Methods of treating endometriosis and providing effective contraception

Abstract

This invention relates to methods for treating endometriosis and providing effective contraception. Specifically, it relates to drospirenone in methods for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, the method comprising administering drospirenone in a biphasic regimen. The invention also relates to the use of drospirenone administered in such a biphasic regimen as a contraceptive and for inducing amenorrhea, and to pharmaceutical compositions and devices comprising drospirenone administered in such a biphasic regimen.

Description

[0001] This application is a divisional application of Chinese patent application filed on August 11, 2022, with application number 202280066560.X and invention title "Method for treating endometriosis and providing effective contraception". Technical Field

[0002] This invention relates to the field of women's health, and more specifically, to the treatment of endometriosis, endometriosis-associated pelvic pain, and / or dysmenorrhea. Therefore, this invention relates to drospirenone in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, the method comprising administering drospirenone in a biphasic regimen. The invention further relates to the use of drospirenone administered in such a biphasic regimen as a contraceptive and for inducing amenorrhea, and also to pharmaceutical compositions and devices comprising drospirenone administered in such a biphasic regimen. Background Technology

[0003] Endometriosis is a chronic, estrogen-dependent disease characterized by the presence of endometrial tissue outside the uterus, including the ovaries and other pelvic structures. This damage causes a chronic inflammatory response, which can lead to scarring and adhesions. Women with endometriosis frequently experience symptoms such as dysmenorrhea, premenstrual pain, dyspareunia, and chronic fatigue (Schindler, 2011), as well as occasional symptoms such as pain during ovulation, constipation, and painful urination (Taylor et al., 2017). Furthermore, the presence of ectopic endometrium can also cause infertility, which may occur in up to 50% of women with endometriosis (Vercellini et al., 2014). Women with endometriosis therefore face one or both of two major problems: pain associated with endometriosis and infertility. The severity of symptoms is not necessarily related to the degree of pelvic disease or the size of the lesions. Many women with mild endometriosis complain of severe pelvic pain (Norwitz E.R. and Schorge JO, 2013).

[0004] It is estimated that endometriosis affects 10% of women of reproductive age, and it is estimated that approximately 190 million women worldwide suffer from endometriosis.

[0005] There is currently no cure for endometriosis. Women with endometriosis still need continuous, collaborative, and supportive management of their condition and to understand the significant impact of the disease on their quality of life. The main goals of treatment are to alleviate pain and other symptoms, reduce endometriotic lesions, and improve the quality of life for affected individuals.

[0006] Current hormonal treatments for endometriosis-related pain focus on systemic or local estrogen suppression, tissue proliferation and inflammation suppression, or both. Combined oral contraceptives (COCs) are widely used as first-line treatment for dysmenorrhea or chronic pelvic pain (with or without presumed endometriosis), particularly in adolescents with endometriosis (Vercellini and Buggio, 2018). Nevertheless, estrogen does stimulate metabolic activity in the endometrial mucosa. Therefore, COC administration may result in estrogen dominance and carries a potential risk of disease progression (Casper, 2017).

[0007] Progestin monotherapy has also been used as a first-line treatment for pelvic pain associated with endometriosis and for suppressing the progression of endometriosis lesions. One FDA-approved progestin for treating endometriosis, secondary amenorrhea, and abnormal uterine bleeding is norethindrone acetate (NETA) (5 mg tablets). While NETA can theoretically be administered for 28 consecutive days starting at a dose of 0.35 mg / day to suppress ovulation, it is not approved for contraception because the high doses required to treat endometriosis (5–15 mg / day) are more than 10 times higher than the doses required to suppress ovulation (0.35 mg / day). This high-dose therapy can last up to 6 to 9 months, or until breakthrough bleeding requires temporary discontinuation. Furthermore, at such high doses, NETA can produce androgenic side effects, such as acne, hirsutism, weight gain, and mild voice changes in some women.

[0008] Another approved progestin, dinogest (DNG), is a synthetic progestin currently used in Europe for the clinical treatment of endometriosis at a dose of 2 mg daily (Visanne® 2 mg tablets). DNG has no androgenic activity and is better tolerated than NETA. While 2 mg of DNG daily inhibits ovulation, it does not completely suppress ovarian activity and therefore has not been approved for use as a contraceptive (Caruso, 2019). Therefore, users are formally invited to use barrier contraception or other non-hormonal alternatives when using DNG to treat endometriosis (Vercellini, 2016).

[0009] Currently approved treatments for endometriosis-related pelvic pain do not have a contraceptive indication. Furthermore, hormonal contraceptives are not permitted for concurrent use with certain FDA or European-approved endometriosis medications (e.g., GnRH antagonists, such as the recently approved product oxalagolide (Elagolix), or progestins as dinogest). The need for barrier contraception may limit adherence to these products and could increase discontinuation rates. Therefore, a treatment for endometriosis-related pelvic pain (EAPP) is indeed needed among women seeking hormonal contraception.

[0010] Drospirenone (DRSP) is a derivative of spironolactone and possesses progestin-like, anti-adrenocorticotropic, and anti-androgenic activities. Drospirenone is available as a contraceptive ingredient in oral combination pills, such as those marketed under the names Yasmin® (3 mg DRSP / 30 µg ethinyl estradiol), Yaz® (3 mg DRSP / 20 µg ethinyl estradiol), and Yasminelle® (3 mg DRSP / 20 µg ethinyl estradiol). These pills contain ethinyl estradiol, which enhances the ovulation-suppressing effect of drospirenone while ensuring contraception and cycle control.

[0011] In the EU and the US, DRSPs have recently been approved as a POP (Slinda) for contraception in women of reproductive age. TM / Slynd TM The approved dosage is 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. The DRSP POP formulation can be prepared by methods described in the prior art, such as those described in WO 2012 / 00981 A or WO 2016 / 207298 A. The underlying principle behind the DRSP 24 / 4 regimen (including 4 hormone-free days in each cycle) is to create a progestin-only method that provides predictable, planned bleeding, independent of other progestin-only contraceptive methods (Slinda Public Assessment Report, Swedish MPA Template Version, 2019).

[0012] Menstrual avoidance or cessation achieved through continuous dosing regimens (referred to as “amenorrhea”) has characteristics that may be desirable from a patient’s perspective, including improved adherence to treatment, reduced disruption to daily life and special events, and reduced menstrual-related work or school absences (Côté et al., 2002; Rose et al., 2008; Edelman et al., 2014). Historical data from patient surveys and opinions from participants in clinical studies of hormonal contraceptives suggest that a significant proportion of women prefer to reduce the frequency of menstruation or amenorrhea through continuous dosing regimens (Loudon et al., 1977; Rutter et al., 1988; den Tonkelaar et al., 1999; Glasier et al., 2003; Wiegratz et al., 2004; Ferrero et al., 2006). In a large survey of more than 4,000 women of reproductive age in North America, South America, and Europe, 60% of respondents expressed a desire to delay menstrual bleeding (Szarewski et al., 2012). Therefore, there is a need for a contraceptive that ensures high contraceptive safety and reliability while reducing intermenstrual bleeding (menstruation), i.e., inducing amenorrhea.

[0013] Two phase III trials in the US and Europe, involving 13 28-day treatment cycles, evaluated the contraceptive efficacy and safety of an oral DRSP 4 mg 24 / 4 day regimen in sexually active women (Palacios, 2019 and Kimble et al., 2020). Generally, approximately 40% of users report amenorrhea after 9–13 cycles of the oral DRSP 4 mg 24 / 4 day regimen. However, there remains a need to provide faster and more effective methods for inducing amenorrhea, where more women can benefit from less or no bleeding after fewer cycles of oral DRSP use.

[0014] In a phase II study (study report CF111 / 203, 2014), two different dosing regimens were evaluated over two cycles: a continuous 28-day dosing regimen of DRSP 2.8 mg was compared with the currently approved 24+4 dosing regimen using DRSP 4.0 mg (Slynd™) to assess the ovulation suppression potential of these two regimens as reflected in hormone and ovarian activity in 50 healthy women. Although the results of this study have been published (EudraCT number: 2011-004085-15), the trial disclosure did not provide detailed information on bleeding patterns in women. Summary of the Invention

[0015] Therefore, one aspect of the present invention relates to drospirenone in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, the method comprising administering drospirenone to the subjects in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase.

[0016] In one embodiment of the method of the present invention, the daily dose of drospirenone is administered once daily from day 1 to day 24, and then the lower daily dose of drospirenone is administered once daily from day 25 to day 28.

[0017] In one embodiment of the method of the present invention, 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.

[0018] In another embodiment of the method of the present invention, the lower 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.

[0019] 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.

[0020] In another preferred embodiment of the method of the present invention, the method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea also provides contraception.

[0021] In one embodiment of the method of the present invention, no estrogen is applied.

[0022] In another aspect, the present invention relates to drospirenone in a method of contraception for administering to a female subject, the method comprising administering drospirenone to the subject in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase.

[0023] In a preferred embodiment of the method, administration of drospirenone induces amenorrhea. In a more preferred embodiment of the method, administration of drospirenone induces amenorrhea in more than 25%, preferably more than 30%, of female subjects after two administration cycles.

[0024] In a preferred embodiment of the 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 the subjects after three or even two administration cycles.

[0025] In an even 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 the subjects after one administration cycle.

[0026] In another preferred embodiment of the 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 the subjects after six administration cycles.

[0027] In one embodiment of the method, the daily dose of drospirenone is administered once daily from day 1 to day 24, and then a lower daily dose of drospirenone is administered once daily from day 25 to day 28.

[0028] In another embodiment, 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.

[0029] In another embodiment, the lower 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.

[0030] In another embodiment, the present invention relates to the use of drospirenone as a contraceptive in female subjects, comprising administering drospirenone to said subjects in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase.

[0031] In yet another embodiment, the use of drospirenone induces amenorrhea. 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 female subjects after four, preferably three, and most preferably two administration cycles.

[0032] 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 the subjects after three or even two administration cycles.

[0033] In even more preferred embodiments, 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 the subjects after one administration cycle.

[0034] 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 the subjects after six administration cycles.

[0035] In one embodiment of the use of drospirenone according to the present invention, the daily dose of drospirenone is administered once daily from day 1 to day 24, and then the lower daily dose of drospirenone is administered once daily from day 25 to day 28.

[0036] In another embodiment of the use, 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.

[0037] In yet another embodiment of the use, the lower 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.

[0038] In a preferred embodiment of the use, the daily dose of drospirenone administered from day 1 to day 24 is about 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is about 2.8 mg.

[0039] In one embodiment of the invention, no estrogen is applied.

[0040] In one embodiment of the method of the present invention for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea, and the use of drospirenone as a contraceptive, the route of administration is selected from oral administration, transdermal administration or transmucosal administration, with oral administration being preferred.

[0041] The present invention also relates to a pharmaceutical device comprising one or more packaging units, preferably a contraceptive device, wherein each packaging unit comprises at least 28 active daily dose units, wherein

[0042] a) At least 24 daily dose units contain a first amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and this amount is higher than the amount of drospirenone in daily dose units containing a second amount of drospirenone; and

[0043] b) At least four daily dose units contain a second amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and the amount of drospirenone is less than that of the daily dose units containing a first amount of drospirenone.

[0044] In one embodiment of the pharmaceutical device of the present invention, at least 28 active daily dose units do not contain estrogen.

[0045] In a preferred embodiment of the invention, drospirenone is the only contraceptive active ingredient among at least 28 active daily dose units.

[0046] In one embodiment of the pharmaceutical device 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.

[0047] In another embodiment of the pharmaceutical device 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.

[0048] In a preferred embodiment of the pharmaceutical device 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.

[0049] The present invention also relates to a pharmaceutical composition comprising drospirenone as described above in methods for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0050] In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutically acceptable excipient is at least one binder and at least one filler, wherein:

[0051] (i) The amount of drospirenone is from 1% to 10% by weight.

[0052] (ii) at least one adhesive in an amount of 50% to 65% by weight, and

[0053] (iii) The amount of at least one filler is 25% to 35% by weight.

[0054] The weight percentage is related to the total weight of the pharmaceutical composition.

[0055] In another embodiment of the invention, the pharmaceutical composition further comprises at least one flow aid and at least one lubricant, wherein:

[0056] (iv) At least one glialant in an amount of 0.2% to 6% by weight, and

[0057] (v) The amount of at least one lubricant is from 0.2% to 0.6% by weight.

[0058] The weight percentage is related to the total weight of the pharmaceutical composition.

[0059] In a preferred embodiment of the pharmaceutical composition of the present invention,

[0060] (i) At least one binder is microcrystalline cellulose,

[0061] (ii) At least one filler is anhydrous lactose,

[0062] (iii) At least one flow aid is silica, and

[0063] (iv) At least one lubricant is magnesium stearate.

[0064] The present invention also relates to the use of drospirenone, as defined above as a contraceptive, in pharmaceutical compositions as defined above.

[0065] The present invention also relates to a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects with such need, the method comprising administering drospirenone to the female subject in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase.

[0066] In one embodiment of the method for treating 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 then the lower daily dose of drospirenone is administered once daily from day 25 to day 28.

[0067] In one embodiment of the method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, 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.

[0068] In another embodiment of the method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, the lower 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.

[0069] In a preferred embodiment of the method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, the daily dose of drospirenone administered from day 1 to day 24 is about 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is about 2.8 mg.

[0070] In another embodiment of the method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, contraception is also provided.

[0071] In another embodiment of the method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, estrogen is not administered.

[0072] Embodiments of the present invention also relate to a method for providing contraception to a female subject in need, the method comprising administering drospirenone to the female subject in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase.

[0073] In one embodiment of the method for providing contraception, the daily dose of drospirenone is administered once daily from day 1 to day 24, and then the lower daily dose of drospirenone is administered once daily from day 25 to day 28.

[0074] In one embodiment of the method for providing contraception, 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.

[0075] In another embodiment of the method for providing contraception, the lower 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.

[0076] In a preferred embodiment of the method for providing contraception, the daily dose of drospirenone administered from day 1 to day 24 is about 4.0 mg, and the lower daily dose of drospirenone administered from day 25 to day 28 is about 2.8 mg.

[0077] In another embodiment of the method for providing contraception, estrogen is not administered.

[0078] The present invention also relates to a method for inducing amenorrhea in a female subject, the method comprising administering drospirenone to the female subject in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase.

[0079] In one embodiment of the method, the daily dose of drospirenone is administered once daily from day 1 to day 24, and then a lower daily dose of drospirenone is administered once daily from day 25 to day 28.

[0080] In one embodiment of the method, 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.

[0081] In one embodiment of the method, the lower 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.

[0082] In another embodiment of the method, the route of administration is selected from oral administration, transdermal administration or transmucosal administration, with oral administration being preferred.

[0083] In one aspect, the present invention also relates to drospirenone in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects with such need, the method comprising administering drospirenone to the female subject 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.

[0084] In yet another preferred embodiment, the method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea also induces amenorrhea.

[0085] In a more preferred embodiment, the 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.

[0086] 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 the subjects after three or even two administration cycles.

[0087] In an even 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 the subjects after one application cycle.

[0088] 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 the subjects after six application cycles. Attached Figure Description

[0089] Figure 1 The number of subjects with periodic amenorrhea (FAS) observed during continuous treatment with DRSP 2.8 mg, compared to DRSP 4.0 mg (24 + 4 treatments), as further detailed in Example 1 and Table 1, is disclosed.

[0090] Figure 2 Serum estradiol levels (pmol / L) obtained by continuous treatment with DRSP 2.8 mg compared to DRSP 4.0 mg (24 + 4) are disclosed, as further detailed in Example 1 and Table 2. Detailed Implementation

[0091] definition

[0092] As used herein, the term “active daily dose unit” or “daily dose unit” refers to a physically discrete unit suitable as a single dose that can be applied to a subject to provide the desired amount of an active ingredient, such as drospirenone.

[0093] As used herein, the term “amenorrhea” refers to the absence of bleeding / no bleeding / punctate bleeding in a female subject (preferably a woman of reproductive age) for at least 28 days or one administration cycle.

[0094] As used herein, the term "biphasic" or "biphasic regimen" refers to a dosing regimen with two phases, wherein the amount of active ingredient administered in the first phase differs from the amount administered during the second phase. The amount of active ingredient administered in each phase is constant, meaning that the active ingredient is present in the same amount in each daily dosage form administered during each phase. In each phase, the active ingredient is administered with each daily dosage form; that is, the daily dosage form cannot be without the active ingredient.

[0095] As used in this article, the term "contraceptive kit" refers to a device used to prevent pregnancy when administered to a female patient in an effective daily dose according to the instructions.

[0096] The term "contraceptive method" as used in this article refers to methods of preventing pregnancy.

[0097] As used herein, the term "drospirenone" refers to drospirenone itself, namely the chemical entity identified by CAS Registry No. 67392-87-4, solvates of drospirenone, and derivatives or prodrugs of drospirenone. Drspirenone can be prepared by well-known methods described in the prior art, such as those described in US 4129564, WO9806738, EP11746101, or WO2006061309. The method described in WO2006061309 may be particularly suitable for the preparation of drospirenone.

[0098] The term "dysmenorrhea" used in this article refers to the medical term for painful menstruation caused by uterine contractions. Primary dysmenorrhea refers to recurrent pain, while secondary dysmenorrhea is caused by diseases of the reproductive system.

[0099] As used in this article, the terms “endometriosis” and “endometriosis-associated pelvic pain (EAPP)” refer to a chronic estrogen-dependent disease characterized by the formation of endometriotic lesions outside the uterus (including the ovaries and other pelvic structures), which is one of its most common symptoms, reported as pelvic pain. All subtypes of endometriosis are included, including superficial, cystic, deep invasive, abdominal wall, and menstrual endometriosis. The management efficacy of endometriosis-associated pelvic pain (EAPP) can be assessed using different rating scales, such as the visual analog scale (VAS) or the numerical rating scale (NRS), as are well known to those skilled in the art (see, for example, Gerlinger et al. (2010) and Breivik et al. (2008)). Depending on the rating scale, for example, a difference 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 compared to placebo on a 0-10 NRS scale can be considered clinically significant and provide a genuine benefit to the patient.

[0100] As used in this article, the term "estrogen" defines a group of steroid hormones that promote the development and maintenance of female physical characteristics. Synthetic estrogens are well-known and are commonly used in oral contraceptives or to treat menopause and menstrual disorders.

[0101] As used herein, the terms “oral,” “oral dosage form,” “oral drug dosage form,” “oral administration,” “oral composition,” “oral drug composition,” “oral contraceptive composition,” “oral tablet,” “oral capsule,” “oral intake,” “oral delivery,” “oral route,” etc., refer to any method of oral administration. The oral dosage forms of this invention are generally ingested intact, although they may be crushed (e.g., pulverized) and usually ingested with the aid of water or a beverage to accelerate passage through the mouth.

[0102] The term “progestin-only contraceptive pill” or “progestin-only pill” (also known as “POP”) as used in this article refers to a pill or contraceptive pill that contains progestin as the sole active contraceptive ingredient and does not contain any estrogen.

[0103] As used herein, "therapeutic effective amount" refers to the effective amount of dose and time necessary to achieve a desired therapeutic effect, such as one or more of the following therapeutic effects: significantly delaying the onset or progression of disease; or significantly reducing the severity of one or more symptoms. Therapeutic effective amount is also typically the amount by which any toxic or adverse effect of the active ingredient or pharmaceutical composition is exceeded by the therapeutically beneficial effect.

[0104] As used herein, “treatment” means: (i) preventing or delaying the onset of a disease, condition, and / or illness in a person who may be susceptible to such disease, condition, and / or illness but has not yet been diagnosed with it; (ii) suppressing a disease, condition, or illness, i.e., preventing or slowing its development or progression; and / or (iii) alleviating a disease, condition, or illness, i.e., causing the remission of the disease, condition, and / or illness. In some implementations, such terms refer to the improvement or eradication of a disease or disease-related symptoms.

[0105] The method of the present invention

[0106] This invention relates to drospirenone in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, the method comprising administering drospirenone to the subjects in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase.

[0107] The currently approved drospirenone dosing regimen is the 24+4 regimen, which means administering drospirenone for 24 consecutive days, with days 25-28 used for hormone interruption, during which a placebo is administered. This invention envisions a different 24+4 regimen. The inventors propose a biphasic regimen, which involves administering a certain amount of drospirenone once daily from day 1 to day 24, followed by a lower amount of drospirenone once daily from day 25 to day 28, instead of administering the daily dose of drospirenone followed by a placebo for the first 24 days. 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, and most preferably about 4.0 mg of drospirenone. 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. In the most preferred embodiment, the daily dose of drospirenone administered from day 1 to day 24 is 4.0 mg, and the lowest daily dose of drospirenone administered from day 25 to day 28 is 2.8 mg.

[0108] In a preferred embodiment 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 administration cycle. As mentioned above, progestin-only pills (POPs) have the advantage of avoiding the combined administration of estrogen compared to conventional contraceptive combination pills. Therefore, one object of the present invention is to treat endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in women with this need, while providing reliable contraception by administering only a single daily dosage form. Preferably, the dosage form should not contain any estrogen, although estrogen is beneficial for contraception but detrimental to the treatment of estrogen-induced endometriosis.

[0109] For the treatment of endometriosis, the preferred approach is an extended hormone-free interval regimen that can be performed every 6 months or 1 year.

[0110] In another aspect, the present invention also relates to the application of drospirenone to female subjects in need as described above for the treatment of one or more of the following diseases or conditions in female subjects: dyspareunia, premenstrual pain, fibroids, adenomyosis, uterine fibroids, uterine leiomyomas, or endometrial polyps.

[0111] use

[0112] The present invention also relates to the use of drospirenone as a contraceptive for female subjects in need of it, comprising administering drospirenone to said subject in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase.

[0113] As described above with respect to the method of the present invention, a different kind of 24+4 scheme is envisioned compared to that proposed in the prior art. The inventors propose administering a daily dose of drospirenone once daily from day 1 to day 24, followed by a lower daily dose of drospirenone once daily from day 25 to day 28, instead of administering a single dose of drospirenone followed by a placebo for the first 24 days. 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 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. 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.

[0114] In the Phase II study CF111 / 203 summarized in Example 1, two different dosing regimens were evaluated over two cycles: a continuous 28-day dosing regimen of DRSP 2.8 mg was compared to the currently approved 24+4 dosing regimen using DRSP 4.0 mg (Slynd™). The unpublished results surprisingly showed a higher proportion of subjects experiencing amenorrhea with the continuous DRSP 2.8 mg regimen across both cycles. Seven subjects (28.0%) experienced amenorrhea, compared to three subjects (12.0%) in the DRSP 4.0 mg group. In cycle 1, twelve subjects (48.0%) of the DRSP 2.8 mg regimen and six subjects (24.0%) of the DRSP 4.0 mg regimen reported amenorrhea. In cycle 2, nine subjects (36.0%) of the DRSP 2.8 mg regimen and four subjects (16.0%) of the DRSP 4.0 mg regimen experienced amenorrhea (see Example 1, Table 1).

[0115] In summary, the proportion of women experiencing amenorrhea was higher in the DRSP 2.8 mg group than in the DRSP 4.0 mg group throughout both treatment cycles. As mentioned above, clinical studies of hormonal contraceptives have shown that a significant proportion of women tend to reduce the frequency of menstruation or amenorrhea through continuous dosing regimens. Therefore, a continuous regimen of 2.8 mg drospirenone daily is an effective alternative that can meet the specific needs of women who require control of bleeding patterns and the achievement of desired amenorrhea.

[0116] Drozoprolone is a progestin that works by blocking the production of gonadotropin-releasing hormone (DRSP), which in turn leads 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 compared to those receiving a continuous DRSP 2.8 mg regimen. The difference between the two groups was not statistically significant. Furthermore, neither treatment had a clinically meaningful effect on reducing estradiol levels (see Example 1). A careful balance must be maintained between excessively low and excessively high estrogen levels. Excessively low estrogen levels can lead to undesirable side effects such as osteoporosis, while excessively high estrogen levels are detrimental to estrogen-dependent diseases such as endometriosis. Therefore, another object of the present invention is to provide the benefit of amenorrhea while maintaining estrogen balance, while also providing reliable contraception.

[0117] In one embodiment of the invention, drospirenone is used as a contraceptive to induce amenorrhea as described 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 the subjects after four, preferably three, and most preferably two administration cycles.

[0118] 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 the subjects after three or even two administration cycles.

[0119] In even more preferred embodiments, 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 the subjects after one administration cycle.

[0120] 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 the subjects after six administration cycles.

[0121] In another implementation, vaginal bleeding was reduced after three administration cycles compared to the amount of vaginal bleeding following placebo administration, and even more so after six administration cycles.

[0122] Preferably, vaginal bleeding decreases after three application cycles, resulting in approximately 2.0-5.5 days of vaginal bleeding per cycle (month), preferably less than approximately 4.5 days of vaginal bleeding per cycle (month), and most preferably less than approximately 4.0 days of vaginal bleeding per cycle (month). In a more preferred embodiment, the reduction in vaginal bleeding occurs after two or even one application cycle.

[0123] In a preferred embodiment, vaginal bleeding after six application cycles results in approximately 2.0-5.5 days of vaginal bleeding per cycle (month), preferably less than approximately 4.5 days of vaginal bleeding per cycle (month), and most preferably less than approximately 3.5 days of vaginal bleeding per cycle (month). It should be understood that vaginal bleeding may include spotting.

[0124] In another preferred embodiment, the bleeding also includes unplanned bleeding.

[0125] In another embodiment, unplanned bleeding and / or bleeding intensity decrease after six administration cycles, preferably after three administration cycles, and most preferably after two or one administration cycles.

[0126] Another benefit of the use of the invention is the avoidance of the risk associated with contraceptive failure due to the omission of pills at approximately a 4-day interval in a previous 24+4 regimen, in which the 4 pills did not contain contraceptives.

[0127] When used for contraceptive purposes, the composition is applied to women of reproductive age, from puberty to menopause. Women of reproductive age also include women in the perimenopausal period.

[0128] medicine equipment

[0129] The present invention also provides a medical device, preferably a contraceptive medical device, which is particularly suitable for the above-mentioned methods of contraception and treatment.

[0130] Therefore, the present invention also relates to a pharmaceutical device comprising one or more packaging units, preferably a contraceptive device, wherein each packaging unit comprises at least 28 active daily dose units.

[0131] The medication contains at least 24 daily dose units containing a first amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and this amount is higher than the amount of drospirenone in a daily dose unit containing a second amount of drospirenone.

[0132] At least four daily dose units contain a second amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and the amount of drospirenone is less than that of the daily dose unit containing the first amount of drospirenone.

[0133] In one embodiment of the device of the present invention, at least 28 active daily dose units do not contain estrogen. Estrogens commonly used for contraceptive purposes include, but are not limited to, estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, ethinyl estradiol, estriol, estrone, estriol, estriol succinate, phytoestrogens, and conjugated estrogens.

[0134] In a preferred embodiment of the invention, drospirenone is the only contraceptive active ingredient among at least 28 active daily dose units.

[0135] In one embodiment of the pharmaceutical device 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.

[0136] In another embodiment of the pharmaceutical device 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.

[0137] In a preferred embodiment of the pharmaceutical device 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.

[0138] The medical device comprises one or more packaging units. The one or more packaging units include, but are not limited to, 1 packaging unit, 2 packaging units, 3 packaging units, 4 packaging units, 5 packaging units, and 6 packaging units.

[0139] In some embodiments, the device is characterized in that each packaging unit contains 28 daily dose units and does not include a pharmaceutically acceptable placebo daily dose unit. Such devices are particularly suitable for performing the method of the invention, which involves “continuous” administration of DRSP without any placebo phase in which the contraceptive is not administered.

[0140] The packaging unit described above can have one of the conventional forms commonly used for oral contraceptives. For example, the packaging unit can be a conventional blister pack containing an appropriate number of dosage units in a sealed blister pack (e.g., an aluminum blister pack) with a cardboard, foil, or plastic backing, and sealed in a suitable cap. For ease of compliance, each blister container can be conveniently numbered or labeled. The packaging unit can contain daily dosage units arranged in the order of administration.

[0141] The medical devices of the present invention may comprise any of the pharmaceutical compositions disclosed below.

[0142] The medical device of the present invention may additionally contain other suitable components, such as instructions for use.

[0143] Pharmaceutical Composition

[0144] The present invention also relates to pharmaceutical compositions comprising drospirenone for use in methods of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects as described above, or for use as described above, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0145] The pharmaceutically acceptable excipients in the compositions of the present invention include, but are not limited to, binders, fillers, flow aids, lubricants, granulation aids, colorants, anti-caking agents, plasticizers, disintegrants, dyes, antioxidants, anti-adhesives, softeners, preservatives, and flavorings, all of which are commonly used in the pharmaceutical industry.

[0146] 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 carboxymethyl cellulose, calcium carboxymethyl cellulose, gums such as gum tragali, gum arabic, and gelatin and / or mixtures thereof. Microcrystalline cellulose is preferred. The binder may be present in an amount of about 0.5% by weight to about 20% by weight, preferably 1% by weight to 10% by weight, more preferably 2-7% by weight, and preferably about 5% by weight of the total composition.

[0147] 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, glucose, calcium hydrogen phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, and / or mixtures thereof. Anhydrous lactose is preferred. The filler may be present in amounts of about 20% to about 95% by weight of the total composition, preferably 30% to 90% by weight, more preferably 35% to 80% by weight, and even more preferably 30% to 60% by weight, including about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, and about 60% by weight.

[0148] Lubricants suitable for use in this invention include, but are not limited to, talc, alkaline earth metal salts of stearic acid such as magnesium stearate and calcium stearate, stearic acid, palmitic acid glyceryl stearate, stearic fumarate, zinc stearate, propylene glycol, PEG, vegetable oils, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, mineral oil polyoxyethylene monostearate, and / or mixtures thereof. In a preferred embodiment, the lubricant is magnesium stearate. The lubricant may be present in an amount of about 0% to 5% by weight, preferably about 1% to about 3% by weight (e.g., about 2%) based on the total weight of the composition.

[0149] Examples of flow aids include silica, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate and / or mixtures thereof. In a preferred embodiment, the flow aid is silica.

[0150] Pharmaceutically acceptable excipients that can be used to formulate the pharmaceutical compositions of the present invention are specifically described in the Handbook of Pharmaceutical Excipients of the American Pharmaceutical Association (Pharmaceutical Press, 6th revised edition, 2009).

[0151] In some embodiments, the pharmaceutical compositions of the present invention comprise at least one or more excipients selected from adhesives, fillers, flow aids, and lubricants.

[0152] In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutically acceptable excipient is at least one binder and at least one filler, and wherein:

[0153] (i) The amount of drospirenone is from 1% to 10% by weight.

[0154] (ii) at least one adhesive is present in an amount of 50% to 65% by weight, and

[0155] (iii) The amount of at least one filler is 25% to 35% by weight.

[0156] The weight percentage is related to the total weight of the pharmaceutical composition.

[0157] In another embodiment of the invention, the pharmaceutical composition further comprises at least one flow aid and at least one lubricant, wherein:

[0158] (iv) The amount of at least one glial agent is from 0.2% to 6% by weight, and

[0159] (v) The amount of at least one lubricant is from 0.2% to 0.6% by weight.

[0160] The weight percentage is related to the total weight of the pharmaceutical composition.

[0161] In a preferred embodiment of the pharmaceutical composition of the present invention:

[0162] (i) At least one binder is microcrystalline cellulose,

[0163] (ii) At least one filler is anhydrous lactose,

[0164] (iii) At least one flow aid is silica, and

[0165] (iv) At least one lubricant is magnesium stearate.

[0166] The dosage form according to the invention may further comprise a disintegrant. The disintegrant may be selected from low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, crospovidone carboxymethyl cellulose, 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.

[0167] In some embodiments of the invention, DRSP is in a multiparticulate form. The term "multiparticulate" is defined as comprising beads, pellets, and any other orally administered multiparticulate system. In some embodiments of the invention, DRSP is dispersed in a matrix. In some embodiments of the invention, multiparticulate DRSP may be dispersed in a matrix or contained in capsules. In some embodiments of the invention, DRSP is in a matrix in pellet form. In some embodiments of the invention, DRSP is in coated beads.

[0168] In one embodiment of the foregoing aspects, the pharmaceutically acceptable matrix is ​​a polymer matrix, a non-polymer matrix, or a combination thereof.

[0169] The polymer matrix includes, but is not limited to: hydroxypropyl methylcellulose; hydroxypropyl cellulose; hydroxyethyl cellulose; hydroxymethyl cellulose; carboxymethyl cellulose; sodium carboxymethyl cellulose; calcium carboxymethyl cellulose; polyvinylpyrrolidone; polyethylene oxide; polyvinyl alcohol; methylcellulose; ethyl cellulose; propyl cellulose; ethyl methyl cellulose; isopropyl cellulose; ethylpropyl cellulose; butyl cellulose; benzyl cellulose; cellulose esters, such as cellulose acetate, cellulose butyrate, cellulose propionate, cellulose butyrate and cellulose acetate propionate; cellulose cyanoalkyl ethers, such as cyanoethyl cellulose, cyanomethyl cellulose, cyanoethyl methyl cellulose and cyanopropyl cellulose; 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 acetate phthalate; and mixtures thereof.

[0170] Non-polymer matrices include, but are not limited to, sugars and sugar alcohols, such as sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, threitol, arabinitol, xylitol, galactitol, inositol, trehalose, isomaltitol, 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.

[0171] In some particularly preferred embodiments, the dosage forms of the present invention comprise oral formulations (e.g., tablets or capsules) coated to prevent excessive direct contact of DRSPs with the oral cavity (e.g., tongue, oral mucosa), oropharyngeal mucosal surfaces, esophagus, or stomach. In some preferred embodiments, the dosage forms of the present invention comprise oral formulations coated with a film or polymer.

[0172] In a preferred embodiment, the pharmaceutical composition according to the invention does not contain a large amount of surfactant. A large amount of surfactant may increase the initial dissolution rate of DRSP, thereby impairing its in vitro dissolution properties. Suitable surfactants may be selected from ionic surfactants, such as sodium lauryl sulfate, phospholipids, glyceryl monooleate, sodium docusate, or nonionic surfactants, polyoxyethylene dehydrated sorbitan fatty acid esters, such as polysorbate 80, polyoxyethylene stearate, poloxamer, polyoxyethylene alkyl ethers.

[0173] If present, the amount of surfactant is preferably from about 0.01 wt% to about 5 wt%, more preferably from about 0.1 wt% to about 1 wt%, based on the total weight of the composition. In the most preferred embodiment, the pharmaceutical composition is surfactant-free.

[0174] The pharmaceutical or contraceptive composition according to the invention can be formulated into a galen dosage form suitable for oral administration. Such forms include, but are not limited to, tablets, capsules, granules, pills, powders, and suspensions. In a preferred embodiment, the contraceptive composition is formulated into a solid form for oral administration, such as tablets, capsules, granules, capsules, and pills. This solid form is particularly suitable for use as a daily active dose unit in a pharmaceutical device according to the invention.

[0175] When a pharmaceutical or contraceptive composition is formulated into a solid form such as a tablet or pill, the solid form can be conveniently coated with a suitable film-forming agent such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, or ethylcellulose, wherein suitable excipients may optionally be added, such as softeners such as glycerin, propylene glycol, diethyl phthalate, or triacetin, fillers such as sucrose, sorbitol, xylitol, glucose, or lactose, or colorants such as titanium hydroxide.

[0176] Pharmaceutical or contraceptive compositions in tablet, pill, or granule form can be prepared by conventional methods such as direct compression, dry granulation, and wet granulation.

[0177] The pharmaceutical or contraceptive compositions described herein are suitable for daily oral administration in various administration regimens, with preferred administration regimens as described above for contraception and the medical purposes mentioned herein.

[0178] In a specific embodiment, the composition is suitable for administration to female subjects in need in a daily active oral form within a regimen comprising 28 consecutive days of administration of the active oral form, wherein at least 24 daily dose units in the medication contain a first amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and this amount is higher than the amount of drospirenone in a daily dose unit containing a second amount of drospirenone. At least four daily dose units contain a second amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and the amount of drospirenone is lower than that in a daily dose unit containing the first amount of drospirenone.

[0179] It is anticipated that any feature described herein may be optionally combined with any embodiment of any medical or contraceptive use, composition, device, method of contraception, treatment method, or method of manufacture of the present invention; and any embodiments discussed in this specification may be implemented for any of these embodiments. It should be understood that the specific embodiments described herein are shown by way of example and not as limitations of the invention.

[0180] All publications and patent applications are incorporated herein by reference to the same extent that each individual publication or patent application is expressly and individually indicated to be incorporated by reference.

[0181] The use of the terms "a" or "an" can mean "one," but it is also consistent with the meanings of "one or more," "at least one," and "one or more." The term "another" can also refer to one or more. The use of the term "or" in the claims is to mean "and / or," unless it is explicitly stated that it refers only to alternatives or that the alternatives are mutually exclusive.

[0182] As used herein and in one or more claims, the words “comprising” (and any form of inclusion, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of inclusion, such as “includes” and “include”), or “containing” (and any form of inclusion, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unlisted elements or method steps. The term “comprising” also covers and explicitly discloses the terms “consists of” and “consists essentially of”. As used herein, the phrase “consists essentially of” limits the scope of the claims to specific materials or steps that do not substantially affect the essential and novel characteristics (one or more) of the claimed invention. As used herein, the phrase “consisting of” excludes any element, step, or ingredient not specified in the claims, except for impurities typically associated with that element or limitation.

[0183] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC, and also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB if the order is important in the particular context. Continuing with this example, explicitly included are combinations containing repetitions of one or more items or terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so on. Those skilled in the art will understand that there is typically no limit to the number of items or terms in any combination unless it is obvious from the context.

[0184] As used herein, approximate terms such as, but not limited to, “about,” “around,” and “approximately” refer to a condition that, when modified in this way, is understood to be not necessarily absolute or perfect, but rather considered sufficiently close to the level of a person skilled in the art to guarantee the existence of the specified condition. The degree of variability in the description will depend on how much change can be made while still allowing a person skilled in the art to recognize that the modified feature retains the desired characteristics and capabilities of the unmodified feature. Generally, but in accordance with the foregoing discussion, numerical values ​​modified herein by approximate terms such as “about” may differ from the specified value by ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, 8%, ±9%, or ±10%. Therefore, the term “about” may mean an indication of its value ±5%, preferably an indication of its value ±2%, and most preferably, the term “about” means exactly the indication value (±0%).

[0185] The following examples are used to illustrate the present invention and should not be construed as limiting the scope of the invention.

[0186] Example

[0187] Example 1: Evaluation of two different doses of drospirenone (4.0 mg for 24 days or 2.8 mg daily for 28 days) in 50 healthy individuals An open-label randomized study of the effects of two treatment cycles on hormones and ovarian activity in young women.

[0188] The main objective of the experiment:

[0189] The ovulation-suppressing potential of drospirenone (DRSP) as reflected in hormone and ovarian activity was evaluated in 50 healthy women with two different dosages and intake regimens. Subjects were assigned to one of the two treatment regimens after stratification on the day of ovulation in the previous cycle.

[0190] Recruitment details:

[0191] Healthy premenopausal women of any race (18 to 35 years of age, including smokers under 30 years of age; smokers ≤ 30 years of age, no more than 10 cigarettes per day), BMI of 18-30 kg / m2, regular menstrual cycle history, and blood pressure between 90-140 mmHg (systolic) and 50-90 mmHg (diastolic) after 5 minutes of rest.

[0192] arm:

[0193] Over two treatment cycles, 50 participants were assigned to either treatment group 1 (4.0 mg DRSP for 24 days, followed by 4 placebo tablets) or treatment group 2 (2.8 mg DRSP for 28 days).

[0194] Arm description:

[0195] arm experiment

[0196] a) Treatment Group 1

[0197] -Drug name under investigation: Drospirenone 4.0 mg coated tablets

[0198] -Dosage form: Tablets

[0199] - Route of administration: Oral

[0200] - Dosage and administration details: 28 coated tablets, orally, once daily; 24 tablets contain 4.0 mg DRSP, and 4 placebo tablets.

[0201] - Excipients for 4 mg DRSP tablets (white): anhydrous lactose, microcrystalline cellulose, colloidal silica, magnesium stearate, opalry II (white)

[0202] - Excipient placebo tablets (green): Anhydrous lactose, microcrystalline cellulose, colloidal silica, magnesium stearate, opadry II green.

[0203] b) Treatment group 2

[0204] -Research drug name: Drospirenone 2.8 mg coated tablets

[0205] -Dosage form: Tablets

[0206] - Route of administration: Oral

[0207] - Dosage and administration details: 28 coated tablets, orally, once daily.

[0208] - Excipients 2.8 mg DRSP tablets (pink): Anhydrous lactose, microcrystalline cellulose, colloidal silica, magnesium stearate, opalry II (pink)

[0209] This Phase II study evaluated two different dosing regimens over two cycles: a continuous 28-day dosing regimen of DRSP 2.8 mg versus the currently approved 24+4 dosing regimen of DRSP 4.0 mg (Slynd™).

[0210] 1.) Results Summary: Ovulation Inhibition Potential

[0211] Efficacy assessments in this clinical trial included the Hoogland score (a combined parameter of follicle size, estradiol, and progesterone levels), as well as LH and FSH levels, endometrial thickness, and bleeding pattern. The primary endpoint was the Hoogland score (FAS). One participant receiving DRSP 2.8 mg had a Hoogland score of "5" in cycle 1, likely due to accompanying diarrhea. Two participants receiving DRSP 4.0 mg had Hoogland scores of "6" (one in cycle 1 and the other in cycle 2). The Hoogland score in cycle 2 was also "6," likely due to accompanying vomiting. However, progesterone levels (maximum values ​​of 5.34 nmol / L, 5.34 nmol / L, and 6.17 nmol / L, respectively) were not sustained and were below normal luteal phase levels.

[0212] Overall, the DRSP 4.0 mg 24 / 4 regimen showed more significant inhibition of ovarian activity than the DRSP 2.8 mg 28 / 0 regimen.

[0213] The logistic regression model for binary responses with Hoogland scores ≤4 and >4, as predicted in the protocol, proved inapplicable to the data from period 2. Therefore, an additional logistic regression model was calculated for binary responses with Hoogland scores ≤3 and >3.

[0214] In cycle 1, the proportions of subjects with a Hoogland score ≤3 were 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 proportions of subjects with a Hoogland score ≤3 were 7 (28.0%) in the DRSP 2.8 mg group and 11 (44.0%) in the DRSP 4.0 mg group. Therefore, the differences supporting the high-dose regimen were more pronounced in cycle 2.

[0215] Compared with the DRSP 2.8 mg 28 / 0 regimen, the estimated odds ratio [95% CI] for Hoogland scores of 3 or lower with the DRSP 4.0 mg 24 / 4 regimen was 1.4167 [0.4449; 4.6240] in cycle 1 and 2.0202 [0.6317; 6.8038] in cycle 2. CI indicated that these results were not statistically significant. Chi-square test showed no significant effect of treatment on Hoogland scores (p = 0.5563 in cycle 1 and p = 0.2417 in cycle 2).

[0216] Throughout both treatment cycles, follicles in the DRSP 4.0 mg group were generally 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 follicle 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 4-day hormone interruption in the DRSP 4.0 mg group, the maximum follicle size did not increase significantly at the start of cycle 2 and remained lower than that in the DRSP 2.8 mg group.

[0217] The proportion of women with follicle diameter ≥ 15 mm measured three times consecutively using the DRSP 4.0 mg 24 / 4 protocol (28.0% in cycle 1 and 36.0% in cycle 2) was lower than that using the DRSP 2.8 mg 28 / 0 protocol (52.0% in cycle 1 and 60.0% in cycle 2). Progesterone levels were similar in both groups. With the high-dose formulation, the highest mean (SD) level per cycle was 3.89 (1.10) nmol / L in cycle 1 and 3.74 (1.01) nmol / L in cycle 2. With the low-dose formulation, the highest mean (SD) level per cycle was 3.54 (1.06) nmol / L in cycle 1 and 3.48 (1.11) nmol / L in cycle 2.

[0218] 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. With the DRSP 4.0 mg regimen, the median maximum values ​​for each cycle were 287.0 pmol / L in cycle 1 and 309.0 pmol / L in cycle 2, while with the DRSP 2.8 mg regimen, the values ​​were 450.0 pmol / L in cycle 1 and 377.0 pmol / L in cycle 2.

[0219] Follicular activity increases not only with size but also with accompanying serum estradiol levels. Therefore, in another analysis, follicular size and serum estradiol levels were combined: among subjects with follicle sizes > 13 mm, the proportion of subjects with E2 levels 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%]).

[0220] Regarding endometrial thickness, there were no relevant differences between the treatment groups. In cycle 1, the mean (SD) maximum endometrial thickness per cycle in the DRSP 2.8 mg group (6.50 [1.44] mm) was higher than that in the DRSP 4.0 mg group (6.33 [1.23] mm). In contrast, in cycle 2, the mean (SD) maximum endometrial thickness in the DRSP 2.8 mg group (6.57 [1.70] mm) was lower than that in the DRSP 4.0 mg group (6.60 [1.38] mm).

[0221] Throughout both treatment cycles, serum LH levels in both treatment groups were significantly below the ovulation threshold of 14.0 U / L. The mean (SD) serum LH level in the DRSP 2.8 mg group (maximum observed on day 6 of cycle 1, 7.67 (2.87) U / L) was higher than that in the DRSP 4.0 mg group (maximum observed on day 3 of cycle 1, 6.30 (1.78) U / L).

[0222] 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 the treatment groups.

[0223] In summary, compared to the DRSP 2.8 mg 28 / 0 regimen, subjects using the DRSP 4.0 mg 24 / 4 regimen tended to have smaller follicles and lower estradiol and LH levels. No significant differences were observed between the two regimens regarding endometrial thickness, progesterone, and FSH levels.

[0224] 2.) Results Summary: Induction of amenorrhea

[0225] The proportion of patients experiencing amenorrhea across both cycles was 7 (28.0%) in the DRSP 2.8 mg continuous treatment group, compared to 3 (12.0%) in the DRSP 4.0 mg group. In cycle 1, twelve (48.0%) patients in the DRSP 2.8 mg group and six (24.0%) patients in the DRSP 4.0 mg group reported amenorrhea. In cycle 2, nine (36.0%) patients in the DRSP 2.8 mg group and four (16.0%) patients in the DRSP 4.0 mg group experienced amenorrhea. In summary, the proportion of patients experiencing amenorrhea was higher in the DRSP 2.8 mg group than in the DRSP 4.0 mg group across both treatment cycles (see Table 1 and...). Figure 1 ).

[0226] Table 1: The number of amenorrhea subjects counted by period (FAS) DRSP 2.8 mg continuous (N = 25) DRSP 4.0 mg (24 + 4) (N = 25)

[0227] statistics DRSP 2.8 mg consecutively (N = 25) DRSP 4.0 mg (24 + 4) (N = 25) Cycle 1 n（%） 12（48.0%） 6（24.0%） Cycle 2 n（%） 9（36.0%） 4（16.0%） Two cycles n（%） 7（28.0%） 3（12.0%）

[0228] Furthermore, the mean and median serum estradiol levels were observed to be lower in subjects receiving the DRSP 4.0 mg 24 / 4 regimen than in those receiving the DRSP 2.8 mg 28 / 0 regimen. However, the difference between the two groups was not statistically significant.

[0229] Table 2: Serum estradiol levels (pmol / L): DRSP 2.8 mg consecutively (N = 25) DRSP 4.0 mg (24 + 4) (N = 25)

[0230]

[0231] The results of this trial, which have not yet been published, show that, Figure 1 As shown, a higher proportion of patients experienced amenorrhea with the 2.8 mg regimen. Furthermore, data indicated that continuous treatment had no effect on reducing estradiol levels below those at the start of treatment.

[0232] Example 2: A multicenter, phase III, double-blind, randomized clinical trial to evaluate LPRI-CF113 compared to placebo. Efficacy and safety of treating endometriosis after 3 cycles of medication followed by 3 open-label cycles

[0233] The information described in this article is excerpted from the protocol of a Phase III clinical trial, namely a multicenter, double-blind, randomized clinical trial to evaluate LPRI-CF113 compared with placebo over three treatment cycles. Subsequently, three open-label treatment cycles were administered. The efficacy and safety of post-treatment for endometriosis.

[0234] Materials and methods

[0235] Main objectives and endpoints

[0236] The primary objective was to demonstrate the efficacy of LPRI-CF113 in managing endometriosis-related pelvic pain (EAPP) after 3 cycles of treatment, assessed using the Numerical Rating Scale (NRS).

[0237] Secondary goals and endpoints

[0238] To evaluate the efficacy of LPRI-CF113 versus placebo in terms of treatment response.

[0239] Key secondary endpoints:

[0240] 1. Changes in dysmenorrhea after 1, 3, and 6 cycles of medication compared to baseline (assessed via NRS pain score).

[0241] 2. Changes in nonmenstrual pelvic pain (NMPP) after 1, 3, and 6 cycles of medication compared to baseline (assessed via NRS pain score).

[0242] 3. Changes in resuscitation drug intake after 1, 3, and 6 cycles of treatment compared to baseline.

[0243] 4. Changes in EAPP after 1 and 6 treatment cycles compared to baseline (assessed via NRS pain score).

[0244] Other secondary therapeutic endpoints:

[0245] 1. Changes in dyspareunia after 1, 3, and 6 cycles of medication compared to baseline.

[0246] 2. Number and percentage of individuals with amenorrhea

[0247] 3. Vaginal bleeding pattern

[0248] Secondary safety endpoints:

[0249] 1. Adverse events.

[0250] 2. Average absolute and relative changes in laboratory values.

[0251] 3. Vital signs

[0252] Overall Design

[0253] This is a multicenter clinical trial for postmenopausal and premenopausal women aged ≥ 15 years and ≤ 45 years with a histologically confirmed diagnosis of endometriosis and an EAPP score ≥ 3 within the last 3 months prior to trial initiation. The clinical trial includes a screening period (up to 100 days), a treatment period (including 3 placebo-controlled, double-blind treatment cycles), and an open-label extension period during which all participants will receive 3 cycles of aggressive LPRI-CF113 treatment.

[0254] Informed consent / consent will be obtained at the first visit (V1a), and the screening process will be conducted. An electronic diary will also be distributed, and subjects will be instructed on how to complete it. If applicable, subjects will be asked to remove hormonal contraceptives or hormone therapy used to treat endometriosis for one menstrual cycle during the screening period at the first visit (V1a). The 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 (internal bleeding) will be considered the baseline cycle. A baseline cycle length of 21 to 35 days is acceptable. The first visit (V1b) should be scheduled at least 29 days after V1a and before the expected last day of the baseline cycle.

[0255] At the first visit (1b), after eligibility is confirmed, subjects will be randomly assigned to either the LPRI-CF113 or placebo group and will receive the study drug (IP). The first IP intake will be taken on the first day of the next menstrual period following the first visit (1b). If menstrual bleeding begins in the evening and the subject prefers to take the IP in the morning, she may begin her first IP intake on the second day [day 2 of menstrual bleeding]. Subsequently, subjects will visit the research center at the second and third visits on day 20 (+6) of the first and third treatment cycles, respectively. The end-of-treatment visit (fourth visit / early discontinuation visit [EDV]) will be taken three days after the last IP intake of the sixth treatment cycle.

[0256] In addition, research center staff will regularly call the subjects on day 1 (+2) of each medication cycle to collect basic information, especially any potential adverse events (AEs), and to review the compliance of the electronic diary. Furthermore, a follow-up visit (by phone or in person) will be conducted 10 days (+4) after the last IP intake of the sixth medication cycle.

[0257] If necessary, participants may take a nonsteroidal anti-inflammatory drug (NSAID) as a rescue medication during the trial. Participants should take the same NSAID (including the strength version) as the rescue medication throughout the trial. They will be permitted to continue using one of the NSAIDs they were taking before the start of the trial, to switch to another NSAID, or, if medically feasible, to begin using the selected NSAID at the first visit (if they have not previously used an NSAID). However, switching to another NSAID and prophylactic NSAID intake after the first visit, as well as starting a new pain medication during the trial, are not permitted.

[0258] Study population

[0259] Number of participants (planned):

[0260] Screening: Approximately 236 subjects. Screening will continue until a sufficient number of subjects are allocated for treatment.

[0261] Random: At least 212 objects, with a random ratio of 3:1

[0262] Postmenopausal and premenopausal women aged ≥ 15 years and ≤ 45 years with a histologically confirmed diagnosis of endometriosis and an NRS EAPP score ≥ 3 for at least 3 months will be randomized to receive LPRI-CF 113 (4 mg / day for 24 days, followed by 2.8 mg / day for 4 days per 28-day cycle) or placebo. Analysis will be conducted on participants who have received at least one corresponding IP and have at least one outcome measure after baseline (full analysis set [FAS]).

[0263] treat

[0264] Research product identity

[0265] Tested product name: LPRI-CF113

[0266] Dosage form: Oral film-coated tablets

[0267] Active ingredient: drospirenone (DRSP)

[0268] Strength / Concentration: 4 mg / 2.8 mg DRSP (24 / 4)

[0269] Excipients 4 mg DRSP tablets (white): anhydrous lactose, microcrystalline cellulose, colloidal silica, magnesium stearate, opalry II 85F18422 (white)

[0270] Excipients for 2.8 mg DRSP tablets (pink): Anhydrous lactose, microcrystalline cellulose, colloidal silica, magnesium stearate, opalry II (pink)

[0271] Description: 24 white tablets, followed by 4 pink tablets.

[0272] Reference product (matched placebo):

[0273] Name: LPRI-CF113 placebo

[0274] Dosage form: Oral film-coated tablets

[0275] Active ingredient: Not applicable

[0276] Strength / Concentration: Not applicable

[0277] Excipients for placebo tablets (white): anhydrous lactose, microcrystalline cellulose, colloidal silica, magnesium stearate, opadry II 85F18422 (white)

[0278] Excipients for placebo tablets (pink): Anhydrous lactose, microcrystalline cellulose, colloidal silica, magnesium stearate, opadry II (pink)

[0279] Description: 24 white tablets, followed by 4 pink tablets.

[0280] Dosage selection and timing for each subject

[0281] Each participant will receive either LPRI-CF113 or a matched placebo for the first three cycles of treatment in the trial. Afterward, each participant will receive an additional three cycles of LPRI-CF113 for active treatment. The first visit (LPRI-CF113 / placebo) and the third visit (LPRI-CF113) will provide a three-cycle medication package and one backup cycle. Investigators will provide detailed instructions on medication use based on the information in the participant information sheet.

[0282] The subject must take the first tablet on the day of the next menstrual bleeding following the first visit (1b). If menstrual bleeding begins in the evening and the subject prefers to take the medication in the morning, she may begin her first IP intake on the second day of her menstrual bleeding. From day 1 to day 28 of the treatment cycle, one tablet should be pushed out of the blister pack and swallowed whole once daily. The tablets must be taken at approximately the same time each day, so that the interval between two tablet intakes is always 24 hours. The tablets should be taken in the order shown on the blister pack. The first tablet of the next blister pack is taken directly the day after the last tablet of the previous blister pack is taken, i.e., there is no break in the medication, and regardless of whether bleeding has occurred, stopped, or is still continuing. Each treatment cycle will begin on the same day of the week. IP administration will continue in this manner for a total of 6 treatment cycles.

[0283] If any bleeding or spots occur, IP administration should continue. In cases of unusually severe bleeding, the subject should consult the investigator for a definitive diagnosis. Hormone treatments for bleeding are not permitted during the trial, as this may affect the results.

[0284] If a dose of IP is missed, the missed tablet should be taken as soon as it is remembered, even if this means taking two tablets at the same time. The next tablet should be taken at the usual time. If vomiting or diarrhea occurs within 3 to 4 hours after taking the tablet, a new (replacement) tablet should be removed from the blister pack as soon as possible. If possible, the new (replacement) tablet should be taken within 12 hours of the usual time of tablet administration. If more than one dose is missed, the last missed tablet (only one) should be taken. Other missed tablets (one or more) should remain in the blister pack.

[0285] Reference List

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[0287] Casper, RF (2017). "Progestin-only pills may be a better first-linetreatment for endometriosis than combined estrogen-progestin contraceptivepills." Fertil Steril 107(3): 533-536.

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[0289] 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.

[0290] Vercellini, P, Viganò, P, Somigliana, E and Fedele, L (2014). "Endometriosis: pathogenesis and treatment." Nature Reviews Endocrinology 10(5): 261-275.

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[0296] Rose, JG, Chrisler, JC and Couture, S (2008). "Young women'sattitudes toward continuous use of oral contraceptives: the effect of primingpositive attitudes toward menstruation on women's willingness to suppressmenstruation." Health Care Women Int 29(7): 688-701.

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[0300] 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.

[0301] Wiegratz, I, Hommel, HH, Zimmermann, T and Kuhl, H (2004). "Attitudeof German women and gynecologists towards long-cycle treatment with oralcontraceptives." Contraception 69(1): 37-42.

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[0303] Palacios, S, Colli, E and Regidor, PA (2019). "Multicenter, phase IIItrials on the contraceptive efficacy, tolerability and safety of a newdrospirenone-only pill." Acta Obstet Gynecol Scand 98(12): 1549-1557.

[0304] Kimble, Thomas, et al (2020). A 1-year prospective, open-label,single-arm, multicenter, phase 3 trial of the contraceptive efficacy andsafety of the oral progestin-only pill drospirenone 4 mg using a 24 / 4-dayregimen. Contraception: X, 2020, vol. 2, p. 100020.

[0305] Gerlinger et al. (2010). "Defining a minimal clinically importantdifference for endometriosis-associated pelvic pain measured on a visualanalog scale: analyzes of two placebo-controlled, randomized trials". Healthand Quality of Life Outcomes 2010, 8:138.

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[0307] The project of this invention

[0308] 1. Drospirenone in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, the method comprising administering drospirenone to said subjects in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase.

[0309] 2. The drospirenone in the method of claim 1 for treating endometriosis and / or endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea, wherein the daily dose of drospirenone is administered once daily from day 1 to day 24, and subsequently the lower daily dose of drospirenone is administered once daily from day 25 to day 28.

[0310] 3. The drospirenone in the 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 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.

[0311] 4. The drospirenone in the method of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea according to claims 1 to 3, wherein the lower 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.

[0312] 5. The drospirenone in the method of 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.

[0313] 6. Drospirenone in the method of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea according to claims 1 to 5, wherein said treatment also provides contraception.

[0314] 7. Use of drospirenone as a contraceptive, comprising administering drospirenone to a female subject in need of the contraceptive in a biphasic regimen, wherein a daily dose of drospirenone is administered to the subject in a first phase and a lower daily dose of drospirenone is administered to the subject in a second phase.

[0315] 8. The use of drospirenone according to claim 7, wherein the administration of drospirenone induces amenorrhea.

[0316] 9. Use of drospirenone according to claim 7 or 8, wherein the daily dose of drospirenone is administered once daily from day 1 to day 24, and subsequently a lower daily dose of drospirenone is administered once daily from day 25 to day 28.

[0317] 10. 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 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.

[0318] 11. Use of drospirenone according to any one of claims 7 to 10, wherein the lower 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.

[0319] 12. The use of drospirenone in the method according to any one of claims 1 to 6 and the use of drospirenone according to any one of claims 7 to 11, wherein the route of administration is selected from oral administration, transdermal administration or transmucosal administration, preferably oral administration.

[0320] 13. A contraceptive device, preferably a medication, comprising one or more packaging units, wherein each packaging unit contains at least 28 active daily dose units, wherein

[0321] a) At least 24 daily dose units contain a first amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and this amount is higher than the amount of drospirenone in daily dose units containing a second amount of drospirenone; and

[0322] b) At least four daily dose units contain a second amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and the amount of drospirenone is less than that of the daily dose units containing a first amount of drospirenone.

[0323] 14. The medical device of claim 13, wherein at least 28 active daily dose units do not contain estrogen.

[0324] 15. The contraceptive device according to claim 13 or 14, wherein drospirenone is the sole contraceptive active ingredient in at least 28 active daily dose units.

[0325] 16. The medical device 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.

[0326] 17. The medicine device 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.

[0327] 18. A pharmaceutical composition comprising drospirenone used in any of claims 1 to 6 for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects in need, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0328] 19. Use of drospirenone in a contraceptive composition according to any one of claims 7 to 12, wherein the composition further comprises one or more pharmaceutically acceptable excipients.

[0329] 20. The pharmaceutical composition of claim 18 or the contraceptive composition of claim 19, wherein the pharmaceutically acceptable excipient is at least one binder and at least one filler, and wherein:

[0330] (i) The amount of drospirenone is from 1% to 10% by weight.

[0331] (ii) at least one adhesive in an amount of 50% to 65% by weight, and

[0332] (iii) The amount of at least one filler is 25% to 35% by weight.

[0333] The weight percentage is related to the total weight of the pharmaceutical composition.

[0334] 21. The pharmaceutical composition of claim 20, further comprising at least one flow aid and at least one lubricant, wherein:

[0335] (iv) At least one glialant in an amount of 0.2% to 6% by weight, and

[0336] (v) The amount of at least one lubricant is from 0.2% to 0.6% by weight.

[0337] The weight percentage is related to the total weight of the pharmaceutical composition.

[0338] 22. The pharmaceutical composition or contraceptive composition according to claim 21, wherein:

[0339] (i) At least one binder is microcrystalline cellulose,

[0340] (ii) At least one filler is anhydrous lactose,

[0341] (iii) At least one flow aid is silica, and

[0342] (iv) At least one lubricant is magnesium stearate.

[0343] 23. Use of drospirenone as a contraceptive in the pharmaceutical composition of any one of claims 12 to 14, according to any one of claims 4 to 7.

Claims

1. A method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, the method comprising administering drospirenone to the subjects in a biphasic regimen, wherein 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, and wherein the lower 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.

2. The drospirenone in the method of claim 1 for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, 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.

3. Drospirenone in the method of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea according to claim 1 or 2, wherein the treatment also provides contraception.

4. Use of drospirenone as a contraceptive, comprising administering drospirenone in a biphasic regimen, wherein a daily dose of drospirenone is administered during a first phase and a lower daily dose of drospirenone is administered during a second phase, preferably wherein the administration of drospirenone induces amenorrhea.

5. Use of drospirenone according to claim 4, wherein the daily dose of drospirenone is administered once daily from day 1 to day 24, and subsequently a lower daily dose of drospirenone is administered once daily from day 25 to day 28.

6. The use of drospirenone according to claim 5, wherein 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.

7. Use of drospirenone according to any one of claims 4 to 6, wherein the lower 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.

8. A contraceptive device, preferably a medication, comprising one or more packaging units, wherein each packaging unit contains at least 28 active daily dose units, wherein a) At least 24 daily dose units contain a first amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and the amount is higher than the amount of drospirenone in daily dose units containing a second amount of drospirenone; and b) At least four daily dose units contain the second amount of drospirenone, wherein each of these daily dose units contains the same amount of drospirenone, and the amount of drospirenone is lower than that of the daily dose unit containing the first amount of drospirenone.

9. The contraceptive device according to claim 8, wherein the at least 28 active daily dose units do not contain estrogen, preferably wherein drospirenone is the only contraceptive active ingredient in the at least 28 active daily dose units.

10. The medical device according to any one of claims 8 or 9, 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.

11. The medicine device according to any one of claims 8 to 10, 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.

12. A pharmaceutical composition comprising drospirenone as used in any one of claims 1 to 3 for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, preferably wherein the pharmaceutically acceptable excipients are at least one binder and at least one filler, and wherein: (i) The amount of drospirenone is from 1% to 10% by weight. (ii) The amount of the at least one adhesive is from 50% to 65% by weight, and (iii) The amount of the at least one filler is 25% to 35% by weight. The weight percentage is related to the total weight of the pharmaceutical composition.

13. The pharmaceutical composition for use according to claim 12, further comprising at least one flow aid and at least one lubricant, wherein: (iv) The amount of the at least one gliding agent is from 0.2% to 6% by weight, and (v) The amount of the at least one lubricant is from 0.2% to 0.6% by weight. The weight percentage is related to the total weight of the pharmaceutical composition.

14. The pharmaceutical composition for use according to any one of claims 12 or 13, wherein: (i) The at least one adhesive is microcrystalline cellulose, (ii) The at least one filler is anhydrous lactose. (iii) The at least one flow aid is silica, and (iv) The at least one lubricant is magnesium stearate.

15. Use of drospirenone as a contraceptive according to any one of claims 4 to 7 in a pharmaceutical composition as defined in any one of claims 12 to 14.

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