unit" also encompasses capsules containing a liquid, e.g., an oil, in which estetrol and drospirenone are dissolved or dispersed.

[0062] Tablets and equivalent solid and semi-solid dosage units may suitably contain materials such as binders (e.g., hydroxypropyl methylcellulose, 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., magnesium stearic acid and talc). These tablets and equivalent solid dosage units may be prepared by any suitable means, as described in detail in the art (e.g., (Non-Patent Document 18)). Non-limiting examples of methods for processing estetrol and drospirenone in manufacturing the dosage units include, for example, wet granulation using aqueous or organic solutions, direct compression, 3D printing, or by coating carrier particles with estetrol and optionally drospirenone using organic or inorganic solvents (on the same carrier particles or separate particles).

[0063] Optionally, the additive may be an active ingredient additive, a binder additive, a carrier additive, a co-processing additive, a coating system additive, a release-controlling additive, a diluent additive, a disintegration additive, a dry powder inhalation additive, an effervescent system additive, an emulsifying additive, a lipid additive, a lubricant additive, a release-modifying additive, a penetration-enhancing additive, a permeation-enhancing additive, a pH-adjusting additive, a plasticizing additive, a preservative additive, a solubilizing additive, a solvent additive, a sustained-release additive, a sweetening additive, a taste-making excipient, a thickening additive, a viscosity-adjusting additive, a bulking additive, a compression additive, a dry granulation additive, a hot-melt extrusion additive, a wet granulation additive, a rapid release additive, a bioavailability-enhancing additive, a dispersing additive, a dissolution-enhancing additive, a stabilizing additive, a capsule-filling additive, or any combination thereof. Those skilled in the art will recognize that the use of such vehicles and agents for pharmaceutical active substances is conventional and that the incorporation of these additives is therefore well known in the art. It is clear that all components used must be non-toxic in the concentrations contained in the final pharmaceutical composition or dosage unit and should not negatively interfere with the activity of one or more pharmaceutically active components, at least estetrol and drospirenone in the context of the present invention.

[0064] As described above, the compositions, and therefore the (oral) dosage units, may contain one or more suitable additives. The term "additive" 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 (Tween 80 or Polysorbate 80), colloids, dispersion media, vehicles, fillers, chelating agents (including, but not limited to, EDTA or glutathione), amino acids, proteins, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, sweeteners, colorants, flavors, aromatisers, thickeners, any agent suitable for achieving a depot effect, coatings, antifungal agents, any preservatives (including, but not limited to, Thimerosal™, benzalkonium chloride or benzyl alcohol), antioxidants (including, but not limited to, ascorbic acid, sodium bisulfite), isotonicity agents, absorption delaying agents, adjuvants, fillers (including, but not limited to, lactose, mannitol) and any other components that may affect any parameter or characteristic of the oral dosage unit that is the subject of the present invention. Those skilled in the art will understand that one or more additives may be used in the composition or oral dosage unit, provided that the one or more additives are compatible with the pharmaceutical ingredients (in the context of the present disclosure, at least estetrol and drospirenone) and result in a pharmaceutically acceptable formulation.

[0065] Optionally, a composition containing estetrol and drospirenone, a filler, a superdisintegrant, a binder and disintegrants, a further binder, and a lubricant is contained in the tablet. In a preferred embodiment, a composition containing estetrol and drospirenone, lactose, sodium starch glycolate, cornstarch / cornstarch, povidone, and magnesium stearate is contained in the tablet. Preferably, a composition containing estetrol monohydrate, drospirenone, lactose monohydrate, sodium starch glycolate Type A, cornstarch, povidone K30, and magnesium stearate is contained in the tablet. Optionally, the tablet is coated with a coating agent. In a further optional embodiment, the coating agent includes hypromellose, hydroxypropyl cellulose, titanium dioxide, red mineral oxide, hydrogenated cottonseed oil, and talc. By way of example and not limitation, a suitable coating agent is AquaPolish Pink 044.08 MS. Those skilled in the art will further recognize that any additives present in any dosage unit, such as an oral dosage unit, must adhere to pharmaceutical grade industry quality standards, such as Ph.Eur. and USP-NF.

[0066] The (solid) oral dosage unit may be suitable, or more specifically, may be manufactured 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 orodispersible 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 more 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 also be an orodispersible dosage unit. In such an embodiment, the dosage unit rapidly disintegrates in the oral cavity upon contact with saliva, dispersing the estetrol and / or drospirenone in the saliva so that the dosage unit can be absorbed through the mucosal lining of the oral cavity. Those skilled in the art are aware of methods for determining the release rate of pharmaceutically active ingredients such as estetrol and drospirenone from dosage units. Non-limiting standard tests commonly accepted in the art include, for example, Ph.Eur.2.9.1 ("Disintegration of tablets and capsules") and USP 2004 / 01006294, using water as the disintegration medium. <701> ("Disintegration") testing.

[0067] The term "sublingual" as used herein refers to a pharmacological route of administration in which estetrol and / or drospirenone (contained in the dosage unit) diffuses into the blood through tissues under the tongue.

[0068] The term "buccal" as used herein refers to the route of pharmacological administration whereby estetrol and / or drospirenone (contained in the dosage unit) diffuses into the blood through the tissues of the buccal vestibule, which is the area inside the mouth between the inner lining of the cheek (buccal mucosa) and the teeth / gums.

[0069] As used herein, the term "under the lip" refers to a pharmacological route of administration in which estetrol and / or drospirenone (contained in a dosage unit) is placed between the lip and gum.

[0070] 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 lacquered tablets or sugar-coated tablets, granules, aqueous or oily solutions, syrups, emulsions, suspensions, ointments, pastes, lotions, gels, inhalants, or suppositories. In embodiments in which an effective amount of estetrol and drospirenone is administered orally, oral dosage units according to the present invention are preferably solid or semi-solid dosage units such as tablets, capsules, cachets, pellets, pills, powders, and granules. The term "solid or semi-solid dosage unit" also encompasses 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 semi-solid dosage units may suitably contain materials such as binders (e.g., hydroxypropylmethylcellulose, polyvinylpyrrolidone, other cellulosic materials and starches), 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., stearic acid and talc). These tablets and equivalent solid dosage units may be prepared by any suitable means as described in detail in the art (e.g., (Non-Patent Document 18)). Non-limiting examples of processing estetrol and drospirenone when manufacturing dosage units include, for example, wet granulation using aqueous or organic solutions, direct compression, 3D printing, or by coating carrier particles with estetrol and drospirenone using organic or inorganic solvents.

[0071] By way of example and not limitation, oral dosage units comprising the composition of the present disclosure's subject matter may be manufactured by a process including wet granulation.Those skilled in the art will recognize that the wet granulation process may suitably include the following successive steps: charging and sieving active ingredients and additives, blending the sieved material in a processor, granulating, selecting (i.e., further sieving) the granules, and blending the sieved granules with one or more additional additives one or more times.Then, if desired, the granules may be compressed, for example, into tablets, taking into account the final dosage unit, and optionally including a coating step for the tablet.

[0072] Estetrol may be included in the composition and final dosage unit as particles. Optionally, the estetrol particles have a D(10) of about 0.5 μm to about 10 μm, preferably about 1 μm to about 5 μm, and more preferably about 1.5 μm to about 2.5 μm. Optionally, the estetrol particles 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, and most preferably about 8 μm to about 12 μm. Optionally, the estetrol particles have a D(90) of about 15 μm to about 50 μm, preferably about 20 μm to about 30 μm, and more preferably about 22 μm to about 28 μm. Optionally, the estetrol particles are further granulated into larger granules. In certain embodiments, the estetrol is contained in the composition as a multiplicity of larger granules having a volume median diameter of about 100 μm to about 4000 μm, preferably about 200 μm to about 1000 μm, and more preferably about 200 μm to about 600 μm.

[0073] Numerous measurement techniques are available for determining particle size distribution values, including sieve analysis, wind sieving, image analysis, optical measurement, electrical resistivity, sedimentation, laser diffraction, laser obscuration, time of transition, acoustic spectroscopy, ultrasound attenuation microscopy, cascade impactor, or any combination thereof. Unless expressly stated otherwise, the particle size distribution values ​​in this disclosure are obtained by laser diffraction analysis. Laser diffraction analysis, interchangeably referred to in the art as laser diffraction spectroscopy, is a particle measurement technique based on the observation of the diffraction pattern of a laser 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., as reviewed in detail in Non-Patent Document 19 regarding particle analysis).

[0074] Pain associated with or caused by endometriosis may be the result of endometrial tissue engraftment in the pelvis, excluding the uterine cavity, optionally accompanied by adenomyosis and uterine fibroids. As used herein, "pelvis" should be interpreted according to the generally accepted definition in the art, i.e., the lower torso between the abdomen and thighs. The pelvis contains a deeply embedded skeleton, commonly referred to as the pelvic bones. Similarly, those skilled in the art will readily recognize that the uterine cavity refers to the interior of the uterus. The uterine cavity is formed by the inner part of the uterine body and is flanked by the fallopian tubes (the crest of the internal cervical os allows communication with the cervix). Optionally, pain is due to endometriosis in distal (extraperitoneal) sites, including, but not limited to, the colon, kidneys, liver, pancreas, and lungs. Optionally, endometrial tissue engraftment may lead to ovarian lesions, peritoneal lesions, rectovaginal lesions, or any combination thereof, as further described below. Optionally, the pain is due to endometrial tissue engraftment located on the ovaries, fallopian tubes, tissues holding the uterus in place (ligaments), outer surface of the uterus, vagina, cervix, vulva, intestine, bladder, rectum, or any combination thereof.

[0075] Optionally, the pain is pain selected from the group consisting of 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. As used herein, "chronic pelvic pain" is defined as pain in the pelvic region that lasts for six months or more. Chronic pelvic pain may be continuous or periodic, optionally cyclical, and this does not limit the scope of the present invention. As referred to herein, the "pouch of Douglas," interchangeably referred to by the terms "rectometrium pouch," "rectovaginal pouch," or "cul-de-sac," refers to the extension of the peritoneum between the rectum and the posterior wall of the uterus. The pouch of Douglas is generally known to be the deepest part of the peritoneal cavity.

[0076] The compositions for use, uses, and methods described herein each result in a significant improvement in pain associated with or induced by endometriosis in subjects, particularly characterized by a VAS score of at least about 40 mm, at least about 50 mm, at least about 60 mm, or at least about 70 mm, and a clear improvement can be observed when compared to hormonal treatment strategies described in the art. The method for assessing this improvement in pain does not limit the present invention. Optionally, the improvement is measured by the Clinician Global Impressions-Improvement Scale (CGI-I scale), which has been described in detail in the art and is therefore familiar to those skilled in the art (e.g., (Non-Patent Document 20)). The CGI-Improvement (CGI-I) is assessed every time a patient is seen by a clinician after starting drug therapy, and the patient's overall clinical condition is compared to that just one week before starting drug therapy (the so-called baseline visit). The following question is scored on a 7-point scale: "Compared to the patient's condition at admission to the project [before starting drug therapy], this patient's condition is..." 1 = Much improved since the beginning of treatment; 2 = very improved; 3 = minimal improvement; 4 = no change from baseline (beginning of treatment); 5 = minimal but worse; 6 = very bad; 7 = "Much worse since the beginning of treatment."

[0077] 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 when compared to the situation before the start of administration of the composition. Alternatively, pain improvement may be "minimally improved" corresponding to a CGI-I of 3, preferably "very improved" corresponding to a CGI-I of 2, and most preferably "much improved" corresponding to a CGI-I of 1, since the start of treatment. CGI-I scale scoring is significantly improved when compared to known treatment strategies, such as, but not limited to, preparations comprising ethinyl estradiol and drospirenone, more particularly 20 μg ethinyl estradiol and 3 mg drospirenone in a fixed-dose combination tablet administered in a flexible extended-cycle oral contraceptive regimen. Optionally, an improvement on the CGI-I scale corresponding to "minimally improved or better" (CGI-I score 1-3) is obtained in at least about 75% of subjects, preferably at least about 77.5% of subjects, more preferably at least about 80% of subjects, and most preferably at least about 82% of subjects.

[0078] Alternatively, improvement may be measured by the Patient Global Impressions-Improvement Scale (PGI-I scale), known to those skilled in the art (e.g., (Non-Patent Document 21)). Improvement may result in an improvement graded as "barely satisfied or better" (PGI-I scores 1-3) 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, compared to the situation before the start of administration of the composition. Improvement may result in an improvement graded as "markedly satisfied or better" (PGI-I scores 1 and 2) in at least about 10%, preferably at least about 20%, and more preferably at least about 24% of patients. Alternatively, pain improvement may 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, since the start of treatment. The PGI-I scale scoring is significantly improved when compared to known treatment strategies, such as, but not limited to, preparations containing ethinylestradiol 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. Optionally, an improvement in the PGI-I scale corresponding to "marginally satisfied or better" (PGI-I score 1-3) is obtained in at least about 67.5% of subjects, preferably at least about 70% of subjects, more preferably at least about 72.5% of subjects, and most preferably at least about 75% of subjects.

[0079] Optionally, use of the compositions and methods described herein may result in a significant improvement in a subject's quality of life when compared to a time point before the start of use (i.e., treatment). Several testing methods for assessing a subject's quality of life, such as the Quality of Life Scale (QOLS), have been described in the art (Non-Patent Document 22). Thus, a subject's quality of life as measured by the QOLS may be improved by at least 10%, preferably at least 20%, preferably at least 30%, preferably at least 40%, and preferably at least 50% when compared to the subject's QOLS score before the start of administration of the composition.

[0080] The compositions for use, uses, and methods described herein are characterized by a high responder rate (across the general population). Optionally, the compositions for use, uses, and methods result in a responder rate of at least about 40%, preferably at least 50%, more preferably at least about 60% or about 70%. The responder rate is significantly improved when compared to known treatment strategies, such as, but not limited to, preparations containing ethinyl estradiol and drospirenone, more particularly, 20 μg ethinyl estradiol and 3 mg drospirenone in a fixed-dose combination tablet administered in a flexible extended-cycle oral contraceptive regimen.

[0081] Optionally, the dosage unit is administered to the subject according to a continuous administration schedule. As used herein, the terms "continuous" and "continuously" mean that the dosage unit is administered at relatively regular intervals without significant (therapeutic) interruptions. Naturally, minor interruptions that do not affect the overall effect of the method of the present invention may occur, and indeed, such deviations are encompassed by the present invention. Preferably, and more arithmetically, a dosing regimen is considered continuous if the longest drug-free period between two subsequent administrations is not more than 3.5 times the length of the average drug-free period. Even more preferably, the longest drug-free period is not more than 2.5 times, most preferably not more than 1.5 times the length of the average drug-free period. By way of example and not limitation, the treatment strategies and methods of treatment described herein preferably use continuous administration of estetrol and drospirenone for a period of at least 10 days, preferably at least 20 days.

[0082] Preferably, the pharmaceutical compositions described herein are used in a 21-28 day cycle of daily administration (i.e., a cyclical administration schedule), such as administering an active dosage unit daily for 21-28 days. The pharmaceutical compositions described herein may also be used in a 21, 22, 23, 24, 25, 26, 27, or 28 day cycle of daily administration, with administration of an equivalent amount of active dosage units daily. The cycle preferably further includes a 7, 6, 5, or 4 day rest period without administration. Preferably, the cycle includes a 4 day rest period without administration.

[0083] As shown above and supported by the examples below, use of the composition results in a significant reduction in VAS scores from before administration to after the third administration cycle, preferably from before administration to after the second administration cycle. It is understood that one administration cycle corresponds to one period of daily administration as described above, supplemented by a drug holiday without administration as described above. Optionally, use results in a reduction in VAS scores of 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%, and more preferably at least 90% from before administration to after the third administration cycle. Preferably, use results in a reduction in VAS scores of 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%, and more preferably at least 90% from before administration to after the second administration cycle. Optionally, use results in a reduction in VAS score to the extent that a VAS score of less than about 40 mm, 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 is obtained after a third administration cycle, preferably after the second administration cycle. Optionally, use results in a reduction in VAS score of 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, from pre-administration to after the third administration cycle.

[0084] The reduction in VAS score described above is maintained (i.e., remains stable or usually at a constant reduced score) with further administration cycles, such as after the second or third administration cycle. The pain-reducing, pain-suppressing effect of use of the composition is therefore a sustained effect, without any decrease in effectiveness over time.

[0085] Optionally, use of the composition results in an improvement in at least one parameter selected from the group consisting of a reduction in Douglas induration, restriction of uterine mobility, severity of pelvic tenderness, size of ovarian chocolate cysts as assessed by TVUS or MRI, and number of ovarian chocolate cysts. In a preferred embodiment, each of these parameters is improved by use of the composition. Preferably, the severity of Douglas induration is improved 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," in the context of the Douglas pouch of the present disclosure, refers to thickening and / or hardening of soft tissues of the body. Preferably, the long axis of ovarian chocolate cysts is reduced by at least about 10 mm, preferably at least 20 mm, preferably at least 24.88 mm. Preferably, the minor axis of the ovarian chocolate cyst is reduced by at least about 10 mm, preferably at least 20 mm, preferably at least 26.24 mm. Preferably, the volume of the ovarian chocolate cyst is reduced by at least about 10 cm. 3 , preferably at least 20 cm 3 , preferably at least 30 cm 3 , preferably at least 39.56 cm 3 Reduce.

[0086] In a preferred embodiment, use of the composition results in a reduction of cancer antigen 125 (CA125). Preferably, CA125 serum levels are reduced to less than 35 U / ml. "CA125" may also be referred to interchangeably in the art as "MUC-16" or "mucin-16," and in humans is encoded by the MUC16 gene.

[0087] The compositions, uses, and methods for use described herein are characterized by a low incidence of treatment-emergent adverse events (TEAEs) when compared with treatment strategies known in the art that rely 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. It should be recognized that a TEAE is an undesirable event caused by the use of a particular pharmaceutically active component, composition, or dosage unit in a subject that was not present prior to its administration to said subject. Optionally, the TEAE is selected from the group consisting of missed periods, 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 when compared to known treatment strategies such as treatments relying on the administration of estrogen and drospirenone, more particularly 20 μg ethinyl estradiol and 3 mg drospirenone in a fixed-dose combination tablet administered in a flexible extended-cycle oral contraceptive regimen.

[0088] Drospirenone, particularly 2.5 mg to 3.5 mg of drospirenone, more particularly about 3 mg of drospirenone, is highly preferred in the context of the present invention, although other progestogen components are also envisaged as alternatives, examples of which include, but are not limited to, levonorgestrel, norgestimate, norethisterone, dydrogesterone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel, 17-deacetylnorgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, amgestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, one), dimethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate, gastrinone, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol, mecirogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone, norethynodrel, norgestrel (d-norgestrel and dl-norethindrone) (including lugestrel), norgestrienone, normethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one, tibolone, trimegestone, algestone acetophenide, nestrone, promegestone, 17-hydroxyprogesterone ester, 19-nor-17hydroxyprogesterone, 17alpha-ethynyltestosterone progestogens, such as d-17beta-acetoxy-13beta-ethyl-17alpha-ethynylgon-4-en-3-one oxime, 6beta,7beta;15beta,16beta-dimethylene-3-oxo-17-pregna-4,9(11)-diene-21,17beta-carbolactone or tanaproget, as well as precursors of these compounds capable of liberating these progestogens in vivo.

[0089] A further aspect of the present invention relates to a packaging unit containing the dosage units described herein. The packaging unit may contain at least 14, preferably at least 21, and even more preferably at least 28 containers for holding separately packaged, individually removable dosage units, each container containing at least one dosage unit containing about 13.5 to about 16.5 mg of estetrol or estetrol monohydrate, preferably about 15 mg of estetrol monohydrate, and about 2.5 to about 3.5 mg of drospirenone, preferably about 3 mg of drospirenone. Preferably, the separately packaged, individually removable dosage units are oral dosage units. More preferably, each separately packaged, individually removable dosage unit contains about 13.5 to about 16.5 mg of estetrol or estetrol monohydrate, preferably about 15 mg of estetrol monohydrate, and about 2.5 to about 3.5 mg of drospirenone. Optionally, each additional container for holding a dosage unit containing estetrol and drospirenone is individually visibly arranged to indicate a recommended sequence of administration.

[0090] Those skilled in the art will recognize that within the scope of the present invention, each packaging unit, e.g., blister pack, may be numbered or marked. The packaging units may be provided in any suitable packaging means known in the art, non-limiting examples being a lozenge, sachet, pouch, bottle, film, spray, microcapsule, implant, rod or blister pack.

[0091] By way of example and not limitation, each packaging unit may be a cardboard, paperboard, or plastic foil-backed sealed blister pack, or may be enclosed in a suitable bag. Packaging units such as bottles are also contemplated in any one of the aspects defined herein. The material of the bottle is not particularly limited. In a preferred embodiment, the bottle is a glass bottle characterized by a color that can reduce or prevent degradation of the contents of the bottle, for example, by UV light, while maintaining transparency that allows visual inspection of the contents of the bottle. Suitable colors include, but are not limited to, amber, cobalt, or vintage green.

[0092] In certain embodiments of the invention, the packaging unit comprises 28 containers or a plurality of 28 containers, such as 2 to 12 times 28 containers.

[0093] The packaging unit of the contraceptive kit disclosed herein may be a "compliance package." As known in the art, a "compliance package" is a packaging unit of variable size and style intended to provide a suitable storage means for one or more medications, and subsequently to provide assistance and / or guidance to the subject for complying with the intended timely administration (Non-Patent Document 23). As a non-limiting example, the packaging unit may be provided with numerical indicators and / or symbols that enable the subject to keep track of, for example, the subject's menstrual cycle. In an alternative non-limiting example, the packaging unit may include a means for sending an electronic signal to the subject when a predetermined time for administration (i.e., a particular day) has been reached and the current dosage unit is still contained in the packaging unit. In these examples, the electronic signal may be sent to a data storage means and / or a user-defined electronic device, with smartphones and smartwear being illustrative examples. In certain embodiments, distinct portions of the packaging unit provide the subject with different sensory triggers, non-limiting examples being distinct colors or textures.

[0094] While the present invention has been described in connection with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. It is therefore intended, as follows, to embrace all such alternatives, modifications, and variations within the spirit and broad scope of the appended claims. Aspects and embodiments of the invention disclosed herein are further supported by the following non-limiting examples. The following specific experimental examples in support of the claimed invention are provided but should not be construed as limiting the scope of the invention. [Example]

[0095] Example 1. An open-label, parallel-group study to explore the pharmacodynamic effects, pharmacokinetics, and safety of 15 mg E4 monohydrate / 3 mg DRSP tablets during three cycles of treatment in Japanese patients with endometriosis. Test objectives To explore the pain relief effects, pharmacodynamic effects on the blood coagulation / fibrinolysis system and endocrine system, pharmacokinetics, and safety during three treatment cycles of 15 mg E4 monohydrate / 3 mg DRSP tablets (hereafter "E4 / DRSP") in patients with endometriosis, administered daily for 24 days followed by a 4-day placebo medication period for 28 days.

[0096] Study design Multicenter, open-label, randomized, parallel-group Phase, type of study Phase II, Clinical Pharmacology

[0097] Eligibility Criteria Inclusion criteria 1. Diagnosed with endometriosis by laparotomy / laparoscopy and / or ovarian chocolate cysts by TVUS or MRI 2. ≥ 20 years old and < 50 years old 3. Pelvic pain during the baseline observation phase (defined as a VAS score ≥ 40 mm) 4. Regular menstrual cycle (25-38 days) during the baseline observation phase 5. BMI < 30 kg / m² 6. I fully understand the contents of this clinical trial and have given written consent to participate in the trial. Exclusion criteria 1. Undiagnosed abnormal vaginal bleeding in the 6 months prior to screening 2.≥40 years old with endometrioma >10cm in maximum diameter 3. Endometrioma containing solid components 4. Have undergone surgical treatment for endometriosis by cyst puncture (e.g., transvaginal alcohol fixation), laparotomy, or laparoscopy (laparoscopy) within 2 months prior to the screening test. 5. Progestin-containing oral contraceptives or hormone preparations have not improved endometriosis symptoms (moderate or severe pelvic pain) 6. Patients whose organic disease is deemed by the investigator to be a surgical treatment priority 7. Presence or history of malignancy (e.g., cervical intraepithelial neoplasia, cervical cancer, breast cancer). Non-melanoma skin cancer is acceptable. 8. Presence or history of deep vein thrombosis, thrombophlebitis (excluding superficial), pulmonary embolism, cerebrovascular disease, coronary artery disease, etc. 9. Smoker ≥ 15 cigarettes / day ≥ 35 years old 10. Migraine with aura (phosphenes, starbursts, etc.) 11. Valvular heart disease associated with pulmonary hypertension or atrial fibrillation or a history of subacute bacterial endocarditis 12. Diabetes associated with vascular lesions such as diabetic nephropathy and diabetic retinopathy 13. Thrombotic predisposition (e.g., deficiency of antithrombin, protein S, and protein C) 14. Phospholipid antibody syndrome (e.g., antiphospholipid antibody positive or unknown systemic lupus erythematosus) 15. Surgery was scheduled within 4 weeks after consent was obtained or surgery was performed within 2 weeks before consent was obtained 16. Presence of severe liver dysfunction (e.g., acute viral hepatitis, severe liver cirrhosis, etc.) 17. Presence of liver tumors 18. Presence of severe (GFR < 60 mL / min / 1.73 m2) or acute renal dysfunction 19. History or presence of uncomplicated heart disease, such as valvular heart disease 20. Hypertension [systolic blood pressure ≥ 140mmHg and / or diastolic blood pressure ≥ 90mmHg] 21. Patients with otosclerosis 22. History of jaundice, persistent pruritus, or herpes during pregnancy 23. Pregnant women or women who may be pregnant 24.Having given birth or having a second trimester miscarriage within 6 weeks prior to enrollment 25. Breastfeeding women 26. Hypersensitivity to the active component of the test drug 27. There was a contraindication for Yaz Flex combination tablets. 28. History of discontinuation of sex steroid hormone therapy due to adverse events or hypersensitivity 29. Have been taking drugs or their derivatives that are thought to affect sex hormone secretion 30. Had taken the following medications within one month prior to screening: -Hormonal preparations containing progestin and estrogen, low-dose contraceptive pills, fixed-dose combinations of progestin and estrogen -GnRH agonists / antagonists, testosterone derivatives -Estrogen antagonists, aromatase inhibitors -Herbal medicines for treating dysmenorrhea, endometritis, and menstrual pain -Anticoagulants - Hypercholesterolemic drugs, antidiabetic drugs (including insulin), drugs that affect serum potassium levels (ACE inhibitors, ARBs, potassium-sparing diuretics, aldosterone antagonists) -Minor tranquilizer, antispasmodic 31.Currently using or using the following drugs within the month prior to enrollment -CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John's wort, etc.) -CYP3A4 inhibitors (e.g., cobicistat, indinavir, itraconazole, ritonavir, telaprevir, voriconazole, clarithromycin, nelfinavir, saquinavir, grapefruit juice, etc.) -HIV protease inhibitors, HCV protease inhibitors, non-nucleoside reverse transcriptase inhibitors 32. Regular use of analgesics for medical reasons other than relief of endometrial pain during the study (occasional use is permitted; prophylaxis is not permitted) 33. Participated in another clinical trial within one month prior to the screening test or received other investigational drugs within three months prior to the screening test. Participated in a clinical trial of other oral contraceptives containing active ingredients approved in Japan and completed the clinical trial within two months prior to the screening test. 34. Patients who wish to become pregnant or who do not agree to prohibit sexual intercourse or contraception *) During the exam period *) Use of barrier contraceptives approved or certified in Japan (latex condoms or contraceptive diaphragms for humans) 35. Determined to be ineligible by the investigator.

[0098] Number of subjects A total of 80 subjects: 40 subjects each in the E4 / DRSP group or the Yaz Flex group.

[0099] [Note] Because this clinical trial was an exploratory clinical pharmacology study, the number of cases was set with reference to the results of previous clinical trials. Based on the results of a Phase III study of YazFlex combination tablets in patients with endometriosis (change in VAS score for most advanced pelvic pain - lower abdominal pain / lower back pain - from the previous observation period), the effect size was 0.5, and the dropout rate was 15%, the number of cases with 80% detection power was estimated.

[0100] Dose, route of administration and duration of treatment Clinical trial arm: -E4 Monohydrate 15mg / DRSP 3mg, Fixed Dose Combination Tablet Twenty-four days of oral administration followed immediately by four days of placebo were given in three 28-day cycles (84 days). Reference group: -Yaz Flex (EE 20μg / DRSP 3mg, fixed dose combination tablet) Regardless of bleeding, the drug was administered continuously until Day 24. If bleeding (including minor bleeding) occurred for three consecutive days after Day 25, the drug was discontinued for four days. Regardless of whether bleeding had ended or continued, continuous administration of the drug was initiated. The drug administration period was 84 days.

[0101] Excluded medications and foods Standards for Prohibited Medication -Hormonal preparations containing progestin and / or estrogen, low-dose OCs, fixed-dose combinations of progestin and estrogen -GnRH agonists / antagonists, testosterone derivatives, estrogen antagonists, aromatase inhibitors -Drugs or their derivatives that are thought to affect the secretion of sex hormones -Minor tranquilizer, antispasmodic -CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John's wort, etc.) -CYP3A4 inhibitors (e.g., cobicistat, indinavir, itraconazole, ritonavir, telaprevir, voriconazole, clarithromycin, nelfinavir, saquinavir, grapefruit juice, etc.) -Herbal medicines for treating dysmenorrhea, endometritis, and menstrual pain -Anticoagulants - Hypercholesterolemic drugs, antidiabetic drugs (including insulin), drugs that affect serum potassium levels (ACE inhibitors, ARBs, potassium-sparing diuretics, aldosterone antagonists) -HIV protease inhibitors -HCV protease inhibitor -Non-nucleoside reverse transcriptase inhibitors - Any other investigational drug other than the investigational drug used in this clinical trial Criteria for Prohibited Treatments - Cyst puncture (e.g. transvaginal alcohol fixation), laparotomy, or laparoscopic treatment or examination Use of painkillers - Occasional use of analgesics for medical reasons (unbearable pain associated with endometriosis and adverse events) was permitted during the study: loxoprofen tablets or granules (60 mg per dose, ≤ 3 times per day), ibuprofen tablets or granules (200 mg per dose, ≤ 3 times per day). - Any NSAID other than loxoprofen and ibuprofen was not tolerated during the study and, if applicable, was discontinued before visit 1

[0102] Main criteria and analysis 1. Most severe pelvic pain Visual analog scale (VAS) collected by patient diary 2. Gynecological examination Douglas induration, restricted uterine mobility, pelvic tenderness 3. Hemostasis and related parameters Protein S (total activity, antigen (total), specific activity, antigen (free)), free TFPI antigen, antithrombin activity, APC sensitivity ratio (APTT-based, ETP-based), D-dimer, fibrinogen, factors V / VII / X, prothrombin time, protein C, plasminogen, tPA-PAI-1 complex, prothrombin fragment 1+2, soluble fibrin monomer complex, APTT, SHBG 4. Endocrine Parameters Estradiol, progesterone, LH, FSH 5.Safety Adverse events, clinical tests, weight, vital signs (blood pressure, pulse, temperature), 12-lead ECG, physical examination 6. Pharmacokinetics Plasma concentrations of E4, EE, and DRSP

[0103] Key statistical considerations 1. Most severe pelvic pain (VAS): Per protocol population Descriptive statistics (number of subjects, arithmetic mean, standard deviation, % coefficient of variation, quartiles, minimum and maximum values) were estimated to summarize the change from baseline in VAS by stratification factor, by visit, and by group. ANOVA was also performed with stratification factors as fixed effects. Within the framework of ANOVA, LS means and two-sided 95% confidence intervals were estimated for the values ​​of change from baseline by visit and by group. 2. Pain and dysmenorrhea scores associated with endometriosis: Per Protocol Population Descriptive statistics were used for the change from baseline in Endometriosis Pain Score and Dysmenorrhea Score during treatment by group and by visit. 3. Gynecological examination Descriptive statistics of frequencies were estimated for continuous variables and categorical data, respectively. 4. Endocrine-related parameters Descriptive statistics were used for absolute and relative changes from baseline by group and by visit. 5. Hemostasis and related parameters: Per protocol population Descriptive statistics were used to summarize the change from baseline (observed and relative %) for each parameter by visit and by group. ANOVA was performed to estimate LS means and two-sided 95% confidence intervals for the change from baseline (relative %) by visit and by group. The same ANOVA analysis was performed for the LS mean difference (E4 / DRSP-Yaz) and two-sided 95% confidence intervals using a model that considered treatment-by-visit interaction. 6. Safety: Safety analysis set Descriptive statistics were used to summarize continuous variables by visit and by group (clinical tests, blood pressure, pulse, temperature, weight, 12-lead ECG). Frequency tables showing the number and percentage of subjects in each category were used to summarize categorical (AE) variables. The latest version of MedDRA was used. 7. Pharmacokinetics: Safety analysis population Descriptive statistics were used to summarize serum or plasma concentrations of E4, EE, and DRSP by group and by visit. In addition, nonlinear mixed-effects models were applied to explore exposure-response relationships, where applicable.

[0104] Summary of results 1. Effectiveness for endometriosis-related pain Both E4 / DRSP and Yaz Flex were found to similarly reduce the VAS values ​​for the most severe pelvic pain (lower abdominal pain and lower back pain) in the per protocol analysis set (PPS) and full analysis set (FAS). The change from baseline in VAS values ​​remained essentially stable after the second cycle of administration or 56 days of Flex administration, resulting in a reduction of -32.48 ± 19.575 (mean ± standard deviation) mm and -33.93 ± 27.024 mm in the E4 / DRSP and Yaz Flex groups, respectively, by the efficacy evaluation period (EAP), i.e., the third cycle of administration or 84 days of Flex administration.

[0105] Numerical rating scales (NRS) also suggested that all types of endometriosis-associated pain improved equally between the E4 / DRSP and Yaz Flex groups throughout the treatment period.

[0106] The dysmenorrhea score, consisting of items on dysmenorrhea symptom severity and analgesic use, also decreased in both groups after the second / third cycle or after 56 and 84 days of treatment, although slightly greater improvement scores were observed in the YazFlex group. Dysmenorrhea symptom severity and analgesic use showed a similar profile to the dysmenorrhea score. Analgesic use decreased at visits 5 and 6 in both the E4 / DRSP and YazFlex groups, although slightly greater improvement was achieved in the YazFlex group.

[0107] Gynecological examination showed slight improvement in the severity of Douglas induration, restricted uterine mobility and pelvic tenderness, as well as the size and number of ovarian chocolate cysts.

[0108] After three cycles of treatment or 84 days of Flex treatment, the frequency of "improved or better" (CGI-I score 1 and 2) in the Clinical Global Impressions-Improvement (CGI-I) scale was 28.9% (13 / 45 subjects) in the E4 / DRSP group and 40% (16 / 40 subjects) in the Yaz Flex group. Similarly, the frequency of "marginally improved or better" (CGI-I score 1-3) in the E4 / DRSP and Yaz Flex groups was 82.2% (37 / 45 subjects) and 72.5% (29 / 40 subjects), respectively. Additionally, patient global impressions-improvement (PGI-I) revealed that 24% (11 / 45) and 75.5% (34 / 45) of subjects in the E4 / DRSP group were graded as "markedly satisfied or better" (PGI-I scores 1 and 2) and "marginally satisfied or better" (PGI-I scores 1-3), respectively. Similar grades were achieved in the Yaz Flex group, estimated at 32.5% (13 / 40 subjects) for "markedly satisfied or better" (PGI-I scores 1 and 2) and 65.0% (26 / 40 subjects) for "marginally satisfied or better" (PGI-I scores 1-3). 2. Effects on the blood coagulation-fibrinolysis system Both forest plots and ANOVAs suggested that E4 / DRSP had very limited effects on the blood coagulation-fibrinolysis system compared with Yaz Flex. The results are summarized in Tables 1-3.

[0109] [Table 2]

[0110] [Table 3]

[0111] [Table 4]

[0112] 3. Pharmacokinetics High drug concentrations were measured for E4 (E4 / DRSP group), EE (Yaz Flex group), and DRSP (E4 / DRSP and Yaz Flex groups) up to 2 hours after administration, and these were then observed to gradually decrease over time. Nonlinear mixed model analysis was applied to construct two-compartment models with first-order absorption and elimination for both E4 and DRSP. Although there appeared to be a slight relationship between CL for E4 and body size, such as BMI, no statistically significant differences were identified, which is unlikely to suggest potential subject covariance, including DRSP. Nonlinear mixed models were not constructed for EE. 4.Safety Treatment-emergent adverse events (TEAEs) were reported in 88.9% (40 / 45 subjects) of the E4 / DRSP group and 92.7% (38 / 41 subjects) of the Yaz Flex group. Of these, causality could not be ruled out for 77.8% (35 / 45 subjects) and 90.2% (37 / 41 subjects) of the TEAEs in the E4 / DRSP and Yaz Flex groups, respectively. No serious adverse events (SAEs) were reported in the E4 / DRSP group, but one SAE, deep vein thrombosis, was reported in the Yaz Flex group. One severe TEAE, thrombosed hemorrhoids, was observed in the Yaz Flex group, but none were reported in the E4 / DRSP group. No causally related severe TEAEs were reported in either treatment group. One subject discontinued treatment early in the Yaz Flex group due to fatigue and decreased appetite. In contrast, there were no TEAEs leading to premature termination in the E4 / DRSP group.

[0113] In the E4 / DRSP group, the most common TEAEs reported were intermenstrual bleeding (68.9%, 31 / 45 subjects), headache (17.8%, 8 / 45 subjects), and abdominal discomfort / nausea / heavy menstrual bleeding (6.7%, 3 / 45 subjects, respectively). Of these, causally related TEAEs were intermenstrual bleeding (68.9%, 31 / 45 subjects), headache (6.7%, 3 / 45 subjects), and heavy menstrual bleeding (6.7%, 3 / 45 subjects). In the Yaz Flex group, the most common TEAEs reported were intermenstrual bleeding, headache, nausea, and heavy menstrual bleeding in 73.2% (30 / 41 subjects), 26.8% (11 / 41 subjects), 22.0% (9 / 41 subjects), and 12.2% (5 / 41 subjects), respectively. Fatigue, edema, and nasopharyngitis occurred in 3 / 41 subjects (7.3%). Of these, causally related TEAEs were intermenstrual bleeding (73.2%), nausea (22.0%), headache and heavy menstrual bleeding (9.8%), and edema (7.3%).

[0114] After three cyclical or Flex administrations, the endometrial thickness was 4.35±2.340 mm (mean / sd, same below) in the E4 / DRSP group and 3.73±1.666 mm in the Yaz Flex group, which were relatively thin.

[0115] The number of bleeding days was counted as 30.4±14.58 days in E4 / DRSP and 27.4±14.29 days in Yaz Flex. Both groups had similar bleeding events, which were determined to be 4.5±1.19 events in E4 / DRSP and 3.4±1.39 events in Yaz Flex. Bleeding events lasted 7.32±4.750 days in E4 / DRSP and 8.65±5.137 days in Yaz Flex. In the E4 / DRSP group, minor bleeding events were reported in 23.3% (251 / 1076 days), 15.1% (159 / 1056 days), and 10.4% (110 / 1056 days) of the first, second, and third cycles of treatment (excluding the placebo medication period), respectively. In contrast, in the Yaz Flex group, events occurred at rates of 22.9% (255 / 1113 days), 10.6% (105 / 991 days), and 8.8% (74 / 840 days) for the 28-, 56-, and 84-day flex treatments. Similar results were obtained for bleeding events: E4 / DRSP—29.0% (312 / 1076 days) in cycle 1, 8.0% (85 / 1056 days) in cycle 2, and 10.0% (106 / 1056 days) in cycle 3; Yaz Flex—27.9% (310 / 1113 days) for the 28-day flex regimen, 7.6% (75 / 991 days) for the 56-day flex regimen, and 4.5% (38 / 840 days) for the 84-day flex regimen. The number of vaginal bleeding events was lower with Yaz Flex than with E4 / DRSP during the hormone-free washout period, and was mainly spotting.

[0116] There were no notable findings in either group on clinical examinations (hematology, biochemistry, urinalysis, physical examination, and body mass (height, weight, BMI)).

[0117] No abnormal changes were noted on ECG after the second visit in E4 / DRSP. In contrast, ECG examination after the second visit revealed three events in two subjects in the Yaz Flex group (abnormal ECG, right bundle branch block, and first-degree atrioventricular block), all of which were diagnosed as complications.

[0118] No abnormal changes in QTc interval were observed in either the E4 / DRSP or Yaz Flex groups. In the E4 / DRSP group, QTcB (corrected by Bazett's formula) and QTcF (corrected by Fredericia's formula) were determined to be 409.7 ± 42.29 msec and 406.6 ± 42.92 msec at Visit 6 / EOS. Similar measurements were obtained for the Yaz Flex, i.e., 419.3 ± 21.99 msec (QTcB) and 415.0 ± 20.04 msec (QTcF).

[0119] Ad-hoc analysis results after database lock This analysis aimed to characterize the subject population in which E4 / DRSP FDC (fixed-dose combination) tablets may provide clinical benefits compared with EE / DRSP FDC (Yaz Flex) in Japanese patients with endometriosis.

[0120] The most severe pelvic pain (pre-treatment period) over the course of two different menstrual phases was estimated to be a median VAS value of approximately 70 mm across the E4 / DRSP and Yaz Flex groups, meaning that 50% of randomized subjects suffered from a pain intensity equivalent to 70 mm or greater.

[0121] The analysis consisted of three distinct parts. First, individual pain intensity (VAS) time profiles were expressed based on daily VAS values, and spline functions were applied to elucidate the VAS time profiles for each medication, i.e., the E4 / DRSP and Yaz Flex groups. As shown in Figure 1, the spline curve profiles suggested that pain intensity was differentially suppressed during the non-withdrawal bleeding phase between the two medications, with E4 / DRSP achieving a more suppressive VAS reduction during the active medication period compared with Yaz Flex. Second, noteworthy VAS time profiles were quantified according to the following definition: the percentage of days in which VAS values ​​decreased by 70 mm or more from baseline for 80% or more of the evaluation period (Figure 2). Subjects who met this criterion are provisionally referred to as "responders" in this analysis report. Finally, an important question was what clinical benefit was achieved by responders, and CGI-I and PGI-I scores were investigated to correlate this criterion. For this purpose, the primary interest was whether higher CGI-I and / or PGI-I scores were observed in responders. The Cochran-Armitage test indicated a statistically significant trend in responders but not in non-responders (p = 0.009), resulting in both investigators and subjects marking responders (diagonal stripes, Figure 3) as very improved / satisfied or higher compared with non-responders (solid gray fill, Figure 3). Finally, the proportion of responders was compared between E4 / DRSP and Yaz Flex. The E4 / DRSP group achieved a responder rate of approximately 60%, compared with approximately half the rate in the Yaz Flex group (Figure 4). Statistical significance was confirmed by chi-square test (p = 0.033).

[0122] In summary, it was suggested that E4 / DRSP could reduce pelvic pain during the non-menstrual period more effectively than Yaz Flex, leading to improvements in CGI-I and PGI-I.

[0123] Example 2. Efficacy and safety of estetrol monohydrate 15 mg / drospirenone 3 mg combination (E4 / DRSP) in a cyclic regimen for the treatment of pain associated with endometriosis and objective gynecological findings: a multicenter, placebo-controlled, double-blind, randomized study Materials and Methods Study design A multicenter, randomized, double-blind, placebo-controlled, parallel-group design study was conducted in Japanese subjects with endometriosis. The objective was to investigate the potential of E4 / DRSP for treating endometriosis-associated pelvic pain (EAPP) after 6 cycles of treatment with E4 / DRSP for 24 weeks (24 days per cycle, followed by a 4-day hormone-free rest period).

[0124] subject Subjects aged ≥20 years and diagnosed with endometriosis were enrolled. Clinical diagnosis was determined by laparotomy / laparoscopy, transvaginal ultrasound (TVUS), magnetic resonance imaging (presence of ovarian endometrioma), or gynecological examination. Another confirmatory eligibility criterion was an EAPP of ≥40 mm on the visual analog scale (VAS) during the baseline observation period. Demographic and baseline characteristics are shown in Table 4.

[0125] [Table 5]

[0126] Additional inclusion and exclusion criteria Regular menstrual cycles (25-38 days) for the last two menstrual periods before randomization and BMI < 30 kg / m 2 Japanese patients with the above condition were included. Patients who signed a consent form with a full understanding of the clinical trial were included.

[0127] Additional exclusion criteria were patients with undiagnosed abnormal vaginal bleeding within 6 months prior to the screening test; patients aged ≥ 40 years with ovarian endometriomas that were > 10 cm in maximum diameter; patients with ovarian endometriomas containing solid components; patients who had undergone surgical treatment for endometriosis, adenomyosis, and uterine fibroids by cyst aspiration (e.g., transvaginal alcohol fixation), laparotomy, or laparoscopy within 2 months prior to screening; patients who had not had improvement in endometriosis symptoms (moderate or severe pelvic pain) with progestin-containing combined oral contraceptives or hormonal preparations; and patients who had not had improvement in endometriosis symptoms (moderate or severe pelvic pain) with progestin-containing combined oral contraceptives or hormonal preparations during the study. Patients who regularly use analgesics for medical reasons other than the relief of endometriosis pain (occasional use is permitted; prophylaxis is not permitted); patients diagnosed with surgical treatment; patients with a history or presence of hormone-related malignancies (non-melanoma skin cancer is permitted); patients with a history or presence of deep vein thromboembolism, thrombophlebitis (except superficial), pulmonary thromboembolism, cerebrovascular disease, and coronary artery disease; patients ≥ 35 years of age and smoking ≥ 15 cigarettes / day; patients with a history or presence of migraine with aura; patients with pulmonary hypertension or atrial fibrillation, subacute bacterial endocardial infarction Patients with valvular disease and a history of inflammation; patients with diabetes mellitus with vascular disease (e.g., diabetic nephropathy, diabetic retinopathy); patients with known thrombogenic mutations (e.g., factor V Leiden; prothrombin mutations; protein S, protein C, and antithrombin deficiencies); patients with the presence of antiphospholipid antibody syndrome (e.g., antiphospholipid antibody-positive or unknown systemic lupus erythematosus); patients scheduled to undergo surgery within 4 weeks after signing the informed consent, or patients who have undergone surgery within 2 weeks before signing the informed consent. Patients who are undergoing screening or are on long-term bed rest at the time of signing informed consent; patients with severe liver damage (e.g., acute viral hepatitis, severe cirrhosis); patients with liver tumors, severe or acute kidney injury; patients with a history of cardiac disease (e.g., uncomplicated valvular disease) or complications; patients with hypertension (except mild hypertension), severe dyslipidemia (e.g., severe familial dysbetalipoproteinemia), otosclerosis, or uncontrolled thyroid disorder; patients who have been clinically diagnosed with severe depression in the past year before screening or currently;Patients with a history of jaundice, persistent pruritus, or herpes during pregnancy; patients who are pregnant or possibly pregnant; patients who have given birth or had a mid-trimester miscarriage within 6 weeks prior to screening; lactating women; patients with a predisposition to hypersensitivity to any component of the investigational product; patients with a history of side effects or hypersensitivity that required discontinuation of treatment during sex steroid hormone therapy; patients receiving drugs and derivatives that are thought to affect sex hormone secretion; patients who have taken progestins, estrogen-containing hormone preparations, low-dose oral contraceptives, combinations of progesterone and estrogen, testosterone derivatives, estrogen antagonists, aromatase inhibitors, herbal medicines for dysmenorrhea, endometritis, menstrual pain, anti-anxiety drugs, or antispasmodics within 1 month prior to screening, or who have taken GnRH analogues within 2 months prior to screening; patients who are currently using or have used drugs that may trigger interactions with combined oral contraceptives within 1 month prior to subject randomization. This includes, but is not limited to, CYP3A4 inducers, CYP3A4 inhibitors, HIV and / or HCV protease inhibitors, and non-nucleoside reverse transcriptase inhibitors; patients who have participated in other clinical trials within one month prior to screening or who have received other investigational drugs within three months prior to screening; patients who wish to become pregnant during this study or who do not agree to abstain from sexual intercourse or use contraceptive measures (use of barrier-type contraceptive devices (male condoms or contraceptive diaphragms) approved or certified in Japan); and patients who are deemed ineligible by the investigator or sub-investigator for other reasons.

[0128] treatment Eligible subjects were randomly assigned to the E4 / DRSP group or placebo group in equal proportions, balanced by baseline VAS (<60 mm or ≥60 mm) and comorbidities (uterine fibroids and adenomyosis). Immediately after randomization, subjects took one tablet daily, starting on the first day of menstruation. In the E4 / DRSP group, subjects were treated with E4 / DRSP in a cyclic regimen for 24 weeks for six consecutive cycles. The placebo group received oral placebo tablets daily for 28 days per cycle for six cycles. Stratified randomization codes were generated by an interactive web response system using a permuted-block design and were administered by a secretariat independent of the investigators and other study stakeholders to ensure the blinding of the study.

[0129] Evaluation of evaluation items The primary endpoint was the change in the VAS score from baseline for the most severe EAPP after six treatment cycles (Non-Patent Document 24; Non-Patent Document 25). During the baseline observation and treatment periods, subjects were asked to grade their most severe EAPP (lower abdominal pain / low back pain) using an electronic diary device equipped with a VAS. The baseline was the most severe EAPP during the observation period before randomization. Secondary endpoints included: 1) Numerical Rating Scale (NRS) for pelvic, chronic, acute, and defecation pain and dyspareunia; 2) Responder rates achieving a ≥30% or ≥50% reduction in the most severe EAPP VAS or averaged NRS from baseline to cycles 5 and 6; 3) Gynecological examination: cul-de-sac induration, pelvic tenderness, and limited uterine mobility; 4) Number and size of ovarian endometriomas (two-dimensional measurements) and endometrial thickness measured by TVUS; 5) Interference with daily activities and sleep on a 5-point scale; 6) 7-point scale scored by the investigator (Clinical Global Impression of Improvement: CGI-I) and the subject (Patient Global Impression of Satisfaction: PGI-I); and 7) Serum E2, P4, FSH, LH, CA125. All secondary variables were collected using electronic patient diaries, and patients were interviewed or examined by the investigator at the study site.

[0130] Treatment-emergent adverse events (TEAEs) were monitored as safety endpoints throughout the study and were reviewed by investigators for their severity and causality. Bleeding events were recorded by subjects using an electronic diary device.

[0131] statistical analysis The primary analysis was performed using a repeated measures mixed-effects model to evaluate the point estimate of the group difference (E4 / DRSP-placebo) with a two-sided 95% confidence interval (CI) for the change in the VAS for the most severe EAPP from baseline to the sixth treatment cycle. Secondary endpoints were determined using Wilcoxon tests, Fisher's exact tests, and two-sided 95% CIs. Any efficacy analysis was performed on the full analysis set (FAS): subjects who received at least one study drug and had a VAS score for EAPP. Safety analyses included the frequency of any TEAEs, drug-related TEAEs, and severity and causality. This was performed using the safety analysis set of subjects taking at least one study tablet. All descriptive statistics were expressed as mean ± standard deviation. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., NC, USA).

[0132] result subject The study included 162 subjects from 25 clinical trial sites in Japan.

[0133] The FAS included 79 and 83 subjects in the E4 / DRSP and placebo groups, respectively. Demographic characteristics were comparable between groups (Table 4). Mean age and body mass index were 34.7 years and 21.4 kg / m, respectively. 2 Of the 162 subjects, 44 (27.2%) and 26 (16.0%) presented with adenomyosis and uterine fibroids, respectively, and both complications were observed in 13 subjects (8.0%).

[0134] Effectiveness On average, E4 / DRSP reduced the most severe EAPP VAS score by -33.2 mm from baseline after six treatment cycles. A mean reduction in pain intensity of -22.2 mm was observed in the placebo group. As presented in Table 5, the point estimate of the group difference was -8.5 mm (two-sided 95% CI: -16.1 to -0.9 mm), which was significant after 24 weeks of treatment (p = 0.028).

[0135] [Table 6]

[0136] The responder rates of patients achieving a ≥30% and ≥50% reduction in the most severe EAPP VAS from baseline during the fifth or sixth cycle were 53.2% and 36.4%, respectively, in the E4 / DRSP group, which were significant compared with the placebo group.

[0137] NRS rating indicated that E4 / DRSP significantly reduced pain intensity, but not dyspareunia or defecation. In the E4 / DRSP group, mean NRS rating responder rates were 55.8% and 36.4% for a ≥30% and ≥50% reduction from baseline rating, respectively, which were significant compared with the placebo group.

[0138] After six treatment cycles, gynecological examinations demonstrated objective improvement in the E4 / DRSP group (Table 6). No worsening findings were diagnosed for cul-de-sac induration, and 23.1% of subjects demonstrated significant improvement in the E4 / DRSP group. Similar results were obtained for uterine mobility restriction. E4 / DRSP also prevented the progression of pelvic tenderness compared with the proportion of subjects who worsened in the placebo group (E4 / DRSP 1.3% vs. placebo 12.0%) (Figure 5A). Substantial improvement was also observed in subjects with adenomyosis (Figure 5B). The volume of the largest ovarian endometrioma was reduced by approximately 45.0% in the E4 / DRSP group compared with the placebo group. Ovarian endometriomas also disappeared in 7.7% of subjects in the E4 / DRSP group. Serum CA125 levels returned to the normal range (<35 U / ml) in 19.2% of the E4 / DRSP group and only 2.4% of the placebo group.

[0139] [Table 7]

[0140] Daily activities did not improve significantly in the E4 / DRSP group. Nevertheless, six cycles of E4 / DRSP treatment did not result in any subjects rating themselves as "extremely disturbed," and unlike the placebo group, it reduced the percentage of subjects rating themselves as "very disturbed" by 9.0%. Sleep disturbances improved significantly in the E4 / DRSP group, with the percentage of subjects rating themselves as "not at all disturbed" increasing by 52.6%. A significant improvement was observed in global impression, with this percentage reaching approximately 45% in the E4 / DRSP group. Serum endocrine hormone levels decreased in the E4 / DRSP group throughout the study. Endometrial thickness changed from 9.81 ± 3.66 mm at baseline to 4.83 ± 2.48 mm at 24 weeks in the E4 / DRSP group.

[0141] safety TEAEs were reported in 77 of 79 subjects (97.5%) in the E4 / DRSP group and 72 of 83 subjects (86.7%) in the placebo group. In the E4 / DRSP group, interphase bleeding events were common and decreased with treatment cycle: 51.9% during the first cycle and 24.7% after treatment. Minor bleeding was the predominant event after the third treatment cycle, accounting for approximately 50% of bleeding events. Interphase bleeding / minor bleeding occurred less than one day after the second treatment cycle. TEAEs related to the study drug in the E4 / DRSP group were similar to those commonly reported for OCPs, including nausea (6.3%), abdominal pain (2.5%), diarrhea (2.5%), somnolence (6.3%), and headache (6.3%). One subject in the placebo group discontinued treatment due to increased D-dimer levels. Notably, little difference was observed in the proportion of subjects with hemostatic parameters outside the reference range between the E4 / DRSP and placebo groups. No deaths or other serious AEs occurred during treatment. No clinically important changes were observed in other safety endpoints.

[0142] Consideration In this study, E4 / DRSP improved the most severe EAPP in the cyclic regimen, as well as EE / DRSP in the flexible extended regimen (Non-Patent Document 26), confirming its superiority over placebo. The responder rate also demonstrated more definitive findings for EAPP reduction (Non-Patent Document 27), suggesting that approximately 40% of subjects experienced a ≥50% reduction in pain intensity from baseline. Furthermore, pain intensity decreased by <40 mm, the goal for chronic pain management, in ≥50% of subjects treated with E4 / DRSP for 24 weeks (Non-Patent Document 28).

[0143] Objective findings of gynecological examination revealed significant improvements in cul-de-sac induration, pelvic tenderness, and restricted uterine mobility in the E4 / DRSP group. Ovarian endometrioma volume was significantly reduced in the E4 / DRSP group, as well as in the EE / DRSP and EE / norethisterone groups. ((Non-Patent Document 29); (Non-Patent Document 30)) These treatment benefits are best illustrated by the significant advantages in QoL-related questionnaire and global impression scores in the E4 / DRSP group.

[0144] Safety evaluation revealed that intermediate bleeding events were the most frequently reported TEAE associated with E4 / DRSP. The frequency decreased with the number of cycles, consistent with a previous Phase III study involving 2,234 participants outside of Japan (Non-Patent Document 31). Other reported TEAEs were those commonly associated with OCPs, such as nausea and headache. No VTEs were reported, and the proportion of subjects with D-dimers above the upper range was comparable to that of the placebo group, suggesting a minimal impact of E4 / DRSP on hemostatic parameters.

[0145] E4 / DRSP met the following requirements for treating endometriosis: reduction of EAPP, improvement in objective gynecological findings, and restoration of QoL and global impression. No safety concerns were raised, including hemostasis and bleeding patterns.

[0146] conclusion This study demonstrated that E4 / DRSP was clinically effective for treating EAPP and improved objective gynecological findings, QoL, and global impression in patients with endometriosis. Therefore, E4 / DRSP should be considered as a first-line endometriosis treatment.

Claims

1. 1. A pharmaceutical composition comprising about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and about 2.5 mg to about 3.5 mg of drospirenone for use in alleviating pain associated with endometriosis in a subject, The pharmaceutical composition, wherein the pain in the subject is pain during a non-withdrawal bleeding period.

2. 1. A pharmaceutical composition for use in treating a subject suffering from pelvic pain, comprising about 13.5 mg to about 16.5 mg of estetrol or estetrol hydrate and about 2.5 mg to about 3.5 mg of drospirenone, The pharmaceutical composition, wherein the pelvic pain in the subject is pelvic pain during a non-withdrawal bleeding period.

3. 3. The composition for use according to claim 1 or 2, wherein the pain or pelvic pain of the subject is measured using a VAS (visual analogue scale), preferably the subject 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.

4. 3. The composition for use according to claim 1 or 2, wherein the subject is suffering from pelvic pain associated with endometriosis with a VAS score of greater than about 40 mm, about 50 mm, about 60 mm or about 70 mm prior to administration, preferably, the subject is suffering from pelvic pain induced by endometriosis with a VAS score of greater than about 40 mm, about 50 mm, about 60 mm or about 70 mm prior to administration.

5. 3. The composition for use according to claim 1 or 2, wherein the pain or pelvic pain is caused by engraftment of endometrial tissue outside the uterine cavity in the pelvis.

6. 3. The composition for use according to claim 1 or 2, wherein the pain or pelvic pain is pelvic pain such as chronic pelvic pain, lower abdominal pain and / or lower back pain, pain during defecation and pain during sexual intercourse, or pain caused by endometrial adhesions in the pouch of Douglas.

7. 3. The composition for use according to claim 1 or 2, wherein said use results in an improvement in the CGI-I scale (Clinician Global Impressions-Improvement Scale), preferably said use results in an improvement in the CGI-I scale of about 28.9%.

8. 3. The composition for use according to claim 1 or 2, wherein said use results in an improvement on the PGI-I scale (Patient Global Impressions-Improvement Scale) rated as "very satisfied or better", preferably said use results in an improvement on the PGI-I scale rated as "very satisfied or better" of about 24%.

9. 3. The composition for use according to claim 1 or 2, wherein said use results in a responder rate of about 60%.

10. The composition for use according to claim 1, wherein the subject is diagnosed with endometriosis by laparotomy / laparoscopy and / or with ovarian chocolate cysts as assessed by transvaginal ultrasound (TVUS) and / or magnetic resonance imaging (MRI).

11. 3. The composition for use according to claim 1 or 2, wherein the composition is used in a cycle of 21 to 28 day daily active dosage units of the composition, preferably the composition is used in a cycle of 24 day daily active dosage units of the composition.

12. 12. The composition for use according to claim 11, wherein the cycle comprises a 7-day drug-free period, preferably a 4-day drug-free period.

13. 12. The composition for use according to claim 11, wherein use of the composition results in a reduction in VAS score from before administration to after the second or third administration cycle, preferably the reduction remains substantially stable after the second or third administration cycle.

14. A composition for use according to claim 1, wherein use of the composition results in an improvement in the severity of Douglas induration, restriction of uterine mobility and / or pelvic tenderness, a reduction in the size and / or number of ovarian chocolate cysts as assessed by TVUS or MRI.

15. 3. The composition for use according to claim 1 or 2, wherein use of the composition results in fewer TEAEs than use of a fixed-dose combination tablet of EE 20 μg / DRSP 3 mg, preferably the TEAEs are selected from the group consisting of intermenstrual bleeding, headache, nausea and heavy menstrual bleeding.

16. The composition for use according to claim 1 , wherein the subject has adenomyosis and / or uterine fibroids in addition to endometriosis.

17. 1. A pharmaceutical composition comprising about 13.5 mg to about 16.5 mg of estetrol or estetrol monohydrate and about 2.5 mg to about 3.5 mg of drospirenone for use in alleviating pain associated with endometriosis in a subject, said use comprising a step of determining whether said subject has pre-administration pelvic pain defined by a VAS score of greater than about 40 mm, about 50 mm, about 60 mm, or about 70 mm, and wherein said pain in said subject is pain during the non-withdrawal bleeding phase.

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