Methods for treating endometriosis and methods for providing effective contraception

Abstract

The present invention relates to drospirenone for use in a method for treating endometriosis, endometriosis associated pelvic pain (EAPP) and / or dysmenorrhea comprising administering drospirenone in a biphasic regimen. The present invention further relates to the use of drospirenone administered in such a biphasic regimen as a contraceptive and for inducing amenorrhea, as well as to pharmaceutical compositions and kits comprising drospirenone administered in such a biphasic regimen.

Description

Technical Field

[0001] The present invention relates to the field of women's health, more specifically to the treatment of endometriosis, endometriosis-associated pelvic pain and / or dysmenorrhea. Accordingly, the present invention relates to drospirenone for use in a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, which comprises administering drospirenone in a biphasic regimen. The present invention further relates to the use of drospirenone administered in such a biphasic regimen as a contraceptive and for inducing amenorrhea, and to pharmaceutical compositions and kits comprising drospirenone administered in such a biphasic regimen.

Background Art

[0002] Endometriosis is an estrogen-dependent chronic disease characterized by the presence of endometrial tissue outside the uterus, including the ovaries and other pelvic structures. These lesions can cause a chronic inflammatory reaction and lead to the formation of scar tissue and adhesions. Women with endometriosis frequently experience less common symptoms such as pain during ovulation, constipation, and pain during urination (Non-Patent Document 2), along with symptoms of dysmenorrhea, premenstrual pain, dyspareunia, and chronic fatigue (Non-Patent Document 1). Furthermore, the presence of ectopic endometrium can cause infertility, which can be seen in up to 50% of women with endometriosis (Non-Patent Document 3). Thus, women with endometriosis face one or both of the two major problems of pain associated with endometriosis and infertility. The severity of the symptoms does not necessarily correlate with the degree of pelvic disease or the size of the lesions. Many women with mild endometriosis complain of severe pelvic pain (Non-Patent Document 4).

[0003] Endometriosis is estimated to affect 10% of women of reproductive age, which extrapolates to approximately 190 million women worldwide.

[0004] Currently, there is no cure for endometriosis. Women with endometriosis still need continuous, collaborative, and supportive management of their condition, as well as an understanding of the significant impact the condition can have on their quality of life. The main goals of treatment are to alleviate pain and other symptoms, reduce endometrial lesions, and improve the quality of life for affected individuals.

[0005] Current hormonal therapies for pain associated with endometriosis focus on systemic or local estrogen suppression, inhibition of tissue proliferation and inflammation, or both. Concomitant oral contraceptives (COCs) are widely used as a first-line treatment for dysmenorrhea or chronic pelvic pain, particularly in adolescents with endometriosis, regardless of whether endometriosis is suspected or not (Non-Patent Literature 5). Nevertheless, estrogen has a stimulating effect on the metabolic activity of the endometrium. Therefore, COC administration may lead to estrogen dominance, potentially increasing the risk of disease progression (Non-Patent Literature 6).

[0006] Progestin monotherapy is also used as a first-line treatment for pelvic pain associated with endometriosis and to reduce the severity of endometrial lesions. One progestin approved by the FDA for the treatment of endometriosis, secondary amenorrhea, and abnormal uterine bleeding is norethisterone acetate (NETA) (5 mg tablets). In principle, NETA can provide ovulation inhibition starting at a dose of 0.35 mg / day when administered continuously for 28 days, but the high doses required to treat endometriosis (5 mg / day to 15 mg / day) are more than 10 times the dose required for ovulation inhibition (0.35 mg / day), and it is not approved for contraceptive use. Treatment may be maintained at this high dose level for up to 6 to 9 months, or until breakthrough bleeding requests temporary discontinuation of treatment. Furthermore, at such high doses, NETA may produce androgenic side effects such as acne, hirsutism, weight gain, and, in some women, slightly more severe voice changes.

[0007] Another approved progestin, Dienogest (DNG), is a synthetic progestin currently used in Europe for the clinical treatment of endometriosis, at a daily dose of 2 mg (Visanne® 2 mg tablets). DNG, lacking androgenic activity, is more tolerable than NETA. While 2 mg of DNG per day provides ovulation inhibition, it does not completely suppress ovarian activity and is therefore not approved as a contraceptive (Non-Patent Literature 7). Consequently, users are advised to employ barrier contraception or other non-hormonal alternatives when using DNG for the treatment of endometriosis (Non-Patent Literature 8).

[0008] Currently approved treatments for endometriosis-related pain do not include contraception. Furthermore, the combined use of some FDA or European-approved endometriosis medications (e.g., GnRH antagonists such as the recently approved product Elagolix, or progestins as Dinagest) with hormonal contraceptives is not permitted. The need for barrier contraception may limit compliance with these products and increase discontinuation rates. Therefore, there is a critical need for treatments for endometriosis-associated pelvic pain (EAPP) in women seeking hormonal contraception.

[0009] Drospirenone (DRSP) is a derivative of spironolactone and possesses progest-mimicking activity, antimineralocorticoid activity, and antiandrogenic activity. Drospirenone as a contraceptive ingredient is available in oral combination pills such as Yasmin® (3 mg DRSP / 30 μg ethinylestradiol), Yaz® (3 mg DRSP / 20 μg ethinylestradiol), and Yasminelle® (3 mg DRSP / 20 μg ethinylestradiol). These tablets contain ethinylestradiol, which enhances the ovulation-inhibiting effect of drospirenone and ensures contraception and cycle control.

[0010] In Europe and the United States, DRSP was recently approved as a POP (Slinda® / Slynd®) contraceptive for women of reproductive age. The approved pharmacologics are one white active tablet (DRSP 4 mg) daily for the first 24 days, followed by one green inactive tablet daily for the next 4 days. DRSP POP formulations may be prepared in the manner described in the prior art, for example, Patent Document 1 or Patent Document 2. The rationale behind the DRSP 24 / 4 regimen was to create a progestogen-only method that provides predictable, scheduled bleeding, including four hormone-free days in each cycle, and otherwise is not associated with progestogen-only contraception (Non-Patent Document 9).

[0011] The avoidance or absence of menstruation, known as "amenorrhea," achieved through continuous medication regimens, has potentially desirable characteristics from a patient's perspective, including improved adherence to treatment, reduced interference with daily life and special events, and a decrease in habitual menstrual-related absences from work or school (Non-Patent Documents 10, 11, and 12). Past patient survey data and feedback from participants in clinical trials of hormonal contraceptives suggest that a significant proportion of women prefer reduced menstrual frequency or amenorrhea associated with continuous medication regimens (Non-Patent Documents 13, 14, 15, 16, 17, and 18). A large-scale survey of over 4,000 women of reproductive age in North America, South America, and Europe found that 60% of respondents desired to postpone menstrual bleeding (Non-Patent Document 19). Therefore, there is a need to provide contraceptives that are highly safe and reliable, while simultaneously reducing intermenstrual bleeding (menstruation), i.e., inducing amenorrhea.

[0012] Two Phase III trials involving up to 13 28-day treatment cycles in sexually active women evaluated the contraceptive efficacy and safety of the oral DRSP 4 mg 24 / 4 day regimen in the United States and Europe (Non-Patent Literature 20 and Non-Patent Literature 21). Generally, approximately 40% of users reported amenorrhea after 9 to 13 cycles of use of the oral DRSP 4 mg 24 / 4 day regimen. However, there is still a need for a more rapid and efficient method of inducing amenorrhea that would allow more women to benefit from less or no bleeding after fewer cycles of oral DRSP use.

[0013] In a Phase II study (Research Report CF111 / 203, 2014), two different drug regimens were evaluated over two cycles: a 28-day continuous regimen of DRSP 2.8 mg compared to a 24+4 dose regimen of the currently approved DRSP 4.0 mg (Slynd®) in 50 healthy women, to assess the ovulation-inhibiting ability of two regimens as reflected in hormonal and ovarian activity. The results of this study have been published (EudraCT number: 2011-004085-15), but the study disclosure does not provide details regarding the women's bleeding patterns. [Prior art documents] [Patent Documents]

[0014] [Patent Document 1] International Publication No. 2012 / 00981 [Patent Document 2] International Publication No. 2016 / 207298 [Non-patent literature]

[0015] [Non-Patent Document 1] Schindler, 2011 [Non-Patent Document 2] Taylor et al., 2017 [Non-Patent Document 3] Vercellini et al., 2014

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[0016] Accordingly, in one embodiment, the present invention relates to drospirenone used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, comprising administering drospirenone to a subject in a two-phase regimen, wherein a daily dose of drospirenone is administered during Phase 1, and a smaller daily dose of drospirenone is administered during Phase 2.

[0017] In one embodiment of the method of the present invention, the above daily dose of drospirenone is administered once a day from day 1 to day 24, and thereafter, a smaller daily dose of drospirenone is administered once a day from day 25 to day 28.

[0018] In one embodiment of the method of the present invention, the daily dose of drospirenone administered from day 1 to day 24 is approximately 2.0 mg to 6.0 mg, preferably approximately 3.0 mg to 5.0 mg, more preferably approximately 3.5 mg to 4.5 mg, even more preferably approximately 3.8 mg to 4.2 mg, and most preferably approximately 4.0 mg of drospirenone.

[0019] In a further embodiment of the method of the present invention, the smaller daily dose of drospirenone administered from day 25 to day 28 is about 2.5 mg to 3.5 mg, preferably about 2.6 mg to 3.2 mg, more preferably about 3.0 mg, and most preferably about 2.8 mg of drospirenone.

[0020] In a preferred embodiment of the method of the present invention, the daily dose of drospirenone administered from day 1 to day 24 is 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is 2.8 mg.

[0021] In a more preferred embodiment of the present invention, the method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea also provides contraception.

[0022] In one embodiment of the method of the present invention, estrogen is not administered.

[0023] In a further embodiment, the present invention relates to drospirenone used in a method for providing contraception to a female subject, wherein the drospirenone is administered to the subject in a two-phase regimen, with a daily dose of drospirenone administered during the first phase and a smaller daily dose of drospirenone administered during the second phase.

[0024] In one preferred embodiment of this method, the administration of drospirenone induces amenorrhea. In a more preferred embodiment of this method, the administration of drospirenone induces amenorrhea in more than 25%, preferably more than 30%, of female subjects after two administration cycles.

[0025] In a preferred embodiment of this method, the administration of drospirenone induces amenorrhea in at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, preferably at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, more preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50% of subjects after three or even two administration cycles.

[0026] In a more preferred embodiment, the administration of drospirenone induces amenorrhea in at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, preferably at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, more preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50% of subjects after one administration cycle.

[0027] In another preferred embodiment of this method, the administration of drospirenone induces amenorrhea in at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, and at least 50% of subjects after six administration cycles.

[0028] In one embodiment of this method, the above daily dose of drospirenone is administered once a day from day 1 to day 24, and then a smaller daily dose of drospirenone is administered once a day from day 25 to day 28.

[0029] In further embodiments, the daily dose of drospirenone administered from day 1 to day 24 is approximately 2.0 mg to 6.0 mg, preferably approximately 3.0 mg to 5.0 mg, more preferably approximately 3.5 mg to 4.5 mg, even more preferably approximately 3.8 mg to 4.2 mg, and most preferably approximately 4.0 mg.

[0030] In further embodiments, the lower daily dose of drospirenone administered from day 25 to day 28 is approximately 2.5 mg to approximately 3.5 mg, preferably approximately 2.6 mg to approximately 3.2 mg, more preferably approximately 3.0 mg, and most preferably approximately 2.8 mg of drospirenone.

[0031] In a further embodiment, the present invention relates to the use of drospirenone as a contraceptive in female subjects, comprising administering drospirenone to the subjects in a two-phase regimen, wherein a daily dose of drospirenone is administered during the first phase, and a smaller daily dose of drospirenone is administered during the second phase.

[0032] In further embodiments, the use of drospirenone as described above induces amenorrhea. In more preferred embodiments, the use of drospirenone as described above induces amenorrhea in at least 20%, preferably at least 25%, and most preferably 30% of female subjects after 4, preferably 3, and most preferably 2, administration cycles.

[0033] In a preferred embodiment, the use of drospirenone induces amenorrhea in at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, preferably at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, more preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50% of subjects after three or even two administration cycles.

[0034] In a more preferred embodiment, the use of drospirenone induces amenorrhea in at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, preferably at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, more preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50% of subjects after a single administration cycle.

[0035] In one preferred embodiment, the use of drospirenone induces amenorrhea in at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, and at least 50% of subjects after six administration cycles.

[0036] In one embodiment of the use of drospirenone according to the present invention, the above daily dose of drospirenone is administered once a day from day 1 to day 24, and thereafter, a smaller daily dose of drospirenone is administered once a day from day 25 to day 28.

[0037] In further embodiments of the above use, the daily dose of drospirenone administered from day 1 to day 24 is approximately 2.0 mg to 6.0 mg, preferably approximately 3.0 mg to 5.0 mg, more preferably approximately 3.5 mg to 4.5 mg, even more preferably approximately 3.8 mg to 4.2 mg, and most preferably approximately 4.0 mg.

[0038] In further embodiments of the above use, the lowest daily dose of drospirenone administered from day 25 to day 28 is approximately 2.5 mg to approximately 3.5 mg, preferably approximately 2.6 mg to approximately 3.2 mg, more preferably approximately 3.0 mg, and most preferably approximately 2.8 mg of drospirenone.

[0039] In the preferred embodiment of the above use, the daily dose of drospirenone administered from day 1 to day 24 is approximately 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is approximately 2.8 mg.

[0040] In one embodiment of the use of the present invention, estrogen is not administered.

[0041] In one embodiment of the use of drospirenone as a contraceptive to the present invention, as a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, the route of administration is selected from oral administration, transdermal administration, or transmucosal administration, with oral administration being preferred.

[0042] The present invention further comprises a kit, preferably a contraceptive kit, comprising one or more packaging units, each packaging unit comprising at least 28 active daily dose units. a) At least 24 daily dose units contain a first dose of drospirenone, and each of these daily dose units contains the same amount of drospirenone, and the amount is greater than the amount of drospirenone in a daily dose unit of a second dose of drospirenone. b) At least four daily dose units contain the second dose of drospirenone, and each of these daily dose units contains the same amount of drospirenone, but the amount of drospirenone is less than that of a daily dose unit containing the first dose of drospirenone. Regarding the kit.

[0043] In one embodiment of the kit of the present invention, at least 28 active daily dose units do not contain estrogen.

[0044] In a preferred embodiment of the present invention, drospirenone is the sole contraceptive active ingredient in at least 28 active daily dose units.

[0045] In one embodiment of the kit of the present invention, the first amount of drospirenone is about 2.0 mg to 6.0 mg, preferably about 3.0 mg to 5.0 mg, more preferably about 3.5 mg to 4.5 mg, even more preferably about 3.8 mg to 4.2 mg, and most preferably about 4.0 mg of drospirenone.

[0046] In further embodiments of the kit of the present invention, the second amount of drospirenone is about 2.5 mg to about 3.5 mg, preferably about 2.6 mg to about 3.2 mg, more preferably about 3.0 mg, and most preferably about 2.8 mg.

[0047] In a preferred embodiment of the kit of the present invention, the first amount of drospirenone is approximately 4.0 mg, and the second amount of drospirenone is approximately 2.8 mg.

[0048] The present invention further relates to a pharmaceutical composition comprising drospirenone used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea as described herein, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives.

[0049] In one embodiment of the pharmaceutical composition of the present invention, the above-mentioned pharmaceutically acceptable additives are at least one binder and at least one filler. (i) The amount of drospirenone is 1% to 10% by weight, (ii) The amount of at least one binder is 50% to 65% by weight, (iii) At least one filler accounts for 25% to 35% by weight, The weight percentage refers to the total weight of the above-mentioned pharmaceutical composition.

[0050] In a further embodiment of the present invention, the pharmaceutical composition further comprises at least one lubricant and at least one lubricating agent, (iv) The amount of at least one lubricant is between 0.2% and 6% by weight, (v) The amount of at least one lubricant is 0.2% to 0.6% by weight, The weight percentage refers to the total weight of the above-mentioned pharmaceutical composition.

[0051] In a preferred embodiment of the pharmaceutical composition of the present invention, (i) At least one binder is microcrystalline cellulose, (ii) At least one filler is anhydrous lactose, (iii) At least one lubricant is silicon dioxide, (iv) At least one lubricant is magnesium stearate.

[0052] The present invention further relates to the use of drospirenone as defined herein as a contraceptive in a pharmaceutical composition as defined herein.

[0053] The present invention further relates to a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects requiring treatment for endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, comprising administering drospirenone to the female subjects in a two-phase regimen, wherein a daily dose of drospirenone is administered during Phase 1, and a smaller daily dose of drospirenone is administered during Phase 2.

[0054] In one embodiment of the above treatment method for endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, a daily dose of drospirenone is administered once daily from day 1 to day 24, and thereafter, a smaller daily dose of drospirenone is administered once daily from day 25 to day 28.

[0055] In one embodiment of the above treatment method for endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, the daily dose of drospirenone administered from day 1 to day 24 is approximately 2.0 mg to 6.0 mg, preferably approximately 3.0 mg to 5.0 mg, more preferably approximately 3.5 mg to 4.5 mg, even more preferably approximately 3.8 mg to 4.2 mg, and most preferably approximately 4.0 mg of drospirenone.

[0056] In further embodiments of the above-described treatment method for endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, the smaller daily dose of drospirenone administered from day 25 to day 28 is approximately 2.5 mg to approximately 3.5 mg, preferably approximately 2.6 mg to approximately 3.2 mg, more preferably approximately 3.0 mg, and most preferably approximately 2.8 mg of drospirenone.

[0057] In a preferred embodiment of the above treatment method for endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, the daily dose of drospirenone administered from day 1 to day 24 is approximately 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is approximately 2.8 mg.

[0058] Further embodiments of methods for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea also provide contraception.

[0059] In further embodiments of methods for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, estrogen is not administered.

[0060] Embodiments of the present invention further relate to a method for providing contraception to a female subject in need of contraception, comprising administering drospirenone to the female subject in a two-phase regimen, wherein a daily dose of drospirenone is administered during the first phase, and a smaller daily dose of drospirenone is administered during the second phase.

[0061] In one embodiment of the above method for providing contraception, the above daily dose of drospirenone is administered once a day from day 1 to day 24, and thereafter, a smaller daily dose of drospirenone is administered once a day from day 25 to day 28.

[0062] In one embodiment of the above method for providing contraception, the daily dose of drospirenone administered from day 1 to day 24 is approximately 2.0 mg to 6.0 mg, preferably approximately 3.0 mg to 5.0 mg, more preferably approximately 3.5 mg to 4.5 mg, even more preferably approximately 3.8 mg to 4.2 mg, and most preferably approximately 4.0 mg of drospirenone.

[0063] In a further embodiment of the above method for providing contraception, the smaller daily dose of drospirenone administered from day 25 to day 28 is approximately 2.5 mg to approximately 3.5 mg, preferably approximately 2.6 mg to approximately 3.2 mg, more preferably approximately 3.0 mg, and most preferably approximately 2.8 mg of drospirenone.

[0064] In a preferred embodiment of the above method for providing contraception, the daily dose of drospirenone administered from day 1 to day 24 is approximately 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is approximately 2.8 mg.

[0065] In a further embodiment of the method for providing contraception, estrogen is not administered.

[0066] The present invention further relates to a method for inducing amenorrhea in a female subject, comprising administering drospirenone to the female subject in a two-phase regimen, wherein a daily dose of drospirenone is administered during the first phase, and a smaller daily dose of drospirenone is administered during the second phase.

[0067] In one embodiment of the above method, the above daily dose of drospirenone is administered once a day from day 1 to day 24, and then a smaller daily dose of drospirenone is administered once a day from day 25 to day 28.

[0068] In one embodiment of the above method, the daily dose of drospirenone administered from day 1 to day 24 is approximately 2.0 mg to 6.0 mg, preferably approximately 3.0 mg to 5.0 mg, more preferably approximately 3.5 mg to 4.5 mg, even more preferably approximately 3.8 mg to 4.2 mg, and most preferably approximately 4.0 mg of drospirenone.

[0069] In one embodiment of the above method, the daily dose of drospirenone administered from day 25 to day 28 is less than the above amount, which is approximately 2.5 mg to approximately 3.5 mg, preferably approximately 2.6 mg to approximately 3.2 mg, more preferably approximately 3.0 mg, and most preferably approximately 2.8 mg of drospirenone.

[0070] In further embodiments of the above method, the route of administration is selected from oral administration, transdermal administration, or transmucosal administration, with oral administration being preferred.

[0071] The present invention also relates in one embodiment to drospirenone used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects requiring treatment for endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, comprising administering drospirenone to female subjects in a continuous regimen, wherein drospirenone is administered once daily from day 1 to day 28 in an amount of about 2.5 mg to 3.5 mg, more preferably about 3.0 mg, and most preferably about 2.8 mg of drospirenone.

[0072] In a more preferred embodiment, the above method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea also induces amenorrhea.

[0073] In a more preferred embodiment, the above method induces amenorrhea in at least 20%, preferably at least 25%, and most preferably at least 30% of female subjects after four, preferably three, and most preferably two administration cycles.

[0074] In a preferred embodiment, the method induces amenorrhea in at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, preferably at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, more preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50% of subjects after three or even two administration cycles.

[0075] In a more preferred embodiment, the method induces amenorrhea in at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, preferably at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, more preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50% of subjects after one administration cycle.

[0076] In a preferred embodiment, the method induces amenorrhea in at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, and at least 50% of subjects after six administration cycles. [Brief explanation of the drawing]

[0077] [Figure 1] This figure, disclosed in further detail in Example 1 and Table 1, shows the number of subjects with cycle-based amenorrhea (FAS) observed in continuous DRSP 2.8 mg treatment compared to DRSP 4.0 mg (24+4 treatments). [Figure 2] This figure, disclosed in further detail in Example 1 and Table 2, shows the serum estradiol levels (pmol / L) obtained with continuous DRSP 2.8 mg treatment compared with DRSP 4.0 mg (24+4). [Modes for carrying out the invention]

[0078] definition As used herein, the terms “active daily dose” or “daily dose” refer to a physically separated unit suitable as a unit dose that can be administered to a subject to supply the required amount of the active ingredient, such as drospirenone.

[0079] As used herein, the term “amenorrhea” refers to the absence of bleeding / trace bleeding in a female subject, preferably a woman of reproductive age, for at least 28 days or one administration cycle.

[0080] As used herein, the terms “two-phase” or “two-phase regimen” refer to a dosage regimen having two phases, in which the amount of active ingredient administered in Phase 1 is different from the amount of active ingredient administered in Phase 2. The amount of active ingredient administered in each phase is constant; that is, the same amount of active ingredient is present in each daily dosage form administered in each phase. In each phase, the active ingredient is administered in each daily dosage form; that is, there is no daily dosage form that does not contain the active ingredient.

[0081] As used herein, the term “contraceptive kit” refers to a kit that, when administered to a female patient in an effective daily dose as directed, helps prevent pregnancy.

[0082] As used herein, “contraception” means a method of preventing pregnancy.

[0083] As used herein, the term “drospirenone” refers to drospirenone itself, i.e., the chemical substance identified by CAS Registry No. 67392-87-4, the solvates of drospirenone, and derivatives or prodrugs of drospirenone. Drospirenone can be prepared by well-known methods described in the prior art, for example, U.S. Patent No. 4,129,564, International Publication No. 9,806,738, European Patent No. 1,1746,101, or International Publication No. 2006,061,309. The method described in International Publication No. 2006,061,309 may be particularly suitable for the preparation of drospirenone.

[0084] As used herein, the term “dysmenorrhea” refers to a medical term relating to the painful menstrual period caused by uterine contractions. Primary dysmenorrhea refers to recurrent pain, while secondary dysmenorrhea is caused by a disorder of the reproductive system.

[0085] As used herein, the terms “endometriosis” and “endometriosis-associated pelvic pain (EAPP)” refer to estrogen-dependent chronic diseases characterized by the formation of extrauterine endometrial lesions, including those in the ovaries and other pelvic structures, and one of its most common symptoms, reported as pelvic pain, respectively. All subtypes of endometriosis are included, including superficial, cystic, deeply invasive, abdominal wall, and catamenial endometriosis. The effectiveness of managing endometriosis-associated pelvic pain (EAPP) can be assessed using different assessment scales, such as visual analog scales (VAS) or numerical rating scales (NRS), which are well known to those skilled in the art (see, for example, Gerlinger et al. (2010) and Breivik et al. (2008)). Depending on the evaluation scale, for example, on an NRS scale of 0 to 10, a difference from placebo of at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, or at least 3.0 can already be considered clinically significant and to provide a real benefit to the patient.

[0086] As used herein, the term “estrogen” refers to a group of steroid hormones that promote the development and maintenance of female physical characteristics. Synthetic estrogens are well known and commonly used in oral contraceptives or for the treatment of menopausal and menstrual disorders.

[0087] In this specification, terms such as "oral," "oral dosage form," "oral pharmaceutical dosage form," "oral administration," "oral composition," "oral pharmaceutical composition," "oral contraceptive composition," "oral tablet," "oral capsule," "oral ingestion," "by mouth," and "oral route" all refer to any method of administration by mouth. The oral dosage forms of the present invention are usually taken as is, but may be taken after modification (e.g., crushing), and may usually be taken with the help of water or a beverage to speed up passage through the mouth.

[0088] As used herein, “progestogen-only contraceptive” or “progestogen-only pill” (also known as “POP”) means a pill or contraceptive that contains progestogen as the sole contraceptive ingredient and contains no estrogen whatsoever.

[0089] As used herein, “therapeutic dose” means the amount and duration of administration that is effective in achieving one or more desirable therapeutic outcomes, such as a significant delay in the onset or progression of a disease, or a significant reduction in the severity of one or more symptoms. A therapeutic dose is also typically the amount in which the therapeutically beneficial effect outweighs any toxic or adverse effects of the active ingredient or pharmaceutical composition.

[0090] As used herein, “treatment,” “to treat,” or “to treat” means (i) preventing or delaying the onset of a disease, disorder, or condition in a subject who is susceptible to such a disease, disorder, or condition but has not yet been diagnosed with it; (ii) preventing a disease, disorder, or condition, i.e., stopping or delaying its onset or progression; and / or (iii) alleviating a disease, disorder, or condition, i.e., causing a regression of the disease, disorder, or condition. In certain embodiments, such terms mean improvement or elimination of a disease or symptoms associated with a disease.

[0091] Method of the present invention The present invention relates to drospirenone used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, comprising administering drospirenone to a subject in a two-phase regimen, wherein a daily dose of drospirenone is administered during Phase 1, and a smaller daily dose of drospirenone is administered during Phase 2.

[0092] The drospirenone dosing regimen approved to date is the 24+4 regimen, which involves administering drospirenone continuously for 24 days, followed by a hormone break from day 25 to day 28 in which a placebo is administered. This invention envisions a different type of 24+4 regimen. Instead of administering a daily dose of drospirenone for the first 24 days, followed by a placebo, the inventors propose using a two-phase schedule, which involves administering a certain amount of drospirenone once daily from day 1 to day 24, and then a smaller daily dose of drospirenone once daily from day 25 to day 28. The daily dose of drospirenone administered from day 1 to day 24 is approximately 2.0 mg to 6.0 mg, preferably approximately 3.0 mg to 5.0 mg, more preferably approximately 3.5 mg to 4.5 mg, and most preferably approximately 4.0 mg of drospirenone. The lower daily dose of drospirenone administered from day 25 to day 28 is approximately 2.5 mg to approximately 3.5 mg, preferably approximately 2.6 mg to approximately 3.2 mg, more preferably approximately 3.0 mg, and most preferably approximately 2.8 mg. In the most preferred embodiment, the daily dose of drospirenone administered from day 1 to day 24 is 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is 2.8 mg.

[0093] In preferred embodiments of the method of the present invention, the method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea also provides reliable contraception throughout the entire administration cycle. As described above, progestogen-only pills (POPs) have the advantage of avoiding the concomitant administration of estrogen compared to conventional contraceptive combination pills. Therefore, one object of the present invention is to provide reliable contraception by administering a single-dose, one-day formulation to female subjects requiring treatment for endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, while simultaneously achieving treatment for endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea. Preferably, this formulation does not contain any estrogen that may be beneficial for contraceptive efficacy but detrimental to the treatment of estrogen-induced endometriosis.

[0094] For the treatment of endometriosis, a regimen of hormone-free intervals every 6 months or 1 year may be preferable.

[0095] In a further embodiment, the present invention also relates to drospirenone administered to female subjects requiring drospirenone as described above, for use in the treatment of one or more diseases or disorders among dyspareunia, premenstrual pain, fibroids, adenomyomas, uterine fibroids, or endometrial polyps in female subjects.

[0096] use The present invention further relates to the use of drospirenone as a contraceptive for female subjects in need of contraception, comprising administering drospirenone to the subjects in a two-phase regimen, wherein a daily dose of drospirenone is administered during the first phase, and a smaller daily dose of drospirenone is administered during the second phase.

[0097] As already stated above regarding the method of the present invention, a different type of regimen from the 24+4 regimen proposed in the prior art is envisioned. Instead of administering a certain amount of drospirenone for the first 24 days and then a placebo, the inventors propose administering a daily dose of drospirenone once daily from day 1 to day 24, and then a smaller daily dose of drospirenone once daily from day 25 to day 28. The daily dose of drospirenone administered from day 1 to day 24 is about 2.0 mg to 6.0 mg, preferably about 3.0 mg to 5.0 mg, more preferably about 3.5 mg to 4.5 mg, even more preferably about 3.8 mg to 4.2 mg, and most preferably about 4.0 mg of drospirenone. The lower daily dose of drospirenone administered from day 25 to day 28 is approximately 2.5 mg to 3.5 mg, preferably approximately 2.6 mg to 3.2 mg, more preferably approximately 3.0 mg, and most preferably approximately 2.8 mg. In the most preferred embodiment, the daily dose of drospirenone administered from day 1 to day 24 is 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is 2.8 mg.

[0098] In the Phase II study CF111 / 203, summarized in Example 1, two different dosing regimens were evaluated over two cycles: a 28-day continuous regimen of DRSP 2.8 mg compared to a 24+4 dosing regimen of DRSP 4.0 mg (Slynd®), which is currently approved. The results, which have not yet been published, surprisingly showed that the continuous DRSP 2.8 mg regimen induced amenorrhea in a higher percentage of subjects in both cycles: 7 subjects (28.0%) compared to 3 subjects (12.0%) in the DRSP 4.0 mg group. In Cycle 1, 12 subjects (48.0%) in the DRSP 2.8 mg group and 6 subjects (24.0%) in the DRSP 4.0 mg group reported amenorrhea. In Cycle 2, nine subjects (36.0%) receiving DRSP 2.8 mg and four subjects (16.0%) receiving DRSP 4.0 mg experienced amenorrhea (see Example 1, Table 1).

[0099] In summary, the proportion of subjects experiencing amenorrhea was higher in the DRSP 2.8 mg group compared to the DRSP 4.0 mg group in both treatment cycles. As noted above, clinical studies of hormonal contraceptives have suggested that a significant proportion of women prefer reduced menstrual frequency or amenorrhea with continuous medication regimens. Therefore, a continuous regimen of drospirenone at a daily dose of 2.8 mg has shown to be a useful option to address women's specific needs in controlling bleeding patterns and achieving desirable amenorrhea.

[0100] Drospirenone is a progestin that acts by blocking the production of gonadotropin-releasing hormone, leading to a decrease in gonadotropins and estrogen production. The Phase II study CF111 / 203 showed that subjects receiving the DRSP 4.0 mg 24+4 regimen tended to have lower mean and median serum estradiol levels per subject compared to subjects receiving the DRSP 2.8 mg continuous regimen. The difference between the groups was not statistically significant. Furthermore, neither treatment had a clinically meaningful effect on reducing estradiol levels (see Example 1). For example, a careful balance needs to be maintained between estrogen levels that are too low, leading to undesirable side effects such as osteoporosis, and estrogen levels that are too high, which are harmful for estrogen-dependent diseases such as endometriosis. Therefore, another further objective of the present invention is to provide the benefits of amenorrhea, which maintains estrogen balance while simultaneously providing reliable contraception.

[0101] In one embodiment of the present invention, the use of drospirenone as a contraceptive induces amenorrhea, as described herein above. In a more preferred embodiment, the use of drospirenone induces amenorrhea in at least 20%, preferably at least 25%, and most preferably at least 30% of subjects after four, preferably three, and most preferably two administration cycles.

[0102] In a preferred embodiment, the use of drospirenone induces amenorrhea in at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, preferably at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, more preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50% of subjects after three or even two administration cycles.

[0103] In a more preferred embodiment, the use of drospirenone induces amenorrhea in at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, preferably at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, more preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50% of subjects after a single administration cycle.

[0104] In a preferred embodiment, the use of drospirenone induces amenorrhea in at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, preferably at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, and at least 50% of subjects after six administration cycles.

[0105] In another embodiment, vaginal bleeding decreases after 3 administration cycles compared to placebo administration, and decreases further after 6 administration cycles.

[0106] A reduction in vaginal bleeding after three administration cycles is preferred, resulting in a vaginal bleeding volume of approximately 2.0 to 5.5 days per cycle (month), preferably less than approximately 4.5 days per cycle (month), and most preferably less than approximately 4.0 days per cycle (month). In a more preferred embodiment, the above reduction in vaginal bleeding occurs after two or even one administration cycle.

[0107] In a preferred embodiment, the amount of vaginal bleeding after six administration cycles results in approximately 2.0 to 5.5 days of vaginal bleeding per cycle (month), preferably less than approximately 4.5 days per cycle (month), and most preferably less than approximately 3.5 days per cycle (month). Vaginal bleeding is understood to include minor bleeding.

[0108] In a more preferred embodiment, the bleeding includes unplanned bleeding.

[0109] In another embodiment, the amount and / or intensity of unplanned bleeding decreases after six administration cycles, preferably after three administration cycles, and most preferably after two or one administration cycle.

[0110] A further advantage of using the present invention is that it avoids the risk associated with contraceptive failure due to a pill being missed close to the 4-day interval, which was present in the previous 24+4 regimen where four pills did not contain contraceptives.

[0111] When used for contraceptive purposes, the composition is administered to female subjects of childbearing age, i.e., from puberty to menopause. Women of childbearing age include women around menopause.

[0112] kit The present invention also provides a kit, preferably a contraceptive kit, that is particularly suitable for use in the above-mentioned methods of contraception and treatment.

[0113] Therefore, the present invention also relates to a kit, preferably a contraceptive kit, comprising one or more packaging units, each packaging unit comprising at least 28 active daily dose units.

[0114] At least 24 daily dose units of the kit contain a first dose of drospirenone, each of which contains the same amount of drospirenone as the second dose of drospirenone in a daily dose unit.

[0115] At least four daily dose units contain a second dose of drospirenone, with each of these daily dose units containing the same amount of drospirenone, but with a smaller amount of drospirenone than the daily dose unit containing the first dose of drospirenone.

[0116] In one embodiment of the kit of the present invention, at least 28 active daily dose units are estrogen-free. Estrogens commonly used for contraceptive purposes include, but are not limited to, estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, ethinylestradiol, estrol, estrone, estriol, estriol succinate, phytoestrogens, and conjugated estrogens.

[0117] In a preferred embodiment of the present invention, drospirenone is the sole contraceptive active ingredient in at least 28 active daily doses.

[0118] In one embodiment of the kit of the present invention, the first amount of drospirenone is about 2.0 mg to 6.0 mg, preferably about 3.0 mg to 5.0 mg, more preferably about 3.5 mg to 4.5 mg, even more preferably about 3.8 mg to 4.2 mg, and most preferably about 4.0 mg of drospirenone.

[0119] In further embodiments of the kit of the present invention, the second amount of drospirenone is about 2.5 mg to about 3.5 mg, preferably about 2.6 mg to about 3.2 mg, more preferably about 3.0 mg, and most preferably about 2.8 mg.

[0120] In a preferred embodiment of the kit of the present invention, the first amount of drospirenone is about 4.0 mg, and the second amount of drospirenone is about 2.8 mg.

[0121] The above kit includes one or more packaging units. These include, but are not limited to, 1-package units, 2-package units, 3-package units, 4-package units, 5-package units, and 6-package units.

[0122] In some embodiments, the kit is characterized in that each packaged unit contains 28 daily dose units and does not contain a pharmaceutically acceptable daily dose unit of placebo. Such a kit is particularly suitable for carrying out the method of the present invention, which consists of administering DRSP "continuously" without any placebo phase in which contraceptives are not administered.

[0123] The packaging units described above may have one of the conventional forms typically used for oral contraceptives. For example, a packaging unit may be a conventional blister pack (e.g., an aluminum blister) sealed in cardboard, paperboard, foil, or plastic backing, containing an appropriate number of dose units, and enclosed in a suitable cover. Each blister container may be numbered or marked for convenience to facilitate compliance. The packaging unit may contain a daily dose unit in the order in which it is to be taken.

[0124] The kit of the present invention may include any of the pharmaceutical compositions later disclosed herein.

[0125] The kit of the present invention may further include other suitable components such as an instruction manual.

[0126] Pharmaceutical composition The present invention further relates to a pharmaceutical composition comprising drospirenone for use in a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects requiring treatment of endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea as described above herein, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0127] Examples of pharmaceutically acceptable additives for the composition of the present invention include, but are not limited to, binders, fillers, lubricants, granulation aids, colorants, anti-solidification agents, plasticizers, disintegrants, pigments, antioxidants, anti-adhesion agents, softeners, preservatives, and fragrances that have been conventionally used in the pharmaceutical field.

[0128] Suitable binders for the compositions of the present invention include, but are not limited to, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, calcium carboxymethylcellulose, gums (such as tragacanth gum, acacia gum, and gelatin), and / or mixtures thereof. Microcrystalline cellulose is preferred. The binder may be present in an amount of about 0.5% to about 20% by weight, preferably 1% to 10% by weight, more preferably 2% to 7% by weight, and preferably about 5% by weight of the total weight of the composition.

[0129] Suitable fillers, also known as diluents, include, but are not limited to, starch, corn starch, pregelatinized starch, modified starch, powdered cellulose, microcrystalline cellulose, silicified cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, sucrose, fructose, dextrose, dibasic calcium phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, and / or mixtures thereof. Preferably, anhydrous lactose is used. The filler may be present in amounts of about 20% to about 95% by weight of the total weight of the composition, preferably 30% to 90% by weight, more preferably 35% to 80% by weight, even more preferably 30% to 60% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, and about 60% by weight.

[0130] Suitable lubricants for the present invention include, but are not limited to, talc, alkaline earth salts of stearic acid, such as magnesium stearate and calcium stearate, stearic acid, glyceryl palmitostearate, stearyl fumarate, zinc stearate, propylene glycol, PEG, vegetable oil, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, mineral oil, polyoxyethylene monostearate, and / or mixtures thereof. In preferred embodiments, the lubricant is magnesium stearate. The lubricant may be present in an amount of about 0% to 5% by weight, preferably about 1% to 3% by weight (e.g., about 2% by weight), based on the total weight of the composition.

[0131] Examples of lubricants include silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate and / or mixtures thereof. In preferred embodiments, the lubricant is silicon dioxide.

[0132] Pharmaceutically acceptable excipients that can be used to formulate the pharmaceutical compositions of the present invention are, in particular, listed in the Pharmaceutical Excipients Handbook of the American Pharmaceutical Association (Pharmaceutical Press; 6th Revised edition, 2009).

[0133] In some embodiments, the pharmaceutical composition of the present invention comprises at least one additive selected from the group consisting of binders, fillers, lubricants, and lubricants.

[0134] In one embodiment of the pharmaceutical composition of the present invention, the above-mentioned pharmaceutically acceptable additive is at least one binder and at least one filler. (i) The amount of drospirenone is 1% to 10% by weight, (ii) The amount of at least one binder is 50% to 65% by weight, (iii) At least one filler accounts for 25% to 35% by weight, The weight percentage refers to the total weight of the above-mentioned pharmaceutical composition.

[0135] In further embodiments of the present invention, the pharmaceutical composition further comprises at least one lubricant and at least one lubricating agent, (iv) The amount of at least one lubricant is between 0.2% and 6% by weight, (v) The amount of at least one lubricant is 0.2% to 0.6% by weight, The weight percentage refers to the total weight of the above-mentioned pharmaceutical composition.

[0136] In a preferred embodiment of the pharmaceutical composition of the present invention, (i) At least one binder is microcrystalline cellulose, (ii) At least one filler is anhydrous lactose, (iii) At least one lubricant is silicon dioxide, (iv) At least one lubricant is magnesium stearate.

[0137] The dosage forms according to the present invention may also include a disintegrant. The disintegrant may be selected from the group consisting of low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crospovidone, sodium croscarmellose, and / or mixtures thereof. The disintegrant may be present in an amount of about 2% to about 50% by weight, preferably about 5% to about 45% by weight, and more preferably 10% to 40% by weight, of the total weight of the composition.

[0138] In some embodiments of the present invention, DRSP is in the form of multiple particles. The term "multiple particles" is defined to include beads, pellets, and any other multiple particle system that can be administered orally. In some embodiments of the present invention, DRSP is dispersed in a matrix. In some embodiments of the present invention, DRSP is in the form of multiple particles that can be dispersed in a matrix or encapsulated in a capsule. In some embodiments of the present invention, DRSP is in the form of pellets within a matrix. In some embodiments of the present invention, DRSP is in the form of coated beads.

[0139] In one embodiment of the above-described model, the pharmaceutically acceptable matrix is ​​a polymer matrix, a non-polymer matrix, or a combination thereof.

[0140] Examples of polymer matrices, though not limited to them, include hydroxypropyl methylcellulose; hydroxypropyl cellulose; hydroxyethyl cellulose; hydroxymethylcellulose; carboxymethylcellulose; sodium carboxymethylcellulose; calcium carboxymethylcellulose; polyvinylpyrrolidone; polyethylene oxide; polyvinyl alcohol; methylcellulose; ethylcellulose; propylcellulose; ethylmethylcellulose; isopropylcellulose; ethylpropylcellulose; butylcellulose; benzylcellulose; cellulose esters such as cellulose acetate, cellulose butyrate, cellulose propionate, cellulose butyrate, and cellulose propionate acetate; cellulose cyanoalkyl ethers such as cyanoethylcellulose, cyanomethylcellulose, cyanoethylmethylcellulose, and cyanopropylcellulose; methacrylic acid-acrylic acid copolymers (e.g., Eudragit RS, Eudragit RL, Eudragit NE, Eudragit RS PO, and Eudragit RL PO), methacrylic acid copolymers; hydroxypropyl methylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose phthalate acetate, and mixtures thereof.

[0141] Examples of non-molecular-weight matrices include, but are not limited to, sugars and sugar alcohols, such as sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, slayitol, adonitol, arabitol, xylitol, dulciitol, inositol, trehalose, isomalt, 30-inulin, and maltodextrin; cyclodextrins, such as 13-cyclodextrin and hydroxypropyl-13-cyclodextrin; polyethylene glycol; polyethylene glycol esters; medium-chain triglycerides; fatty acids; fatty alcohols; waxes; fatty acid esters, and mixtures thereof.

[0142] In some particularly preferred embodiments, the dosage forms of the present invention include oral formulations (e.g., tablets or capsules) coated so that the DRSP does not substantially come into direct contact with the oral cavity (e.g., tongue, oral mucosa), the surface of the oropharyngeal mucosa, the esophagus, or the stomach. In some preferred embodiments, the dosage forms of the present invention include oral formulations coated with a film or polymer.

[0143] In preferred embodiments, the pharmaceutical composition according to the present invention does not contain a substantial amount of surfactant. A substantial amount of surfactant may impair the in vitro solubility profile of DRSP by increasing the initial dissolution rate of DRSP. Suitable surfactants may be selected from the group consisting of ionic surfactants such as sodium lauryl sulfate, phospholipids, glycerol monooleate, and sodium doxate, or nonionic surfactants, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polyoxyethylene stearate, poloxamer, and polyoxyethylene alkyl ethers.

[0144] If present, the surfactant is preferably in an amount of about 0.01% by weight (W%) to about 5% by weight, more preferably about 0.1% by weight to about 1% by weight, based on the total weight of the composition. In the most preferred embodiment, the pharmaceutical composition does not contain a surfactant.

[0145] The pharmaceutical or contraceptive composition according to the present invention may be formulated in a galenos form suitable for oral administration. Such forms include, but are not limited to, tablets, caplets, granules, pills, capsules, powders, and suspensions. In preferred embodiments, the contraceptive composition is formulated in a solid form for oral administration, such as tablets, capsules, granules, caplets, and pills. Such solid forms are particularly suitable for use as the daily active dose unit in the kit according to the present invention.

[0146] When a pharmaceutical composition or contraceptive composition is formulated in solid form such as a tablet or pill, the solid form may be conveniently coated with a suitable film-forming agent such as hydroxypropyl methylcellulose, hydroxypropylcellulose, or ethylcellulose, and suitable additives, such as softeners such as glycerol, propylene glycol, diethyl phthalate, or glycerol triacetate, fillers such as sucrose, sorbitol, xylitol, glucose, or lactose, or colorants such as titanium hydroxide may be optionally added thereto.

[0147] Pharmaceutical compositions or contraceptive compositions in the form of tablets, pills, or granules can be prepared by conventional methods such as direct compression, dry granulation, and wet granulation.

[0148] The pharmaceutical compositions or contraceptive compositions described herein may be suitable for administration as a daily active oral form in various dosing regimens, and preferred dosing regimens are described above herein with respect to contraceptives and the medical purposes referred to herein.

[0149] In certain embodiments, the composition is suitable for administration to female subjects requiring it as a daily active oral form in a regimen comprising administration of the active oral form for 28 consecutive days, wherein at least 24 daily dose units of the kit contain a first amount of drospirenone, each of these daily dose units containing the same amount of drospirenone, and this amount is greater than the amount of drospirenone in a daily dose unit containing a second amount of drospirenone. At least 4 daily dose units contain a second amount of drospirenone, each of these daily dose units containing the same amount of drospirenone, and the amount of drospirenone is less than that in a daily dose unit containing the first amount of drospirenone.

[0150] Any feature described herein may be optionally combined with any embodiment of any medical or contraceptive use, composition, kit, method of contraception, treatment method, or method of manufacture of the present invention, and it is intended that any embodiment considered herein may be carried out in any of these. Specific embodiments described herein are provided as examples, not as limitations of the present invention.

[0151] All publications and patent applications constitute part of this Spec. by reference, as is indicated by each individual publication or patent application that they constitute part of this Spec.

[0152] The use of the words "a" or "an" can mean "one," but it can also mean "one or more," "at least one," and "one or two or more." The use of the term "another" can refer to one or more. The use of the term "or" in a claim is used to mean "and / or" unless it refers only to substitutes or explicitly states that the substitutes are mutually exclusive.

[0153] Where used herein and in the claims, the words “comprising” (and any form of “comprising,” such as “comprise” and “comprises”), “having” (and any form of “having,” such as “have” and “has”), “including” (and any form of “including,” such as “includes” and “include”), or “containing” (and any form of “containing,” such as “contains” and “contain”) are inclusive or open and do not exclude additional, undescribed elements or process steps. The term “comprises” also includes and expressly discloses the terms “consists of” and “consists essentially of.” Where used herein, the phrase “consists essentially of” limits the scope of the claim to those materials or processes that do not materially affect the basic and novel characteristics of the invention described herein. As used herein, the phrase "consisting only of" excludes any elements, processes, or components not explicitly stated in the claims, other than, for example, impurities that normally accompany an element or limitation.

[0154] As used herein, the term “or any combination thereof” means permutations and combinations of all items preceding the term. For example, “A, B, C, or any combination thereof” is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and also intended to include at least one of BA, CA, CB, CBA, BCA, ACB, BAC, or CAB, where the order is important in particular circumstances. Following this example, expressly included are combinations of one or more items or repetitions of terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc. A person skilled in the art will understand that, unless otherwise clearly evident from the context, there is typically no limit to the number of items or any combination of terms.

[0155] Where used herein, approximants such as “about,” “around,” and “approximately,” when modified in this way, are understood not necessarily absolute or perfect, but rather to a state that is considered to be close enough to guarantee to a person skilled in the art that the state exists. The degree to which the description may differ depends on how significant the change may be and whether a person skilled in the art can be convinced that the modified function still possesses the characteristics and capabilities required of the original function. Generally, given the preceding discussion, numerical values ​​in this specification modified by approximants such as “about” may differ from the stated value by ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%. Thus, the term “about” may mean ±5% of the indicated value, preferably ±2%, and most preferably the term “about” means exactly the indicated value (±0%).

[0156] The following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the present invention. [Examples]

[0157] Example 1: An open-label, randomized study evaluating the effects of two different doses of drospirenone (either 4.0 mg for 24 days or 2.8 mg daily for 28 days) on hormone and ovarian activity in 50 healthy young women over two treatment cycles. The main objectives of the exam: The ovulation-inhibiting ability of two different doses and regimens of drospirenone (DRSP), as reflected in hormone and ovarian activity, was assessed in 50 healthy women. Participants were stratified by their ovulation day in the previous cycle and then assigned to one of the two treatment regimens.

[0158] Recruitment details: Healthy premenopausal women, regardless of race (ages 18-35, including both extremes); (smokers under 30; smoking history 30 years or less; no more than 10 cigarettes per day), BMI 18 kg / m² 2 ~30kg / m 2Regular blood pressure cycles, blood pressure of 90mmHg-140mmHg (systolic) and 50mmHg-90mmHg (diastolic) after 5 minutes of rest, etc.

[0159] arm: Fifty subjects were assigned to either Treatment 1 (4.0 mg DRSP for 24 days, followed by 4 days of placebo) or Treatment 2 (2.8 mg DRSP for 28 days) over two treatment cycles.

[0160] Arm description: Arm-type experiment a) Treatment 1 -Name of investigational drug: Drospirenone 4.0mg coated tablets -Pharmacological form: Tablets - Route of administration: Oral use - Dosage and administration details: 28 coated tablets, orally, once daily. 24 tablets contain 4.0 mg DRSP, and 4 tablets contain placebo. - Additive 4mg DRSP Tablets (White): Anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, Opadry II White - Additives: Placebo tablets (green): Anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, Opadry II Green

[0161] b) Treatment 2 -Name of investigational drug: Drospirenone 2.8mg coated tablets -Pharmacological form: Tablets - Route of administration: Oral use - Dosage and administration details: 28 coated tablets, orally, once daily. - Additive 2.8mg DRSP (pink): Anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, Opa Dry II Pink

[0162] This Phase II study evaluated two different dosing regimens over two cycles, comparing a 28-day continuous regimen with drospirenone (DRSP) 2.8 mg to a 24+4 dosing regimen with the currently approved DRSP 4.0 mg (Slynd®).

[0163] 1.) Summary of results: Ovulation inhibitory ability Efficacy assessments in this clinical trial included the Hoogland score (a composite parameter of follicular size, estradiol level, and progesterone level), as well as LH and FSH levels, endometrial thickness, and bleeding pattern. The primary endpoint was the Hoogland score (FAS). One subject receiving DRSP 2.8 mg had a Hoogland score of "5" in cycle 1, which may be explained by concomitant diarrhea. Two subjects receiving DRSP 4.0 mg had a Hoogland score of "6" (one in cycle 1, the other in cycle 2). The Hoogland score of "6" in cycle 2 may be explained by concomitant vomiting. However, progesterone levels (maximum 5.34 nmol / L, 5.34 nmol / L, and 6.17 nmol / L, respectively) were not sustained and remained below normal luteal phase levels.

[0164] Overall, the suppression of ovarian activity was more pronounced with the DRSP 4.0 mg 24 / 4 regimen than with the DRSP 2.8 mg 28 / 0 regimen.

[0165] The logistic regression model with binary responses for Hoogland scores of ≤4 and ≥4, as predicted by the protocol, proved unsuitable for the Cycle 2 data. Therefore, an additional logistic regression model with binary responses for Hoogland scores of ≤3 and ≥3 was calculated.

[0166] In Cycle 1, the proportion of subjects with a Hoogland score of 3 or less was 8 (32.0%) in the DRSP 2.8 mg group and 10 (40.0%) in the DRSP 4.0 mg group. In Cycle 2, the proportion of subjects with a Hoogland score of 3 or less was 7 (28.0%) in the DRSP 2.8 mg group and 11 (44.0%) in the DRSP 4.0 mg group. Therefore, the difference in preference for the high-dose regimen was more pronounced in Cycle 2.

[0167] The estimated odds ratios (95% CI) for a Hoogland score of 3 or less in the DRSP 4.0 mg 24 / 4 regimen and the DRSP 2.8 mg 28 / 0 regimen were 1.4167 (0.4449; 4.6240) in cycle 1 and 2.0202 (0.6317; 6.8038) in cycle 2. The CIs indicated that these results were not statistically significant. The chi-square test showed that the treatment group did not have a significant effect on the Hoogland score (p=0.5563, cycle 1 and p=0.2417, cycle 2).

[0168] Throughout the two treatment cycles, follicles in the DRSP 4.0 mg group tended to be smaller than those in the DRSP 2.8 mg group. This difference was more pronounced in cycle 1 than in cycle 2. In the DRSP 2.8 mg group, the mean (SD) maximum follicular diameter was 17.81 (6.19) mm in cycle 1 and 19.03 (6.57) mm in cycle 2. In the DRSP 4.0 mg group, the mean (SD) was 14.89 (4.45) mm in cycle 1 and 16.66 (6.64) mm in cycle 2. Despite a four-day hormone rest period, the maximum follicular size in the DRSP 4.0 mg group did not significantly increase and remained below that of the DRSP 2.8 mg group in the early stages of cycle 2.

[0169] The percentage of subjects with a follicle diameter of 15 mm or larger measured three consecutive times was lower in the DRSP 4.0 mg 24 / 4 regimen (28.0% in cycle 1, 36.0% in cycle 2) than in the DRSP 2.8 mg 28 / 0 regimen (52.0% in cycle 1, 60.0% in cycle 2). Progesterone levels were similar in the two groups. In the high-dose formulation, the mean (SD) maximum level per cycle was 3.89 (1.10) nmol / L in cycle 1 and 3.74 (1.01) nmol / L in cycle 2. In the low-dose formulation, the mean (SD) maximum level per cycle was 3.54 (1.06) nmol / L in cycle 1 and 3.48 (1.11) nmol / L in cycle 2.

[0170] Most subjects had low estradiol levels, but some subjects (especially in the low-dose group) had elevated estradiol levels. Overall, serum estradiol levels were lower in the DRSP 4.0 mg group than in the DRSP 2.8 mg group. In the DRSP 4.0 mg regimen, the median maximum values ​​per cycle were 287.0 pmol / L in cycle 1 and 309.0 pmol / L in cycle 2, compared to 450.0 pmol / L in cycle 1 and 377.0 pmol / L in cycle 2 in the DRSP 2.8 mg regimen.

[0171] Follicular activity is increased not only by its size but also by the associated serum estradiol level. Therefore, in further analysis, combining follicular size and serum estradiol level, the proportion of subjects with a follicular size greater than 13 mm and an E2 level of 275 pmol / L or higher was lower in the DRSP 4.0 mg group (Cycle 1: 8 subjects (32.0%), Cycle 2: 11 subjects (44.0%)) than in the DRSP 2.8 mg group (Cycle 1: 13 subjects (52.0%), Cycle 2: 16 subjects (64.0%)).

[0172] There were no associated differences in endometrial thickness between the treatment groups. In cycle 1, the mean (SD) maximum endometrial thickness per cycle was higher in the DRSP 2.8 mg group (6.50 (1.44) mm) than in the DRSP 4.0 mg group (6.33 (1.23) mm). In contrast, in cycle 2, the mean (SD) maximum endometrial thickness per cycle was lower in the DRSP 2.8 mg group (6.57 (1.70) mm) than in the DRSP 4.0 mg group (6.60 (1.38) mm).

[0173] In both treatment groups, serum LH levels remained clearly below the ovulatory threshold of 14.0 U / L throughout both treatment cycles. Mean (SD) serum LH levels were higher in the DRSP 2.8 mg group (maximum visit observed on day 6 / cycle 1: 7.67 (2.87) U / L) than in the DRSP 4.0 mg group (maximum visit on day 3 / cycle 1: 6.30 (1.78) U / L).

[0174] Mean (SD) serum FSH levels ranged from 4.67 (1.75) U / L (DRSP 4.0 mg group, day 9 of cycle 2) to 6.71 (2.43) U / L (DRSP 2.8 mg group, day 3 of cycle 1). Overall, there were no significant differences in FSH levels between treatment groups.

[0175] In summary, subjects receiving the DRSP 4.0 mg 24 / 4 regimen tended to have smaller follicles and lower estradiol and LH levels compared to subjects receiving the DRSP 2.8 mg 28 / 0 regimen. No significant differences were observed between the two regimens regarding endometrial thickness, progesterone, and FSH levels.

[0176] 2) Summary of results: Induction of amenorrhea In the DRSP 2.8mg continuous arm, the proportion of subjects experiencing amenorrhea in both cycles was higher in the DRSP 2.8mg group (7 subjects, 28.0%) compared to the DRSP 4.0mg group (3 subjects, 12.0%). In Cycle 1, amenorrhea was reported in 12 subjects (48.0%) in the DRSP 2.8mg group and 6 subjects (24.0%) in the DRSP 4.0mg group. In Cycle 2, amenorrhea was reported in 9 subjects (36.0%) in the DRSP 2.8mg group and 4 subjects (16.0%) in the DRSP 4.0mg group. In summary, the proportion of subjects experiencing amenorrhea was higher in the DRSP 2.8mg group than in the DRSP 4.0mg group in both treatment cycles (see Table 1 and Figure 1).

[0177] TIFF0007850799000001.tif45170

[0178] Furthermore, subjects receiving the DRSP 4.0 mg 24 / 4 regimen tended to have lower mean and median serum estradiol levels per subject than subjects receiving the DRSP 2.8 mg 28 / 0 regimen. However, the differences between the groups were not statistically significant.

[0179] TIFF0007850799000002.tif82170

[0180] Previously unpublished results from this study, as shown in Figure 1, indicate that a higher proportion of patients experienced amenorrhea with the 2.8 mg regimen. Furthermore, the data suggest that continued treatment does not affect the reduction of estradiol levels below the treatment initiation level.

[0181] Example 2: A multicenter, double-blind, randomized phase III clinical trial to evaluate the efficacy and safety of LPRI-CF113 in the treatment of endometriosis, compared to placebo after three open-label drug therapy cycles following three drug therapy cycles. The information described herein is an excerpt from the study protocol of a Phase III clinical trial, a multicenter, double-blind, randomized clinical trial to evaluate the efficacy and safety of LPRI-CF113 in the treatment of endometriosis, which involves three cycles of drug therapy followed by three open-label drug therapy cycles, and then comparison with placebo.

[0182] Materials and methods Main objectives and key outcome items The primary objective is to demonstrate the efficacy of LPRI-CF113 in managing endometriosis-associated pelvic pain (EAPP), as assessed by a numerical rating scale (NRS), after three cycles of drug therapy.

[0183] Secondary objectives and secondary evaluation items The efficacy of LPRI-CF113 versus placebo will be evaluated in terms of treatment response.

[0184] Main secondary outcome measures 1. Change after 1, 3, and 6 cycles of drug treatment compared to baseline for dysmenorrhea (assessed via NRS pain score). 2. Changes after 1, 3, and 6 cycles of drug treatment compared to baseline in non-menstrual pelvic pain (assessed via NMPP and NRS pain scores). 3. Changes after 1, 3, and 6 drug treatment cycles compared to baseline with as-needed medication intake. 4. Changes after 1 and 6 drug treatment cycles compared to baseline in EAPP (assessed via NRS pain score)

[0185] Other secondary efficacy endpoints 1. Changes after 1, 3, and 6 cycles of drug treatment compared to baseline in dyspareunia. 2. Number and percentage of subjects with amenorrhea 3. Vaginal bleeding patterns

[0186] Secondary safety evaluation items 1. Adverse Events 2. Mean absolute change and mean relative change of laboratory values 3. Vital signs

[0187] Overall plan This is a multicenter clinical trial in female subjects aged 15 to 45 years, post-menarche and pre-menopausal, with a definitive histopathological diagnosis of endometriosis and an EAPP score of 3 or higher in the three months prior to trial enrollment. The clinical trial consists of a screening period (up to 100 days), a treatment period consisting of three placebo-controlled, double-blind drug treatment cycles, and an open-label continuation period, during which all subjects will receive active treatment with LPRI-CF113 for three cycles.

[0188] During visit 1a, informed consent will be obtained and the screening procedure will be performed. In addition, an electronic diary will be distributed and the subject will be instructed on how to complete it. If applicable, a washout of hormonal contraceptives or hormonal therapy for the treatment of endometriosis for one menstrual cycle during the screening period will be requested during visit 1a. The subject's next menstrual cycle after the washout cycle will be considered the baseline cycle. For subjects who do not require a washout cycle, the menstrual cycle before the start of IP will be considered the baseline cycle. The length of the baseline cycle is acceptable between 21 and 35 days. Visit 1b must be scheduled at least 29 days after V1a and before the expected end date of the baseline cycle.

[0189] In visit 1b, after confirming eligibility, subjects are randomized to receive either LPRI-CF113 or placebo, and are provided with the investigational drug (IP). The first dose of IP is taken on the first day of the next menstrual bleeding period following visit 1b. If menstrual bleeding begins in the evening and the subject prefers to take IP in the morning, the first dose of IP may be started the following day (day 2 of menstruation). Subsequently, subjects visit the clinic for visits 2 and 3 on day 20 (+6) of the first and third drug treatment cycles. The end-of-treatment visit (visit 4 / early discontinuation visit (EDV)) is conducted up to 3 days after the last IP dose of drug treatment cycle 6.

[0190] Furthermore, on day 1 (+2) of each drug therapy cycle, facility staff will regularly call the subject to collect basic information, especially regarding any possible adverse events (AEs), and to verify compliance with the electronic log. In addition, a follow-up visit (by phone or at the facility) will be conducted 10 days (+4) after the last IP intake of the sixth drug therapy cycle.

[0191] Subjects are permitted to take nonsteroidal anti-inflammatory drugs (NSAIDs) as needed during the study. Subjects must take the same NSAID (including strength) as needed throughout the study. They are permitted to continue taking the same NSAID taken before study enrollment, switch to a different NSAID, or, if medically possible, begin using the NSAID selected at visit 1a (if they have not previously used an NSAID). However, they are not permitted to switch to a different NSAID after visit 1a and prophylactic NSAID intake, and they must not initiate any new analgesics during the study.

[0192] research group Number of subjects (planned): Screened: Approximately 236 subjects. Screening will continue until a sufficient number of subjects are assigned to treatment. Randomization: Randomization ratio 3:1 with at least 212 subjects.

[0193] Female subjects aged 15 to 45 years, post-menarche and pre-menopausal, with a histologically confirmed diagnosis of endometriosis and an EAPP score of 3 or higher on the NRS for at least 3 months, will be randomized to receive either LPRI-CF113 (4 mg / day for 24 days, followed by 2.8 mg / day for 4 days per 28-day cycle) or placebo. Subjects who have received at least one dose of each IP and at least one outcome measurement after baseline (the largest analysis population (FAS)) will be analyzed.

[0194] treatment The identity of the investigational drug (or multiple drugs). Test drug name (may be multiple): LPRI-CF113 Dosage form: Film-coated tablets for oral administration Active ingredient: Drospirenone (DRSP) Strength / Concentration: 4mg / 2.8mg DRSP(24 / 4) Additive 4mg DRSP Tablets (White): Anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, OpaDry II 85F18422 White Additives 2.8mg DRSP Tablets (Pink): Anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, Opa Dry II Pink Presented: 24 white tablets, followed by 4 pink tablets.

[0195] Reference drug (matching placebo): Name (may be multiple): LPRI-CF113 Placebo Dosage form: Film-coated tablets for oral administration Active ingredient: None Intensity / Concentration: Not applicable Additives: Placebo tablets (white): Anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, OpaDry II 85F18422 white Additives: Placebo tablets (pink): Anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, OpaDry II Pink Presented: 24 white tablets, followed by 4 pink tablets.

[0196] Selection and timing of dosage for each subject Each subject will receive either LPRI-CF113 or a matching placebo during the first three treatment cycles of the study. Subsequently, each subject will receive active treatment with LPRI-CF113 for a further three treatment cycles. During visits 1b (LPRI-CF113 / placebo) and 3 (LPRI-CF113), a treatment package for three treatment cycles and one reserve cycle will be provided. Detailed instructions for using the treatment will be provided in the information sheet for the principal investigator and subject.

[0197] The subject must take the first tablet on the day of the next menstrual bleeding after visit 1b. If menstrual bleeding begins in the evening and the subject prefers to take the pill in the morning, the first IP intake may be started the following day (day 2 of menstrual bleeding). From day 1 to day 28 of the drug treatment cycle, one tablet is squeezed out of the blister pack and swallowed whole once daily. The tablets must be taken at approximately the same time each day so that there is always a 24-hour interval between taking two tablets. The tablets must be taken in the order indicated on the blister pack. The first tablet from the next blister pack should be taken the following day, immediately after taking the last tablet from the previous blister pack, i.e., without any pill-free interval, and regardless of whether bleeding has started, stopped, or is still continuing. Each drug treatment cycle begins on the same day of the week. IP administration is thus intended to continue for a total of six drug treatment cycles.

[0198] If bleeding or minor bleeding occurs, continue taking IP. If bleeding is excessively severe, the subject should ask the principal investigator for clarification. Administration of hormonal preparations to treat bleeding is not permitted during the trial period because it may affect the outcome.

[0199] If a subject misses one dose of IP, even if it means taking two tablets at once, the missed tablet should be taken as soon as the subject remembers. The next tablet should be taken at the usual time. If vomiting or diarrhea occurs within 3 to 4 hours of taking a tablet, a new (replacement) tablet from the spare blister pack should be taken as soon as possible. The new (replacement) tablet should preferably be taken within 12 hours of the usual tablet dose time. If more than one dose is missed, only the last missed tablet (only one) should be taken. Any other missed tablets (there may be multiple) should be left in the blister pack.

[0200] List of References Edelman, A, Micks, E, Gallo, MF, Jensen, JT and Grimes, DA (2014). "Continuous or extended cycle vs. cyclic use of combined hormonal contraceptives for contraception." Cochrane Database Syst Rev 2014(7): Cd004695. Casper, RF (2017). "Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills." Fertil Steril 107(3): 533-536. Schindler, AE (2011). "Dienogest in long-term treatment of endometriosis." Int J Womens Health 3: 175-184. Taylor, HS, Giudice, LC, Lessey, BA, Abrao, MS, Kotarski, J, Archer, DF, Diamond, MP, Surrey, E, Johnson, NP, Watts, NB, Gallagher, JC, Simon, JA, Carr, BR, Dmowski, WP, Leyland, N, Rowan, JP, Duan, WR, Ng, J, Schwefel, B, Thomas, JW, Jain, RI and Chwalisz, K (2017). "Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist." N Engl J Med 377(1): 28-40. Vercellini, P, Vigano, P, Somigliana, E and Fedele, L (2014). "Endometriosis: pathogenesis and treatment." Nature Reviews Endocrinology 10(5): 261-275. Norwitz E.R and Schorge J.O. Obstetrics and Gynecology at a Glance Fourth Edition (2013). Wiley-Blacwell. Zondervan, KT, Becker, CM and Missmer, SA (2020). "Endometriosis." New England Journal of Medicine 382(13): 1244-1256. Paolo Vercellini, M.D., Laura Buggio, M.D., Maria Pina Frattaruolo, M.D., Alessandra Borghi, M.D., Dhouha Dridi, M.D., Edgardo Somigliana, M.D. (2018) "Medical treatment of endometriosis related pain" Best Practice & Research Clinical Obstetrics & Gynaecology. 51, 68-91. Vercellini, P, Bracco, B, Mosconi, P, Roberto, A, Alberico, D, Dhouha, D and Somigliana, E (2016). "Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study." Fertil Steril 105(3): 734-743.e733. Cote, I, Jacobs, P and Cumming, D (2002). "Work loss associated with increased menstrual loss in the United States." Obstet Gynecol 100(4): 683-687. Rose, JG, Chrisler, JC and Couture, S (2008). "Young women's attitudes toward continuous use of oral contraceptives: the effect of priming positive attitudes toward menstruation on women's willingness to suppress menstruation." Health Care Women Int 29(7): 688-701. Loudon, NB, Foxwell, M, Potts, DM, Guild, AL and Short, RV (1977). "Acceptability of an oral contraceptive that reduces the frequency of menstruation: the tri-cycle pill regimen." Br Med J 2(6085): 487-490. Rutter, W, Knight, C, Vizzard, J, Mira, M and Abraham, S (1988). "Women's attitudes to withdrawal bleeding and their knowledge and beliefs about the oral contraceptive pill." Med J Aust 149(8): 417-419. den Tonkelaar, I and Oddens, BJ (1999). "Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use." Contraception 59(6): 357-362. Glasier, AF, Smith, KB, van der Spuy, ZM, Ho, PC, Cheng, L, Dada, K, Wellings, K and Baird, DT (2003). "Amenorrhea associated with contraception-an international study on acceptability." Contraception 67(1): 1-8. Wiegratz, I, Hommel, HH, Zimmermann, T and Kuhl, H (2004). "Attitude of German women and gynecologists towards long-cycle treatment with oral contraceptives." Contraception 69(1): 37-42. Szarewski, A, von Stenglin, A and Rybowski, S (2012). "Women's attitudes towards monthly bleeding: results of a global population-based survey." Eur J Contracept Reprod Health Care 17(4): 270-283. Palacios, S, Colli, E and Regidor, PA (2019). "Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill." Acta Obstet Gynecol Scand 98(12): 1549-1557. Kimble, Thomas, et al (2020). A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contraceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg using a 24 / 4-day regimen. Contraception: X, 2020, vol. 2, p. 100020. Gerlinger et al. (2010). "Defining a minimal clinically important difference for endometriosis-associated pelvic pain measured on a visual analog scale: analyzes of two placebo-controlled, randomized trials". Health and Quality of Life Outcomes 2010, 8:138. H. Breivik et al. (2008) "Assessment of pain", BJA: British Journal of Anaesthesia, Volume 101, Issue 1, July 2008, Pages 17-24, https: / / doi.org / 10.1093 / bja / aen103

[0201] Items of the present invention 1. Drospirenone used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, comprising administering drospirenone to a subject in a two-phase regimen, wherein a daily dose of drospirenone is administered during Phase 1, and a smaller daily dose of drospirenone is administered during Phase 2. 2. Drospirenone used in a method for treating endometriosis and / or endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea according to claim 1, wherein the above-mentioned daily dose of drospirenone is administered once daily from day 1 to day 24, and thereafter a smaller daily dose of drospirenone is administered once daily from day 25 to day 28. 3. Drospirenone used in a method for treating endometriosis and / or endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea according to claim 1 or 2, wherein the daily dose of drospirenone administered from day 1 to day 24 is approximately 2.0 mg to 6.0 mg, preferably approximately 3.0 mg to 5.0 mg, more preferably approximately 3.5 mg to 4.5 mg, even more preferably approximately 3.8 mg to 4.2 mg, and most preferably approximately 4.0 mg of drospirenone. 4. Drospirenone used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea according to claims 1 to 3, wherein the smaller daily dose of drospirenone administered from day 25 to day 28 is about 2.5 mg to 3.5 mg, preferably about 2.6 mg to 3.2 mg, more preferably about 3.0 mg, and most preferably about 2.8 mg of drospirenone. 5. Drospirenone used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea according to claims 1 to 4, wherein the daily dose of drospirenone administered from day 1 to day 24 is 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is 2.8 mg. 6. Drospirenone used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea according to claims 1 to 5, wherein the treatment also provides contraception. 7. Use of drospirenone as a contraceptive, comprising administering drospirenone in a two-phase regimen to a female subject in need of contraception, wherein a daily dose of drospirenone is administered to the subject during Phase 1, and a smaller daily dose of drospirenone is administered to the subject during Phase 2. 8. The use of drospirenone according to claim 7, wherein the administration of drospirenone induces amenorrhea. 9. The use of drospirenone according to claim 7 or 8, wherein the above daily dose of drospirenone is administered once daily from day 1 to day 24, and thereafter a smaller daily dose of drospirenone is administered once daily from day 25 to day 28. The use of drospirenone according to any one of claims 7 to 9, wherein the daily dose of drospirenone administered from day 1 to day 24 is approximately 2.0 mg to 6.0 mg, preferably approximately 3.0 mg to 5.0 mg, more preferably approximately 3.5 mg to 4.5 mg, even more preferably approximately 3.8 mg to 4.2 mg, and most preferably approximately 4.0 mg. The use of drospirenone according to any one of claims 7 to 10, wherein the lowest daily dose of drospirenone administered from day 25 to day 28 is about 2.5 mg to about 3.5 mg, preferably about 2.6 mg to about 3.2 mg, more preferably about 3.0 mg, and most preferably about 2.8 mg of drospirenone. 12. Use of drospirenone in the method according to any one of claims 1 to 6, wherein the route of administration is selected from oral administration, transdermal administration or transmucosal administration, and preferably the route of administration is oral administration, and use of drospirenone according to any one of claims 7 to 11. 13. A kit, preferably a contraceptive kit, comprising one or more packaging units, each packaging unit comprising at least 28 active daily dose units, a) At least 24 daily dose units contain a first dose of drospirenone, and each of these daily dose units contains the same amount of drospirenone, and the amount is greater than the amount of drospirenone in a daily dose unit of a second dose of drospirenone. b) At least four daily dose units contain a second dose of drospirenone, and each of these daily dose units contains the same amount of drospirenone, with the amount of drospirenone being less than that of a daily dose unit containing a first dose of drospirenone. kit. 14. The kit according to claim 13, wherein at least 28 active daily dose units are estrogen-free. 15. The kit according to claim 13 or 14, wherein drospirenone is the sole contraceptive active ingredient in at least 28 active daily dose units. 16. The kit according to any one of claims 13 to 15, wherein the first amount of drospirenone is about 2.0 mg to 6.0 mg, preferably about 3.0 mg to 5.0 mg, more preferably about 3.5 mg to 4.5 mg, even more preferably about 3.8 mg to 4.2 mg, and most preferably about 4.0 mg of drospirenone. 17. The kit according to any one of claims 13 to 16, wherein the second amount of drospirenone is about 2.5 mg to about 3.5 mg, preferably about 2.6 mg to about 3.2 mg, more preferably about 3.0 mg, and most preferably about 2.8 mg of drospirenone. 18. A pharmaceutical composition comprising drospirenone for use in a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female subject requiring treatment of endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea according to any one of claims 1 to 6, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives. 19. Use of drospirenone according to any one of claims 7 to 12 in a contraceptive composition, wherein the composition further comprises one or more pharmaceutically acceptable additives. 20. The above pharmaceutically acceptable additives are at least one binder and at least one filler. (i) The amount of drospirenone is 1% to 10% by weight, (ii) The amount of at least one binder is 50% to 65% by weight, (iii) At least one filler accounts for 25% to 35% by weight, The weight percentage refers to the total weight of the above pharmaceutical composition. The pharmaceutical composition according to claim 18, or the contraceptive composition according to claim 19. 21. Further comprising at least one lubricant and at least one lubricating agent, (iv) The amount of at least one lubricant is between 0.2% and 6% by weight, (v) The amount of at least one lubricant is 0.2% to 0.6% by weight, The weight percentage refers to the total weight of the above pharmaceutical composition. The pharmaceutical composition according to claim 20. 22. (i) At least one binder is microcrystalline cellulose, (ii) At least one filler is anhydrous lactose, (iii) At least one lubricant is silicon dioxide, (iv) At least one lubricant is magnesium stearate. The pharmaceutical composition or contraceptive composition according to claim 21. 23. Use of drospirenone as a contraceptive according to any one of claims 4 to 7 in the pharmaceutical composition according to any one of claims 12 to 14.

Claims

1. A drospirenone-containing pharmaceutical for use in a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, comprising administering drospirenone to a subject in a two-phase regimen, wherein in the two-phase regimen, a daily dose of drospirenone is administered during Phase 1, and a lower daily dose of drospirenone is administered during Phase 2, with a daily dose of 3.5 mg to 4.5 mg administered from day 1 to day 24, and a lower daily dose of 2.5 mg to 3.5 mg administered from day 25 to day 28. However, this excludes pharmaceuticals used in methods of administering drospirenone simultaneously with estrogen. Pharmaceuticals.

2. The pharmaceutical product according to claim 1, wherein the daily dose of drospirenone administered from day 1 to day 24 in the two-phase regimen is 4.0 mg, and the daily dose of drospirenone administered from day 25 to day 28 is a smaller dose of 2.8 mg.

3. The pharmaceutical product according to claim 1 or 2, wherein the treatment also provides contraception.

4. A contraceptive containing drospirenone, comprising a two-phase regimen in which drospirenone is administered, with the daily dose of drospirenone administered during Phase 1, and a lower daily dose of drospirenone administered during Phase 2, with the daily dose of drospirenone administered from day 1 to day 24 being approximately 3.5 mg to approximately 4.5 mg. However, this excludes contraceptives used in methods of administering drospirenone simultaneously with estrogen. Contraceptive pills.

5. The contraceptive according to claim 4, wherein the daily dose of drospirenone administered from day 25 to day 28 is approximately 2.6 mg to approximately 3.2 mg, which is less than the aforementioned amount.

6. A contraceptive kit comprising one or more packaging units, each packaging unit comprising at least 28 active daily dose units, a) At least 24 daily dose units each contain a first dose of drospirenone, and each of these daily dose units contains the same amount of drospirenone, which is between 3.5 mg and 4.5 mg, and the amount is greater than the amount of drospirenone in the daily dose unit of the second dose of drospirenone. b) A contraceptive kit in which at least four daily dose units contain the second amount of drospirenone, and each of these daily dose units contains the same amount of drospirenone, wherein the amount of drospirenone is less than that of a daily dose unit containing the first amount of drospirenone, This method of contraception involves administering the daily dose of (a) from day 1 to day 24, and the daily dose of (b) from day 25 to day 28. The aforementioned at least 28 active daily dose units do not contain estrogen. Contraception kit.

7. The kit according to claim 6, wherein drospirenone is the sole contraceptive active ingredient in the at least 28 active daily dose units.

8. The contraceptive kit according to claim 6 or 7, wherein the first amount of drospirenone is about 3.8 mg to about 4.2 mg of drospirenone.

9. The contraceptive kit according to claim 8, wherein the second amount of drospirenone is about 2.5 mg to about 3.5 mg of drospirenone.

10. A pharmaceutical product according to claim 1 or 2, wherein the pharmaceutical product further comprises at least one binder and at least one filler, (i) The amount of drospirenone is between 1% and 10% by weight, (ii) The amount of the at least one binder is 50% to 65% by weight, (iii) The amount of the at least one filler is 25% to 35% by weight, The aforementioned weight percentage relates to the total weight of the pharmaceutical product. Pharmaceuticals.

11. Further comprising at least one lubricant and at least one lubricating agent, (iv) The amount of the at least one lubricant is 0.2% to 6% by weight, (v) The amount of the at least one lubricant is 0.2% to 0.6% by weight, The aforementioned weight percentage relates to the total weight of the pharmaceutical product. A pharmaceutical product for use as described in claim 10.

12. (i) The at least one binder is microcrystalline cellulose, (ii) The at least one filler is anhydrous lactose, (iii) The at least one lubricant is silicon dioxide, (iv) The at least one lubricant is magnesium stearate. The pharmaceutical product according to claim 11.

13. A contraceptive according to claim 4 or 5, wherein the contraceptive further comprises at least one binder and at least one filler, (i) The amount of drospirenone is between 1% and 10% by weight, (ii) The amount of the at least one binder is 50% to 65% by weight, (iii) The amount of the at least one filler is 25% to 35% by weight, The aforementioned weight percentage relates to the total weight of the contraceptive. Contraceptive pills.

14. Further comprising at least one lubricant and at least one lubricating agent, (iv) The amount of the at least one lubricant is 0.2% to 6% by weight, (v) The amount of the at least one lubricant is 0.2% to 0.6% by weight, The aforementioned weight percentage relates to the total weight of the contraceptive. A contraceptive for use according to claim 13.

15. (i) The at least one binder is microcrystalline cellulose, (ii) The at least one filler is anhydrous lactose, (iii) The at least one lubricant is silicon dioxide, (iv) The at least one lubricant is magnesium stearate. The contraceptive according to claim 14.

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