Method and apparatus for providing efficient contraception

Abstract

The present invention relates to levonorgestrel for use in a method of providing contraception to a female subject comprising a sustained intravaginal administration of levonorgestrel of about 60-100 [mu] g / day. The invention further relates to levonorgestrel for use in a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea, comprising a sustained administration of levonorgestrel of about 60-160 [mu] g / day. Dosing devices, preferably vaginal rings, for carrying out these methods are also contemplated.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of women's health, more particularly to the use of levonorgestrel in a method of contraception that provides optimal estrogen suppression while achieving contraception. The present invention also relates to methods of treating endometriosis and related disorders, as well as drug delivery devices, such as vaginal rings, suitable for implementing these methods. BACKGROUND

[0002] Levonorgestrel (LNG) is a synthetic progestogen with no significant estrogenic activity and high progestogenic activity. It suppresses follicular stimulation and ovulation and reduces the permeability of cervical mucus to sperm. As a progestogenic component, levonorgestrel is widely used in a variety of registered contraceptive products worldwide, and is currently one of the most widely used progestogens in combined oral contraceptives (COCs). Cerazet® is an effective progestin-only pill (POP) containing 75 pg of desogestrel in a film-coated tablet (1), whose mechanism of action is mainly to inhibit ovulation. Traditional POPs exert their effects by thickening cervical mucus, delaying ovum transport, and creating an endometrial environment that is unfavorable for embryo implantation. Studies have shown that Cerazet® has an ovulation-inhibiting effect comparable to that of COC tablets. The POP dose of 0.075 mg desogestrel is high enough to inhibit ovulation in at least 98% of cycles, while a formulation containing 0.030 mg LNG can only inhibit ovulation in 72% of cycles (2, 3, 4). This is considered the most reliable mechanism of action of POPs due to sustained ovulation inhibition, and 0.075 mg desogestrel has a better contraceptive effect than 0.030 mg LNG and other low-dose POPs, and is comparable to the effect of COCs (5, 6). Although Cerazet® is a widely used product with a large amount of safety data, subjects receiving this treatment have reported adverse drug reactions such as abnormal bleeding. Therefore, there is a need in the clinic for other types of progestin-only contraceptives.

[0003] Long-acting implants containing only LNG have also been proven to be an effective method of contraception. For example, in a multicenter clinical study of 1393 women using Jadelle® implants, only 8 pregnancies occurred within 5 years (8, 9).

[0004] Ovulation inhibition is directly related to the steady-state blood concentration of levonorgestrel. However, the minimum threshold level of circulating LNG required to achieve contraceptive efficacy is still uncertain. According to early studies on the subcutaneous contraceptive implant Norplant® (Wyeth, Pfizer, New York), a blood LNG concentration of 0.3-0.4 ng / mL is often considered a threshold level, below which the contraceptive effect is reduced.

[0005] After implantation of the implant, mean blood LNG concentrations stabilized between 0.3 and 0.4 ng / mL, slowly declined to 0.28 ng / mL after 5 years of use, and to approximately 0.22 ng / mL (range 0.02-0.35 ng / mL) after 8 years of use. Studies have shown that the LNG concentration at the time of an unintended pregnancy was 0.21 ± 0.06 ng / mL.

[0006] With respect to the ovulation-inhibiting effect of levonorgestrel implants, during the first year of use, ovulation was inhibited in more than 85% of cycles due to the highest release rate of levonorgestrel (10). During the second and third years of use, the ovulation-inhibition rate decreased to approximately 65% of cycles, and during the last two years of use, luteal activity occurred in approximately 50% of cycles. During the 5 years of use of Norplant®, the mean serum estradiol levels of the subjects were similar to those of the control group, remaining in the range of 400-500 pmol / L (109-136 pg / mL).

[0007] Levonorgestrel implants achieve their contraceptive effect by changing the cervical mucus, inhibiting ovulation, and inducing ovulatory dysfunction. In the event of contraceptive failure, pregnancies occurring during use of levonorgestrel implants are more likely to be ectopic than pregnancies occurring during use of other contraceptives. However, due to the excellent contraceptive effect of levonorgestrel implants, the absolute incidence of ectopic pregnancy among users of Jadelle® (a new tradename for Norplant®) is very low.

[0008] Researchers have tested high-dose levonorgestrel-only progestin contraceptives in an attempt to develop a non-estrogen, highly reliable, and acceptable bleeding pattern contraceptive regimen (7). In the study, three groups of subjects (30 people each) were given 0.095 mg, 0.115 mg, and 0.135 mg of levonorgestrel daily for 56 days. The results showed that 0.115 mg of levonorgestrel daily was the minimum effective dose for achieving sustained ovulation inhibition. It is known that levonorgestrel is completely absorbed after oral administration, with a bioavailability close to 100% and without first-pass metabolism, as has been demonstrated, for example, in the commercial combined oral contraceptive containing levonorgestrel and ethinyl estradiol (Seasonique®).

[0009] A multi-center, open-label, single-arm study (NCT02403401) evaluated the contraceptive efficacy and safety of levonorgestrel (40 pg / day) released via an intravaginal ring (IVR). The LNG release rate and dose selection of the IVR in the study were aimed to achieve similar exposure levels as the approved low-dose LNG POP (Norgeston / Microlut, 30 pg / day) and the LNG implant (Norplant / Jadelle) after two years of use. However, the study was forced to terminate prematurely after only about one-third of the planned observation period was completed due to an unacceptably high pregnancy rate.

[0010] Thus, despite the well-established safety profile of levonorgestrel and the extensive experience with different doses, formulations, and delivery systems, the contraceptive efficacy of levonorgestrel as a monotherapy via a vaginal delivery system has not been demonstrated to date.

[0011] Another issue associated with progestin-only contraceptives is the menstrual disturbances caused by the lack of estrogen. This is in fact the most common reason for discontinuation of LNG implants (up to 45%) (11).

[0012] Although the mechanisms of bleeding associated with progestin-only contraceptives are not fully understood, it is known that the pattern of bleeding associated with progestin-only contraceptives depends on the degree of ovarian activity suppression. Typically, if ovulation continues to occur normally, the frequency of menstrual bleeding in women will correspond to their normal cycle characteristics; if ovulation and follicular development are completely suppressed, amenorrhea can result; if ovulation or follicular development (and estrogen secretion sufficient to stimulate endometrial growth) is irregular, irregular and unpredictable bleeding occurs (12).

[0013] Therefore, there is a clinical need for a progestin-only contraceptive that achieves a high contraceptive efficacy by suppressing ovulation, while at the same time providing a good bleeding pattern.

[0014] While increasing the dose in a levonorgestrel formulation can achieve sustained ovulation suppression, the ideal scenario is to achieve complete ovulation suppression using the lowest effective dose in order to improve the contraceptive efficacy while avoiding or mitigating side effects.

[0015] Estrogen suppression resulting from the administration of progestin-only formulations is one of the reasons for the occurrence of major side effects, which can trigger adverse low-estrogen side effects, in particular bone loss. Although there are differences in the sensitivity of different tissues to estradiol, it is generally accepted that an average estradiol concentration of 30-45 pg / mL is sufficient to prevent bone loss (13).

[0016] Reduction of estradiol blood concentrations has also been associated with improvement in other conditions, such as premenstrual syndrome, menorrhagia, and improvement in other conditions thought to be related to estrogen, such as uterine fibroids and subserosal endometrial polyps.

[0017] Estrogen suppression also has a direct impact on the development of endometriosis. Endometriosis is a chronic estrogen-dependent disease characterized by the presence of endometrial tissue outside the uterus, including the ovaries and other pelvic structures. These lesions elicit a chronic inflammatory response that can lead to scar tissue and adhesion formation. Patients with endometriosis often present with symptoms of dysmenorrhea, premenstrual pain, dyspareunia, and chronic fatigue (14), as well as less common symptoms of ovulatory pain, constipation, and painful urination (15). In addition, the presence of ectopic endometrium can lead to infertility, affecting up to 50% of women with endometriosis (16). Current technology indicates that controlling estradiol levels in the range of 40-60 pg / mL can be used to treat endometriosis.

[0018] Currently, there is no definitive cure for endometriosis. Patients still need to control the disease through continuous, coordinated, and supportive comprehensive management, while fully understanding the significant impact of the disease on quality of life. The main goals of treatment are to relieve pain and other symptoms, reduce ectopic endometrial lesions, and improve the patient's quality of life.

[0019] Currently, hormone therapy for endometriosis-related pain focuses on systemic or local estrogen suppression, suppression of tissue proliferation and inflammatory response, or both. Combined oral contraceptives (COCs) are widely used as first-line drugs for the treatment of dysmenorrhea or combined chronic pelvic pain, whether or not associated with suspected endometriosis, especially in adolescents with endometriosis (17). However, estrogen has a stimulating effect on the metabolic activity of the endometrial mucosa, so the use of combined oral contraceptives can lead to estrogen dominance, with a potential risk of lesion progression (18).

[0020] Progestin-only therapy is also used as first-line therapy for the treatment of endometriosis-associated pelvic pain and for suppressing the extent of ectopic endometrial lesions. Norethisterone acetate (NETA) (5 mg tablets) is a progestin approved by the Food and Drug Administration (FDA) for the treatment of endometriosis, secondary amenorrhea, and abnormal uterine bleeding. In principle, daily administration of 0.35 mg of norethisterone acetate for 28 consecutive days suppresses ovulation, but it is not approved for use as a contraceptive because the high dose required for the treatment of endometriosis (5-15 mg daily) is more than 10 times the dose required to suppress ovulation (0.35 mg daily). This high-dose treatment can be continued for a maximum of 6-9 months or needs to be temporarily terminated due to breakthrough bleeding. In addition, at such a high dose, NETA can produce androgen-like side effects such as acne, hirsutism, weight gain, and slight voice changes in some women.

[0021] Another approved progestin, dienogest (DNG), is a synthetic progestin that is 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. DNG at 2 mg daily suppresses ovulation but does not completely suppress ovarian activity and therefore is not approved for use as a contraceptive (19). Therefore, the official recommendation is to use a barrier contraceptive or other non-hormonal alternative when using DNG for the treatment of endometriosis (20).

[0022] None of the currently approved drugs for the treatment of endometriosis-associated pain have a contraceptive indication. In addition, the simultaneous use of hormonal contraceptives is not allowed with certain FDA- or European-approved drugs for the treatment of endometriosis, such as GnRH antagonists, such as the recently approved drug Elagolix, or progestin drugs such as dienogest. The reliance on barrier contraceptive methods can reduce adherence to these drugs and can increase the rate of discontinuation. Therefore, there is an urgent need for a therapy that can simultaneously treat endometriosis-associated pelvic pain (EAPP) for female patients seeking hormonal contraception.

[0023] It is therefore an object of the present application to provide a contraceptive method that has a very high ovulation suppression effect while controlling estrogen suppression at an optimal level (such as the level of the early follicular phase), thereby avoiding the known side effects of the prior art contraceptive with levonorgestrel as the active ingredient.

[0024] It is another object of the present application to provide a contraceptive method that has a very high ovulation suppression effect while being suitable for the treatment of endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea and other related estrogen-dependent diseases. SUMMARY

[0025] Thus, one aspect of the present application relates to the use of levonorgestrel for the manufacture of a method for providing contraception to a female subject, comprising continuously administering levonorgestrel to said subject, wherein the daily administration dose of levonorgestrel is about 60-100 μg / day, wherein the administration route is vaginal.

[0026] In one embodiment, the present application relates to a method for contraception using levonorgestrel in a female subject, comprising continuously administering levonorgestrel to said subject, wherein the average daily administration amount of levonorgestrel is about 75 μg / day, wherein the administration route is vaginal.

[0027] Another aspect of the present application relates to a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea using levonorgestrel in a female subject, comprising continuously administering levonorgestrel to said subject, wherein the daily administration amount of levonorgestrel is about 60-160 μg / day, wherein the preferred administration route is vaginal.

[0028] In one embodiment, the present application relates to a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea using levonorgestrel in a female subject, comprising continuously administering levonorgestrel to said subject, wherein the average daily administration amount of levonorgestrel is about 75-150 μg / day, wherein the preferred administration route is vaginal.

[0029] In one embodiment, the present application relates to a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea using levonorgestrel in a female subject, comprising continuously administering levonorgestrel to said subject, wherein the average daily administration amount of levonorgestrel is about 75 μg / day, about 125 μg / day or about 150 μg / day, wherein the preferred administration route is vaginal.

[0030] In one embodiment, the present application relates to the above method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea using levonorgestrel in a female subject, wherein said treatment has a contraceptive effect at the same time.

[0031] In one embodiment of the method of the present application, no other contraceptive component is administered to the female subject at the same time, preferably no estrogen is administered to the female subject at the same time.

[0032] In one preferred embodiment of the method of the present application, no other antiviral drug is administered to the female subject at the same time.

[0033] In a preferred embodiment of the method of the present application, the tenofovir is not administered concurrently to the female subject.

[0034] In an embodiment of the method of the present application, amenorrhea is induced concurrently with the administration of said levonorgestrel.

[0035] Another aspect of the present application relates to the use of levonorgestrel as a contraceptive, comprising the sustained administration of about 60-200 pg / day of levonorgestrel to a female subject, wherein the administration route is vaginal.

[0036] In an embodiment of this aspect, the present application relates to the use of levonorgestrel as a contraceptive, comprising the sustained administration of about 75-150 pg / day of levonorgestrel to a female subject, wherein the preferred administration route is vaginal.

[0037] In an embodiment of this aspect, the present application relates to the use of levonorgestrel as a contraceptive, comprising the sustained administration of about 75 pg / day, about 125 pg / day or about 150 pg / day of levonorgestrel to a female subject, wherein the preferred administration route is vaginal.

[0038] In a preferred embodiment, the administration route is transmucosal, preferably vaginal.

[0039] In an embodiment of the use of the present application, no other contraceptive component is administered concurrently to the female subject, preferably no estrogen is administered concurrently to the female subject.

[0040] In an embodiment of the use of the present application, amenorrhea is induced concurrently with the administration of said levonorgestrel.

[0041] In an embodiment of the use of the present application, no other antiviral drug is administered concurrently to the female subject.

[0042] In an embodiment of the use of the present application, no tenofovir is administered concurrently to the female subject.

[0043] Another aspect of the present application relates to a drug delivery device, the device comprising: (a) a core layer comprising a polymer; (b) a sheath layer substantially or completely surrounding said core layer, said sheath layer comprising a polymer; (c) levonorgestrel dissolved or dispersed in said core layer and / or said sheath layer, wherein the total amount of levonorgestrel present in said core layer and / or said sheath layer is between about 9 mg and 11 mg.

[0044] In a preferred embodiment, the total content of levonorgestrel in said core layer and / or sheath layer is about 10 mg.

[0045] In one embodiment, the polymer of the core layer is a polyurethane and the polymer of the sheath layer is an ethylene-vinyl acetate copolymer.

[0046] In one embodiment, the ethylene-vinyl acetate copolymer of the sheath layer has a vinyl acetate content of 10-40% w / w, preferably 15-30% w / w.

[0047] In another embodiment, the drug delivery device comprises: (a) a core layer comprising a polyurethane; (b) a sheath layer substantially or completely surrounding the core layer, the sheath layer comprising an ethylene-vinyl acetate copolymer having a vinyl acetate content of about 10-40% w / w, preferably about 15-30% w / w; (c) levonorgestrel dissolved or dispersed in the core layer and / or the sheath layer, wherein the total amount of levonorgestrel in the core layer and / or sheath layer is about 10 mg.

[0048] In another embodiment, the drug delivery device comprises: (a) a core layer comprising a polyurethane; (b) a sheath layer substantially or completely surrounding the core layer, the sheath layer comprising an ethylene-vinyl acetate copolymer having a vinyl acetate content of about 18% w / w; (c) levonorgestrel dissolved or dispersed in the core layer and / or the sheath layer, wherein the total amount of levonorgestrel in the core layer and / or sheath layer is about 10 mg.

[0049] In one embodiment of the drug delivery device, the device releases levonorgestrel at a constant rate over 28 days after administration to a female subject.

[0050] In one embodiment, the present invention relates to a drug delivery device containing levonorgestrel, said device having the following characteristics: when the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, it releases: no more than about 150 μg, preferably no more than about 130 μg, of levonorgestrel during the initial 24 hour release period; from about 60 μg to about 90 μg of levonorgestrel per day over at least 27 days after the initial 24 hour release period.

[0051] In one embodiment, the present invention relates to a drug delivery device containing levonorgestrel, said device having the following characteristics: when the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, it releases: about 70-150 μg, preferably about 70-130 μg levonorgestrel is released during the initial 24 hour release period; about 60-90 μg, preferably about 60-80 μg levonorgestrel is released per day over at least 27 days after the initial 24 hour release period.

[0052] In some embodiments, the average daily release of levonorgestrel over a 28 day treatment cycle, including the initial 24 hour release period and the 27 days after the initial 24 hour release period, is about 60-100 μg, preferably about 70-80 μg, more preferably about 75 μg / day.

[0053] In one embodiment, the release of levonorgestrel per day over a 28 day treatment cycle, including the initial 24 hour release period and the 27 days after the initial 24 hour release period, is not less than about 56 μg / day.

[0054] In another embodiment, the present application is directed to a drug delivery device containing levonorgestrel, said device having the following characteristics: when the device is tested in an in vitro release test in a 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, it releases: no more than about 250 μg levonorgestrel is released during the initial 24 hour release period, about 90-150 μg levonorgestrel is released per day over at least 27 days after the initial 24 hour release period.

[0055] In another embodiment, the present application is directed to a drug delivery device containing levonorgestrel, said device having the following characteristics: when the device is tested in an in vitro release test in a 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, it releases: about 100-200 μg, preferably about 110-170 μg levonorgestrel is released during the initial 24 hour release period, about 90-150 μg, preferably about 90-140 μg levonorgestrel is released per day over at least 27 days after the initial 24 hour release period.

[0056] In some embodiments, the average daily release of levonorgestrel over a 28 day treatment cycle, including the initial 24 hour release period and the 27 days after the initial 24 hour release period, is about 90-160 μg, preferably about 105-140 μg, more preferably about 125 μg / day.

[0057] In one embodiment, the amount of levonorgestrel released per day is not less than about 87 μg / day over a 28 day treatment cycle, including an initial 24 hour release period and the 27 days following the initial 24 hour release period.

[0058] In another embodiment, the present application relates to a drug delivery device containing levonorgestrel, said device having the following characteristics: when the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, it releases: not more than about 300 μg of levonorgestrel during the initial 24 hour release period, about 110-180 μg of levonorgestrel per day for at least 27 days following the initial 24 hour release period.

[0059] In one embodiment, the device releases: when the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, not more than about 250 μg of levonorgestrel during the initial 24 hour release period, preferably about 170-220 μg, about 110-180 μg of levonorgestrel per day for at least 27 days following the initial 24 hour release period, preferably about 120-170 μg.

[0060] In one embodiment, the average daily release of levonorgestrel is about 120-200 μg, preferably about 150 μg / day over a 28 day treatment cycle, including an initial 24 hour release period and the 27 days following the initial 24 hour release period.

[0061] In one embodiment, the amount of levonorgestrel released per day is not less than about 105 μg / day over a 28 day treatment cycle, including an initial 24 hour release period and the 27 days following the initial 24 hour release period.

[0062] In one embodiment, the release of levonorgestrel by the delivery device follows zero order kinetics after the initial 24 hour release period, i.e. the amount of levonorgestrel released per day is constant.

[0063] In one preferred embodiment, the delivery device releases levonorgestrel for a period of 28 days after placement in the body of an individual.

[0064] In one preferred embodiment, the delivery device of the present application does not contain other active ingredients.

[0065] In one preferred embodiment, the delivery device of the present application does not contain other contraceptive ingredients.

[0066] In a preferred embodiment, the delivery device according to the present application does not contain an antiviral drug.

[0067] In a preferred embodiment, the delivery device according to the present application does not contain tenofovir.

[0068] In another preferred embodiment, the delivery device does not contain an estrogen.

[0069] In one embodiment of the drug delivery device according to the present application, the levonorgestrel is present in the core layer in an amount of 0.20 to 1.00 wt% based on the total weight of the core layer.

[0070] In another embodiment, the sheath layer has a thickness of 5 to 500 μm, preferably about 50 to 200 μm.

[0071] In one embodiment of the drug delivery device according to the present application, after placing the delivery device intravaginally in a subject, the mean Cmax value of levonorgestrel is less than 1 ng / ml after one 28-day treatment cycle, less than 0.7 ng / ml after two 28-day treatment cycles, and the mean AUC (0-t) value of levonorgestrel is less than 350 h*ng / ml after one 28-day treatment cycle, and less than 370 h*ng / ml after two 28-day treatment cycles.

[0072] In another embodiment of the drug delivery device according to the present application, after placing the delivery device intravaginally in a subject, the mean Cmax value of levonorgestrel is less than 1.6 ng / ml after one 28-day treatment cycle, and less than 1 ng / ml after two 28-day treatment cycles, and the mean AUC (0-t) value of levonorgestrel is less than 580 h*ng / ml after one 28-day treatment cycle, and less than 540 h*ng / ml after two 28-day treatment cycles.

[0073] In another embodiment of the drug delivery device according to the present application, after placing the delivery device intravaginally in a subject, the mean Cmax value of levonorgestrel is less than 1.5 ng / ml after one 28-day treatment cycle, and less than 1 ng / ml after two 28-day treatment cycles, and the mean AUC (0-t) value of levonorgestrel is less than 480 h*ng / ml after one 28-day treatment cycle, and less than 540 h*ng / ml after two 28-day treatment cycles.

[0074] In one embodiment of the drug delivery device of the present application, the drug delivery device has a shape selected from the group consisting of helical (spiral) or annular, preferably the drug delivery device has an annular shape. In a preferred embodiment, the device is a vaginal ring. BRIEF DESCRIPTION OF DRAWINGS

[0075] Figure 1 In vitro dissolution profile of a levonorgestrel vaginal drug system at 75 μg / day.

[0076] Figure 2 In vitro dissolution profile of a levonorgestrel vaginal drug system at 125 μg / day.

[0077] Figure 3 In vitro dissolution profile of a levonorgestrel vaginal drug system at 150 μg / day.

[0078] Figure 4 Estradiol levels by visit and body mass index classification. The figure shows the mean estradiol levels by BMI category classification for all treatment groups over the treatment period.

[0079] Figure 5 Pharmacokinetic parameters of LNG. The figure shows the mean levonorgestrel concentration-time profile for subjects receiving 75 μg / day, 125 μg / day, and 150 μg / day of LNG VDS treatment.

[0080] Figure 6 Pharmacokinetic parameters of SHBG. The figure shows the mean LNG and SHBG concentration-time profile for subjects receiving 75 μg / day, 125 μg / day, and 150 μg / day of LNG VDS treatment, respectively.

[0081] Figure 7 Pharmacokinetic parameters of levonorgestrel by body mass index classification. The figure shows the mean LNG concentration-time profile for subjects receiving 75 μg / day, 125 μg / day, and 150 μg / day of LNG VDS treatment by BMI classification.

[0082] Figure 8 Pharmacokinetic parameters of SHBG by body mass index classification. The figure shows the mean LNG and SHBG concentration-time profile for subjects receiving 75 μg / day, 125 μg / day, and 150 μg / day of LNG VDS treatment by BMI classification, respectively.

[0083] Figure 9 Schematic representation of two drug delivery device shapes: (A) annular; (B) helical (spiral).

[0084] Figure 10Mean SHBG concentration-time profiles by BMI subgroups (BMI subgroup 1 : 30 < BMI < 35; BMI subgroup 2: BMI > 35) following vaginal administration of levonorgestrel vaginal delivery system (LVDS) over two 28-day treatment cycles (release rate of 75 pg / day), linear plot.

[0085] Figure 11 Mean plasma concentration-time profiles by body mass index (BMI) subgroups (BMI subgroup 1 : 30 < BMI < 35, N=12; BMI subgroup 2: BMI > 35, N=16) following vaginal administration of levonorgestrel vaginal delivery system (LVDS) at a release rate of 75 pg / day over two 28-day treatment cycles, linear plot, PPS. DETAILED DESCRIPTION

[0086] As mentioned previously, one of the objectives of the present application is to provide a contraceptive regimen with a very high ovulation-inhibiting efficacy, while keeping the level of estrogen inhibition within an optimal range, i.e. a level equivalent to that of the early follicular phase, thereby avoiding the well-known side effects induced by the contraceptive drugs of the prior art having levonorgestrel as active ingredient.

[0087] Thus, the inventors set out to develop a delivery device with the desired properties and conducted a multicenter, phase 2, open-label, randomized clinical trial to assess the ovulation-inhibiting efficacy of levonorgestrel (LNG) released from a vaginal delivery system (LNG VDS) at three different doses (75 pg / day, 125 pg / day and 150 pg / day) for 28 days and compared to the efficacy of oral desogestrel (Cerazet® ) in healthy female subjects aged 18-35 years.

[0088] The study comprised four phases: a screening period of minimum 4 weeks, maximum 8 weeks if a washout period was required, a pre-treatment cycle of 28 days, a treatment cycle of 56 days comprising two 28-day treatment cycles (TC1 and TC2) and a post-treatment cycle of 28 days.

[0089] Ovarian activity, and thus ovulation-inhibiting efficacy, was assessed by determining follicular growth, serum estradiol and progesterone concentrations in the subjects.

[0090] In addition, the effects of LNG VDS on cervical mucus, endometrial thickness, ovulation recovery at the post-treatment cycle, as well as the effects of LNG VDS on sex hormone levels and its safety and tolerability were assessed during the trial.

[0091] Overall, of the 268 subjects screened, 137 completed randomization and 130 initiated study treatment. Efficacy evaluations included 128 subjects in the Full Analysis Set (FAS) and 118 subjects in the Per-Protocol Set (PP). In the pharmacokinetic / pharmacodynamic (PK / PD) analysis, 55 subjects constituted the PK population (of which 14 had a BMI > 30 kg / m 2 , 41 had a BMI between 18 and 30 kg / m 2 ).

[0092] Results showed that in TC1, 127 / 128 (99.2%) subjects achieved ovulation suppression. The only subject who did not exhibit ovulation suppression was in the BMI > 18 and < 30 kg / m 2 group and received Cerazet® treatment. In TC2, all subjects achieved complete ovulation suppression (125 / 125 [100%]).

[0093] In TC1, 19 (57.6%), 17 (56.7%), 26 (76.5%) and 26 (83.9%) subjects in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively, exhibited no or minimal ovarian activity (Hoogland score 1-2); in TC2, 15 (48.4%), 19 (63.3%), 28 (84.8%) and 27 (87.1%) subjects in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively. In TC1, the number and proportion of subjects exhibiting residual ovarian activity (Hoogland score 3-4) in the Cerazet, LNG VDS 75, 125 and 150 treatment groups were 13 (39.4%), 13 (43.3%), 8 (23.5%) and 5 (16.1%), respectively; in TC2, the number and proportion of subjects exhibiting residual ovarian activity in the Cerazet, LNG VDS 75, 125 and 150 treatment groups were 16 (51.6%), 11 (36.7%), 5 (15.2%) and 4 (12.9%), respectively.

[0094] In TC1, only 1 (0.8%) subject had a positive Landgren test result, which was in the Cerazet treatment group. In TC2, no positive Landgren scores were observed in any of the groups.

[0095] In summary, the clinical trial data strongly suggest that levonorgestrel administered via the delivery device of the present application is effective in suppressing ovulation at all three release rates of 75 pg / day, 12 pg / day and 150 pg / day and is not influenced by the BMI of the subject.

[0096] Furthermore, the LNG VDS has a good safety profile and no serious treatment-related adverse events were observed during the trial.

[0097] Accordingly, one aspect of the present application relates to the use of levonorgestrel in a method of contraception in a female subject, comprising the continuous administration of levonorgestrel to said subject, wherein the daily amount of levonorgestrel administered is about 60-100 pg / day, and wherein the route of administration is vaginal.

[0098] In one embodiment, the average daily amount of levonorgestrel administered is about 75 pg / day, and wherein the route of administration is vaginal.

[0099] As mentioned before, previous studies have shown that 115 pg / day is the lowest effective dose known to achieve sustained suppression of ovulation when levonorgestrel is administered orally. Levonorgestrel is known to be completely absorbed after oral administration with a bioavailability close to 100% and without first-pass metabolism.

[0100] Surprisingly, it was found in the present application that levonorgestrel administered vaginally at a very low dose of 75 pg / day is able to completely or substantially completely suppress ovulation.

[0101] Ovarian suppression is known to be dose-dependent, the higher the dose of LNG, the stronger the ovarian suppression and the lower the estradiol levels. Surprisingly, 100% ovulation suppression was observed in all study groups, including subjects with a BMI of 30 kg / m 2 Using such a low dose of levonorgestrel has significant advantages and is therefore expected to have lower side effects.

[0102] As mentioned before, estrogen suppression caused by progestin-only formulations is one of the reasons for the major side effects and can trigger adverse low-estrogen side effects, in particular bone loss. Although there are differences in the sensitivity of different tissues to estradiol, it is generally accepted that an average estradiol concentration in the range of 30-45 pg / ml is effective in preventing bone loss (13).

[0103] Therefore, a good balance between estrogen suppression and contraceptive effectiveness has to be established to ensure that the estradiol concentration is maintained in a certain safe range to avoid adverse side effects such as a decrease in bone density.

[0104] It was found that administration of about 75 pg / day of LNG resulted in an estrogen suppression that was within the desired safety range, i.e., above 30 pg / ml, after two treatment cycles.

[0105] Clinical trial data showed that the mean (SD) estradiol concentrations in the Cerazet, LNG VDS 75, 125, and 150 treatment groups were 97.1 (84.3) pg / mL, 59.3 (40.2) pg / mL, 37.3 (21.2) pg / mL, and 32.1 (12.1) pg / mL, respectively, in TC1; and 66.5 (41.6) pg / mL, 48.0 (21.4) pg / mL, 30.4 (10.4) pg / mL, and 26.8 (8.2) pg / mL, respectively, in TC2.

[0106] It was observed that the lower dose of 75 pg / day resulted in a lesser degree of estrogen suppression, and thus a lesser impact on bone loss, compared to the higher doses of 125 pg / day and 150 pg / day, after two cycles of administration of the three doses of levonorgestrel IVR.

[0107] In another embodiment, the reduction in estradiol blood plasma concentration is also associated with an improvement in other conditions, such as premenstrual syndrome, menorrhagia, and other conditions considered to be related to estrogen, such as uterine fibroids and subserosal endometrial polyps.

[0108] In particular, estrogen suppression is directly associated with an improvement in endometriosis. Estrogen plays a key role in the pathophysiological process of endometriosis, as it promotes the implantation of endometrial tissue in the peritoneum, exerts a proliferative and anti-apoptotic effect on endometrial cells, and stimulates local and systemic inflammatory responses (21, 22). Barbieri studies indicate that estradiol levels should be maintained at around 40-60 pg / ml for the treatment of endometriosis (13).

[0109] It was found that administration of about 75 pg / day of levonorgestrel resulted in an estrogen suppression that was within the desired range for the treatment of endometriosis, i.e., 40-60 pg / ml, after two treatment cycles.

[0110] Definitions As used herein, the term "amenorrhea" refers to the absence / lack / punctiform bleeding of a female subject, preferably a woman of childbearing age, for at least 56 days or two administration cycles.

[0111] As used herein, "burst release" refers to the non-uniform release rate of the active pharmaceutical ingredient over time, typically with a higher release rate at the initial stage of the device containing the active pharmaceutical ingredient being implanted into the tissue.

[0112] As used herein, "complete inhibition of ovulation" refers to a 100% inhibition of ovulation in a subject. "Substantially complete inhibition of ovulation" is understood to mean a 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% inhibition of ovulation in a subject.

[0113] As used herein, "contraceptive method" or "method of achieving contraception" refers to a method of preventing pregnancy.

[0114] As used herein, "dysmenorrhea" refers to the medical term for menstrual pain caused by uterine contractions. Primary dysmenorrhea refers to cyclically occurring pain, while secondary dysmenorrhea is caused by diseases of the reproductive system.

[0115] As used herein, the term "dispersion" refers to the formation of a dispersion of the active pharmaceutical ingredient(s) in the core polymer or sheath polymer, such that they are partially or completely suspended in solid particulate form and are surrounded by a continuous phase.

[0116] As used herein, the term "dissolution" refers to the formation of a solution of the active pharmaceutical ingredient(s) in the core polymer or sheath polymer, such that they are distributed in the core polymer or sheath polymer and form a homogeneous phase.

[0117] As used herein, 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, and one of the most common symptoms of this disease is pelvic pain, respectively. The present application encompasses all types of endometriosis, including superficial, cystic, deep infiltrating, abdominal wall and menstrual endometriosis. The therapeutic effect on endometriosis-associated pelvic pain (EAPP) can be assessed by different scoring scales, such as the Visual Analog Scale (VAS) or the Numerical Rating Scale (NRS), which are well known to the person skilled in the art (see, for example, Gerlinger et al. (2010) and Breivik et al. (2008)). Depending on the scoring scale used, for example, a difference of at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0 on a 0-10 NRS scale compared to the placebo group can be considered clinically meaningful and can bring a real benefit to the patient.

[0118] As used herein, "estrogen" refers to a class of steroid hormones that promote the development and maintenance of female sexual characteristics. Synthetic estrogens are known and are commonly used in oral contraceptives or to treat menopausal and menstrual disorders.

[0119] As used herein, the term "levonorgestrel" or "LNG" refers to levonorgestrel itself, CAS Registry Number 797-63-7, solvates, and derivatives or prodrugs.

[0120] As used herein, the term "post-treatment cycle" or "post-treatment" refers to the 28 days after the end of the treatment cycle, counting from the first day after LNG VDS removal or the first day after stopping oral Cerazet.

[0121] As used herein, "progestin-only contraceptive" or "progestin-only pill" (also referred to as "POP") refers to a tablet or contraceptive that contains only a progestin as the sole active contraceptive ingredient and does not contain any estrogen.

[0122] As used herein, "therapeutically effective amount" refers to the amount of a dose and regimen that is effective in achieving the intended therapeutic result, including but not limited to: significantly delaying the onset or progression of a disease; significantly reducing the severity of a single or multiple symptoms. The determination of a therapeutically effective amount is generally based on the therapeutic benefit of the active ingredient or pharmaceutical composition outweighing its potential toxicity or adverse effects.

[0123] As used herein, the term "treatment cycle (TC)" refers to a total of 56 days of consecutive treatment. Treatment cycle 1 (TC1) refers to the first 28-day cycle and treatment cycle 2 (TC2) refers to the second 28-day cycle.

[0124] As used herein, "treatment," "treating," or "treat" refer to: (i) preventing or delaying the onset of a disease, disorder, and / or condition in a subject that can be predisposed to the disease, disorder, and / or condition but does not yet experience or exhibit symptoms of the disease, disorder, and / or condition; (ii) inhibiting the disease, disorder, and / or condition, i.e., arresting or reducing the development or progression of the disease, disorder, and / or condition; and / or (iii) relieving the disease, disorder, and / or condition, i.e., causing regression of the disease, disorder, and / or condition. In certain embodiments, the term refers to ameliorating or eradicating a disease or symptoms associated with a disease.

[0125] As used herein, "vaginal administration" and "vaginally administering" are used interchangeably to refer to the administration of a compound, preferably levonorgestrel, through the vaginal mucosa. It is understood that "vaginal administration" does not include intrauterine administration, e.g., through an intrauterine device (IUD) implanted in the uterus. Vaginal administration can be through a device placed within the vagina, such as an intravaginal ring (IVR).

[0126] As used herein, "zero order" or "near zero order" means that the amount of drug released per unit time is substantially constant or constant over a given period of time. For purposes of the present application, the term "substantially constant amount" is defined using the Higuchi equation, see Journal Pharmaceutical Sciences 1963, vol. 52, 1145-1149.

[0127] Method of the invention One aspect of the present application relates to a method of contraception in a female subject using levonorgestrel, comprising continuously administering levonorgestrel to said subject, wherein the daily administration of levonorgestrel is about 60-100 μg / day.

[0128] In one embodiment, the present application relates to a method of contraception in a female subject using levonorgestrel, comprising continuously administering levonorgestrel to said subject, wherein the average daily administration of levonorgestrel is about 75 μg / day, wherein the administration route is vaginal.

[0129] Surprisingly, an average dose of 75 μg / day was found to achieve complete or substantially complete inhibition of ovulation when administered intravaginally. At the same time, the degree of estrogen suppression was found to be lower in the 75 μg / day vaginal group than in the higher dose groups tested after two treatment cycles, thereby effectively reducing the adverse side effects of estrogen suppression, such as bone loss.

[0130] It was further found that the estrogen suppression effect of an average administration of about 75 μg / day of levonorgestrel after two treatment cycles was in the desired range for the treatment of endometriosis (i.e. 40-60 pg / ml, as described above).

[0131] Accordingly, another aspect of the present application relates to a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female subject using levonorgestrel, comprising continuously administering levonorgestrel to said subject, wherein the daily administration of levonorgestrel is about 60-160 μg / day, preferably the administration route is vaginal.

[0132] In one embodiment, the present application relates to a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female subject using levonorgestrel, comprising continuously administering levonorgestrel to said subject, wherein the average daily administration of levonorgestrel is about 75-150 μg / day.

[0133] In one embodiment, the present application relates to a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female subject using levonorgestrel, comprising continuously administering levonorgestrel to said subject, wherein the average daily amount of levonorgestrel administered is about 75 μg / day, about 125 μg / day or about 150 μg / day, preferably the route of administration is vaginal administration.

[0134] In one embodiment, the average daily amount of levonorgestrel administered is about 75-125 μg / day.

[0135] In another preferred embodiment, the treatment has a simultaneous contraceptive effect. As mentioned before, the three doses tested in the clinical trial allowed complete or substantially complete inhibition of ovulation.

[0136] In one preferred embodiment of the method of the present application, the route of administration is transmucosal, preferably vaginal administration.

[0137] In another embodiment of the method of the present application, no other contraceptive component is administered to the female subject at the same time.

[0138] In one preferred embodiment of the method of the present application, no estrogen is administered to the female subject at the same time.

[0139] In one embodiment of the method of the present application, the administration of levonorgestrel as described above can induce amenorrhea.

[0140] Another aspect of the present application relates to the use of levonorgestrel for the preparation of a medicament for the treatment of other estrogen-dependent disorders, such as uterine fibroids and subserosal endometrial polyps.

[0141] Use Another aspect of the present application relates to the use of levonorgestrel as a contraceptive, comprising continuously administering to a female subject about 60-200 μg / day of levonorgestrel, wherein the route of administration is vaginal administration.

[0142] In one embodiment of this aspect, the present application relates to the use of levonorgestrel as a contraceptive, comprising continuously administering to a female subject an average of about 75-150 μg / day of levonorgestrel, wherein the route of administration is vaginal administration.

[0143] In one embodiment of this aspect, the present application relates to the use of levonorgestrel as a contraceptive, comprising continuously administering to a female subject an average of about 75 μg / day, about 125 μg / day or about 150 μg / day of levonorgestrel, wherein the route of administration is preferably vaginal administration.

[0144] In another embodiment of the application, the other contraceptive component is not administered simultaneously to the female subject, preferably the estrogen is not administered simultaneously.

[0145] In one embodiment of the application, the administration of the levonorgestrel induces amenorrhea.

[0146] In a preferred embodiment of the use of levonorgestrel for a method of treatment, more than 80% of the female subjects resume ovulation within 28 days after treatment. In comparison, only 69.7% of the female subjects in the Cerazet treatment group resume ovulation within 28 days after treatment.

[0147] Device Another aspect of the application relates to a drug delivery device comprising: (a) a core layer comprising a polymer; (b) a sheath layer substantially or completely surrounding the core layer, the sheath layer comprising a polymer; (c) levonorgestrel dissolved or dispersed in the core layer and / or the sheath layer, wherein the total content of levonorgestrel in the core layer and / or the sheath layer is about 9-11 mg.

[0148] In one embodiment, the total content of levonorgestrel in the core layer and / or the sheath layer is about 10 mg.

[0149] In one embodiment of this aspect, the polymer is selected from the group consisting of low density polyethylene, ethylene-vinyl acetate copolymer, styrene-butadiene-styrene copolymer, polyurethane, poly(dimethylsiloxane) or silicone polyether amide copolymer, silicone, silicone-poly(carbonate urethane), poly(carbonate urethane) and silicone-poly(ether urethane), or combinations thereof.

[0150] In one embodiment, the polymer of the core layer is polyurethane and the polymer of the sheath layer is ethylene-vinyl acetate copolymer.

[0151] In one embodiment, the content of vinyl acetate in the ethylene-vinyl acetate copolymer of the sheath layer is 10-40% w / w, preferably 15-30% w / w.

[0152] In one embodiment, the application relates to a drug delivery device comprising: (a) a core layer comprising a polyurethane; (b) a sheath layer substantially or completely surrounding the core layer, the sheath layer comprising an ethylene-vinyl acetate copolymer (EVA) having a content of vinyl acetate of 10-40% w / w, preferably 15-30% w / w; (c) levonorgestrel dissolved or dispersed in the core layer and / or the sheath layer, wherein the total amount of levonorgestrel in the core layer and / or the sheath layer is about 10 mg.

[0153] In another embodiment, the delivery device comprises: (a) a core layer comprising a polyurethane; (b) a sheath layer substantially or completely surrounding the core layer, the sheath layer comprising an ethylene-vinyl acetate copolymer having a vinyl acetate content of about 18% w / w; (c) levonorgestrel dissolved or dispersed in the core layer and / or the sheath layer, wherein the total amount of levonorgestrel in the core layer and / or the sheath layer is about 10 mg.

[0154] The core layer of the device comprises a polyurethane. Polyurethanes (PU) are polymers made up of chains of organic units linked by urethane bonds. Examples of polyurethanes that can be used as the core layer polymer include, but are not limited to, aliphatic polyether-based thermoplastic polyurethanes, aliphatic hydrophilic polyether-based thermoplastic polyurethanes, aromatic polyether-based thermoplastic polyurethanes, aliphatic polycarbonate-based thermoplastic polyurethanes, aromatic polycarbonate-based thermoplastic polyurethanes, aromatic polyether-based polyurethane elastomers, thermoplastic polyether poly(urethane)s, thermoplastic silicone polyether polyurethanes, thermoplastic silicone polycarbonate polyurethanes, and hydrophilic thermoplastic polyurethane elastomers, or combinations thereof. Commercially available suitable polyurethanes include, but are not limited to, Tecophilic®, Tecoflex®, Tecothane®, Carbothane®, Chronothane®, Elasthane®, Pursil®, Hydrothane®, and PATHWAY®. Preferred polyurethanes are Hydrothane® AL25 80A and PATHWAY® PY-PT80AE25.

[0155] PATHWAY® PY-PT80AE25 is an aliphatic polyether-based thermoplastic polyurethane provided by LUBRIZOL.

[0156] Hydrothane® AL25 80A is as disclosed in US Patent US9872829 B2.

[0157] In one embodiment, the core layer contains at least 50% polyurethane. In one embodiment, the core layer contains at least 60% polyurethane. In one embodiment, the core layer contains at least 70% polyurethane. In one embodiment, the core layer contains at least 80% polyurethane. In one embodiment, the core layer contains at least 90% polyurethane. In one embodiment, the core layer contains at least 95% polyurethane. In one embodiment, the core layer consists essentially of polyurethane, i.e., the core layer contains 50-100%, more specifically 75-100%, polyurethane. The above percentages refer to weight percentages (weight of polyurethane / weight of core layer).

[0158] The core layer can also contain one or more of the following additives: release modifiers, including but not limited to polyethylene glycol, dextrose, glycine, ascorbic acid, hydroxyethylcellulose, crosscarmellose sodium, lactose; fillers, including but not limited to high surface area fumed / precipitated silica, clays such as kaolin, crushed quartz, diatomaceous earth, calcium carbonate, barium sulfate, iron oxide, titanium dioxide, and carbon black; antioxidants, including but not limited to octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (Irganox®), ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), citric acid (CA), butylated hydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), and alpha-tocopherol; lubricants, including but not limited to glycerol monostearate (irgawax), talc, fumed silica (aerosol), and stearates such as magnesium stearate; pharmaceutical excipients, including but not limited to water-soluble / water-swellable polysaccharides such as crosscarmellose sodium or hydroxyethylcellulose, dextrose, lactose or other mono- or disaccharides and their water-soluble salts, proteins such as gelatin, non-ionic surfactants, bile salts, organic solvents such as diethoxydiethylene glycol, polyethylene glycol, and fatty acid esters, or combinations thereof.

[0159] In the present application, the sheath layer "substantially surrounds the core layer" means that at least 90%, more specifically 95%, more specifically 100%, of the surface area of the core layer is surrounded by the sheath layer. In one preferred embodiment, the ethylene-vinyl acetate copolymer sheath layer completely surrounds the core layer.

[0160] As mentioned above, the sheath of the device comprises an ethylene vinyl acetate (EVA) copolymer. EVA is a semi-crystalline copolymer of ethylene and vinyl acetate (VA) monomers. The specific ethylene vinyl acetate copolymer used for the sheath depends on the desired drug flux and can be any commercially available ethylene vinyl acetate copolymer. In one embodiment, optionally in combination with any of the embodiments of the above or below described aspects, the sheath comprises EVA having a vinyl acetate (VA) content of 1-50% w / w, preferably 10-40% w / w, more preferably 15-30% w / w. In a preferred embodiment, the EVA sheath has a vinyl acetate content of 15-20% w / w, more preferably about 18% w / w.

[0161] For the purposes of the present application, the "vinyl acetate content" refers to the weight content of vinyl acetate based on the total weight of the ethylene vinyl acetate copolymer.

[0162] Suitable commercially available ethylene vinyl acetate copolymers include products under the trade names Elvax®, VitaIDose®, Evatane®, Lupolen V®, Movriton®, Ultrathene®, Ateva®, Vestypar®, Dupont 760, Equistar UE637-000, Huntsman PE1903 and F100309 (Exxon Mobil).

[0163] In one embodiment, the sheath comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% ethylene vinyl acetate. In one embodiment, the sheath consists essentially of ethylene vinyl acetate, i.e. the sheath comprises 50-100%, more preferably 75-100% ethylene vinyl acetate. The above percentages refer to weight percentages (percentage of ethylene vinyl acetate weight over the weight of the sheath).

[0164] The sheath layer can also include one or more of the following additives: release modifiers including, but not limited to, polyethylene glycol, dextrose, glycine, ascorbic acid, hydroxyethylcellulose, crosscarmellose sodium, lactose; fillers including, but not limited to, high surface area fumed / precipitated silica, clays such as kaolin, crushed quartz, diatomaceous earth, calcium carbonate, barium sulfate, iron oxide, titanium dioxide, and carbon black; antioxidants including, but not limited to, octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (Irganox®), ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), citric acid (CA), butylated hydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), and alpha-tocopherol; lubricants including, but not limited to, glycerol monostearate irgawax, talc, fumed silica aerosil, and stearates such as magnesium stearate; pharmaceutical excipients including, but not limited to, water soluble / water swellable polysaccharides such as crosscarmellose sodium or hydroxyethylcellulose, dextrose, lactose or other mono or disaccharides and their water soluble salts, proteins such as gelatin, non-ionic surfactants, bile salts, organic solvents such as diethoxydiethylene glycol, polyethylene glycol, and fatty acid esters, or combinations thereof.

[0165] In one specific embodiment, optionally in combination with one or more features of the above or below described individual embodiments, the core layer weight is 70-95 wt% of the total device weight, the sheath layer weight is 5-30 wt% of the total device weight, and the total device weight is 100%.

[0166] In one preferred embodiment, LNG is present in the core layer. In a more preferred embodiment, the concentration of LNG in the core layer is below its saturation concentration at 25°C.

[0167] The inventors have found that levonorgestrel has good solubility in the core polymer, especially at the concentrations described below. Thus, when LNG is present at a content below its saturation concentration, there is no crystallization tendency over time at any practical temperature. Therefore, the device of the present application is stable upon long term storage at room temperature, especially for at least 6 months. This feature avoids the need for expensive cryogenic storage and transportation.

[0168] In one preferred embodiment of the drug delivery device of the present application, the core layer comprises a hydrophilic thermoplastic polyurethane (preferably PATHWAY® PY-PT80AE25) and levonorgestrel at a concentration of 0.46 % w / w and 0.51 % w / w, and the sheath layer is a vinyl acetate content of 18% (w / w) ethylene-vinyl acetate copolymer (EVA) polymer.

[0169] The inventors have found that when the devices of the present application, and in particular the devices described above, are placed in tissue or in an in vitro release medium, levonorgestrel is released with zero-order or near zero-order kinetics, thereby minimizing potential blood plasma peak-trough fluctuations and side effects, while maximizing the time that the drug concentration is maintained within the therapeutic window (the effective concentration range). In the present application, "zero-order" or "near zero-order" release means that the amount of drug released per unit time is substantially constant or constant over a specified period of time. For purposes of the present application, "substantially constant" is defined using the Higuchi equation, see Journal Pharmaceutical Sciences 1963, vol. 52, 1145-114.

[0170] In addition, the devices described above also exhibit low initial burst properties. As previously described, "burst" refers to the non-uniform release rate of the active pharmaceutical ingredient over time, typically in the form of a higher release rate during a specified period of time, particularly during the initial period of time after the device containing the active pharmaceutical ingredient is implanted in tissue.

[0171] In one embodiment, the present application is directed to a levonorgestrel-containing drug delivery device having the following characteristics: when the device is tested in an in vitro release test in a 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, no more than about 150 μg, preferably no more than about 130 μg, of levonorgestrel is released during the initial 24 hour release period, about 60-90 μg of levonorgestrel is released per day for at least 27 days after the initial 24 hour release period.

[0172] In one embodiment, the present application is directed to a levonorgestrel-containing drug delivery device having the following characteristics: when the device is tested in an in vitro release test in a 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, about 70-150 μg, preferably about 70-130 μg, of levonorgestrel is released during the initial 24 hour release period, about 60-90 μg, preferably about 60-80 μg, of levonorgestrel is released per day for at least 27 days after the initial 24 hour release period.

[0173] In one embodiment, the device exhibits the following characteristics in the in vitro release test described above: about 90-140 μg of levonorgestrel is released during the initial 24 hour release period, about 65-80 μg of levonorgestrel is released per day for at least 27 days after the initial 24 hour release period.

[0174] In one aspect of the above embodiment, the levonorgestrel is released at least 56 μg over a 28 day period, preferably about 56-90 μg.

[0175] In one aspect of the above preferred embodiment, the levonorgestrel is released at no less than about 56 μg / day over a 28 day treatment cycle, including the initial 24 hour release period and the 27 days following the initial 24 hour release period.

[0176] Further, it is preferred that the average daily release of levonorgestrel is about 60-100 μg, preferably about 70-80 μg, more preferably about 75 μg / day over a 28 day treatment cycle, including the initial 24 hour release period and the 27 days following the initial 24 hour release period.

[0177] In one preferred embodiment, the present application is directed to a drug delivery device containing levonorgestrel, said device having the following characteristics: when the device is tested in an in vitro release test in 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, the levonorgestrel is released at no more than 250 μg over the initial 24 hour release period, the levonorgestrel is released at about 90-150 μg per day over at least 27 days following the initial 24 hour release period.

[0178] In another embodiment, the present application is directed to a drug delivery device containing levonorgestrel, said device having the following characteristics: when the device is tested in an in vitro release test in 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, the levonorgestrel is released at about 100-200 μg, preferably about 110-170 μg, over the initial 24 hour release period, the levonorgestrel is released at about 90-150 μg per day, preferably about 90-140 μg, over at least 27 days following the initial 24 hour release period.

[0179] In one preferred embodiment, the release characteristics of the device are as follows: when the device is tested in an in vitro release test in 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant: the levonorgestrel is released at no more than 220 μg over the initial 24 hour release period, the levonorgestrel is released at about 105-135 μg per day over at least 27 days following the initial 24 hour release period.

[0180] In one aspect of the above preferred embodiments, the levonorgestrel released on day 28 is more than about 85-95 μg.

[0181] In one aspect of the above preferred embodiments, the amount of levonorgestrel released per day over the 28 day treatment cycle, including the initial 24 hour release period and the 27 days following the initial 24 hour release period, is not less than about 87 μg / day.

[0182] In addition, preferably the average daily release of levonorgestrel over the 28 day treatment cycle, including the initial 24 hour release period and the 27 days following the initial 24 hour release period, is about 90-160 μg, preferably about 105-140 μg, more preferably about 125 μg / day.

[0183] In one preferred embodiment, the present application is directed to a levonorgestrel containing drug delivery device having the following characteristics: when the device is tested in-vitro in 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, the release profile is as follows: The amount of levonorgestrel released in the initial 24 hour release period is no more than 300 μg, The amount of levonorgestrel released per day over at least the 27 days following the initial 24 hour release period is about 110-180 μg.

[0184] In one preferred embodiment, when the device is tested in-vitro in 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, the release profile is as follows: The amount of levonorgestrel released in the initial 24 hour release period is no more than 250 μg, preferably about 170-220 μg, The amount of levonorgestrel released per day over at least the 27 days following the initial 24 hour release period is about 110-180 μg, preferably about 120-170 μg.

[0185] In one aspect of the above preferred embodiments, the levonorgestrel released on day 28 is more than about 100-110 μg, preferably more than about 105 μg.

[0186] In one embodiment, the amount of levonorgestrel released per day over the 28 day treatment cycle, including the initial 24 hour release period and the 27 days following the initial 24 hour release period, is not less than about 105 μg / day.

[0187] Furthermore, it is preferred that the average daily release of levonorgestrel over a treatment cycle of 28 days, including the initial 24 hour release period and the 27 days following the initial 24 hour release period, is in the range of about 120 to 200 μg, preferably about 150 μg per day.

[0188] In a preferred embodiment, the release of levonorgestrel from the delivery device follows zero order kinetics, i.e. the amount of levonorgestrel released per day is constant, after the initial 24 hour release period.

[0189] In one embodiment, "constant release" means that the amount of levonorgestrel released per day varies by a maximum of 20 to 25 %.

[0190] In a preferred embodiment, the intravaginal ring according to the present application does not contain further active ingredients.

[0191] In one embodiment of the drug delivery device according to the present application, the concentration of levonorgestrel in the core is in the range of about 0.20 to 1.00 wt% based on the total weight of the core.

[0192] In another embodiment, the sheath has a thickness in the range of about 5 to 500 μm, preferably about 50 to 200 μm.

[0193] In one embodiment of the drug delivery device according to the present application, the average Cmax value of levonorgestrel after one treatment cycle of 28 days, the average Cmax value of levonorgestrel after two treatment cycles of 28 days each, the average AUC (0-t) value of levonorgestrel after one treatment cycle of 28 days, and the average AUC (0-t) value of levonorgestrel after two treatment cycles of 28 days each, provided after placing the delivery device in the vagina of a female subject, are less than 1 ng / ml, less than 0.7 ng / ml, less than 350 h*ng / ml, and less than 370 h*ng / ml, respectively.

[0194] In another embodiment of the drug delivery device according to the present application, the average Cmax value of levonorgestrel after one treatment cycle of 28 days, the average Cmax value of levonorgestrel after two treatment cycles of 28 days each, the average AUC (0-t) value of levonorgestrel after one treatment cycle of 28 days, and the average AUC (0-t) value of levonorgestrel after two treatment cycles of 28 days each, provided after placing the delivery device in the vagina of a female subject, are less than 1.6 ng / ml, less than 1 ng / ml, less than 580 h*ng / ml, and less than 540 h*ng / ml, respectively.

[0195] In another embodiment of the drug delivery device of the application, the mean Cmax value of levonorgestrel is provided less than 1.5 ng / ml after one treatment cycle of 28 days, the mean Cmax value of levonorgestrel is provided less than 1 ng / ml after two treatment cycles of 28 days each; the mean AUC (0-t) value of levonorgestrel is provided less than 480 h*ng / ml after one treatment cycle of 28 days, the mean AUC (0-t) value of levonorgestrel is provided less than 540 h*ng / ml after two treatment cycles of 28 days each after the delivery device is placed intravaginally in the body of a subject.

[0196] In one embodiment of the drug delivery device of the application, the device has a shape selected from the group consisting of helical (spiral) or annular, preferably annular. Various shapes are shown in Figures Figure 9 (A) and (B). In a preferred embodiment, the device is a vaginal ring. More specifically, the annular device has an outer diameter of 50-60 mm, more preferably 52-56 mm, an inner diameter of 40-48 mm, more preferably 44-48 mm, a cross-sectional diameter of 2.5-8 mm, preferably 4 mm.

[0197] Preferably, the dosage form does not contain any estrogen, since although estrogens are beneficial for the contraceptive effect, they can have adverse effects on estrogen-induced diseases.

[0198] It is understood that any feature of the application described can be optionally combined with any embodiment of the medical or contraceptive use, composition, kit, contraceptive method, therapeutic method or manufacturing method of the application; any embodiment discussed in the specification can be applied to any of the above aspects. It is understood that the specific embodiments described herein are shown by way of illustration only and not as a limitation of the application.

[0199] All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0200] The use of "a" or "an" in the claims indicates "one," but also is consistent with the meaning of "one or more," "at least one," and "one or more than one." The use of "or" in the claims is used to mean "and / or" unless explicitly indicated to refer to alternatives selected from the group consisting of alternatives A or B. The use of "comprise", "comprises" or "comprising" in the claims indicates "includes", "contains" or "consists of", but also "consists essentially of" and "consist of".

[0201] In this specification and in the claims, the term "comprising" (as well as any form of comprising, such as "comprise" and "comprises") and "including" (as well as any form of including, such as "include" and "includes") or "containing" (as well as any form of containing, such as "contain" and "contains") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. The term "comprising" also encompasses the meaning of "consisting of" and "consisting essentially of." In the present invention, "consisting essentially of" limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. In the present invention, "consisting of" excludes any element, step, or ingredient not specified in the claim, except for impurities ordinarily associated with the element or limitations specified.

[0202] In the present invention, the term "or combinations thereof" means all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof' is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, if order is important in a particular context, also BCAB, CABAB, CABC, CACAB, ACABC, ABCAB, BACAB, ABCBA, ACBAC, ACBAC, BACBA, or BAABC. When an item is referred to as being "selected from the group consisting of" A, B, C, or combinations thereof, this is intended to mean that the item can be A, B, C, or any combination of these items, unless specifically stated otherwise in the specification.

[0203] In the present application, the terms "about", "around", "approximately" and the like refer to conditions which are not absolute or perfect, but which would be sufficiently close to be considered as having the condition by one of ordinary skill in the art. The extent of variation of the modified description will depend on the extent to which the variation still enables one of ordinary skill in the art to consider the modified feature as having the characteristics and capabilities required of the unmodified feature. In general, but subject to the preceding discussion, numerical values herein modified by "about" or the like can be varied by ±1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the stated value. Thus, the term "about" can refer to values ±5% of the stated value, preferably ±2% of the stated value, and most preferably the term "about" refers to the exact value of the stated value (±0%).

[0204] The following examples are intended to illustrate the present application and should not be construed as limiting the scope of the application.

[0205] Example Example 1 The vaginal delivery system (VDS) comprises the following composition: Table 1: Formulation composition of three different dosage strength VDS

[0206] Manufacturing process: Manufacturing of VDS comprises the following steps: (1) Polymer drying: thermoplastic polyurethane elastomer PY-PT80AE25 was dried in an air oven at 80°C for at least 6 hours.

[0207] (2) Mixing: materials were homogenously mixed using Glen Mills T2F tubular mixer. The materials were fed into the hopper in the following order: (a) thermoplastic polyurethane elastomer component A, (b) micronized levonorgestrel, (c) thermoplastic polyurethane elastomer component B, mixed at 13 rpm for 30 minutes.

[0208] (3) Synthesis: LNG was mixed into the thermoplastic polyurethane elastomer using Leistritz ZSE18 twin screw extruder. The dried mixed LNG and polymer were fed into the extruder through a gravity feeder and extruded through a wire die with circular holes. The processing zone of the extruder was set at 130-150°C and screw speed was set at 120-180 rpm. The extruded strands were cooled in a water bath and directly fed into a pelletizing device.

[0209] (4) Static pelletization: the cooled fibers were directly pulled by the pelletizing device and pelletized into 3.0 mm long pellets.

[0210] (5) Particle drying: The polymer particles loaded with APl are dried in an air dryer at 80°C for at least 4 hours.

[0211] (6) Blending: Mix the dry granules at 13 rpm for 5 minutes.

[0212] (7) Co-extrusion: API-loaded polymer granules are further extruded using a coaxial extrusion unit as the core material, and ethylene-vinyl acetate copolymer (VA content 18% w / w) granules are used as the sheath material. The coaxial extrusion unit includes two extruders, two melt pumps, a co-extrusion die, and connecting pipes. The core extruder process temperature is set at 130-150°C. Core material output is controlled by a melt pump set at 42%. The sheath extruder processing temperature is set at 120-150°C. Sheath material output is controlled by a melt pump set at 30 rpm. The core and sheath fibers exit the co-extrusion die and are cooled in a vertical water bath. The water temperature is set at 9°C.

[0213] (8) Strip cutting: The fiber is pulled out by the traction conveyor belt at a speed of 3.8 m / min and then cut into 157 mm segments / strips. The fiber diameter is continuously controlled at 4 mm by a laser diameter gauge.

[0214] (9) Welding: The ends of the two strips are joined by heat fusion. On a welding device, the ends of the 157mm long strips are fused together, forcing the fibers to form a ring structure, thereby creating an internal vaginal ring with a core-sheath structure. The ring has an outer diameter of 54mm, an inner diameter of 46mm, and a cross-sectional diameter of 4mm.

[0215] Down Figure 1 , 2 Tables 3 and 2-4 show the daily in vitro dissolution curves of the levonorgestrel vaginal rings described above at 75, 125, and 150 μg / day. The in vitro release rate of levonorgestrel from Example 1 was determined by immersing the sample in 200 mL (day 1) and 100 mL (days 2-28) of an aqueous solution containing 1.0% sodium dodecyl sulfate (SLS) surfactant in 0.2 M sodium acetate buffer, and adjusting the pH to 4.2 with continuous stirring at 60 rpm at 37°C. The concentration of levonorgestrel was determined daily by HPLC using a Waters XBridge C18 column at a flow rate of 1.0 mL / min and an injection volume of 25 μL, detected by UV at 240 nm.

[0216] Table 2: Individual data on in vitro dissolution profiles of LVDS at 75 μg / day

[0217]

[0218] Table 3: Individual data of 125 pg / day LVDS in-vitro dissolution profile

[0219]

[0220] Table 4: Individual data of 150 pg / day LVDS in-vitro dissolution profile

[0221] Example 2 A multicenter, phase 2, open-label, randomized clinical trial evaluated the ovulation-inhibiting effect of three doses of levonorgestrel (LNG) vaginal delivery system (VDS) for 28 consecutive days and compared it to desogestrel (Cerazet®). The specific details of the trial were as follows: 1. Test design 1.1. Purpose of the test Primary objective: To evaluate the ovulation-inhibiting effect of levonorgestrel (LNG) vaginal delivery system (VDS) in the first and second treatment cycles (TCs) by ovarian activity (follicle growth, serum estradiol and progesterone concentrations) and compared it to desogestrel (Cerazet).

[0222] Secondary objectives: To evaluate the effect of LNG VDS on cervical mucus and endometrial thickness.

[0223] To evaluate the effect of LNG VDS on sex hormone plasma concentrations.

[0224] To evaluate the safety and tolerability of LNG VDS and the recovery of ovulation in the post-treatment cycle.

[0225] 1.2. Study methods The trial was a multicenter, open-label, randomized phase 2 clinical trial designed to evaluate the ovulation-inhibiting effect of three different dose strengths (75 pg / day, 125 pg / day, and 150 pg / day) of LNG VDS for 28 consecutive days in healthy female subjects aged 18-35 years and compared it to desogestrel (Cerazet).

[0226] The trial comprised of 4 phases: Screening period: minimum of 4 weeks, maximum of 8 weeks if a washout period is required.

[0227] Treatment pre-cycle: 28 days and randomization.

[0228] Treatment period: 56 treatment days (2 cycles, 28 days per cycle).

[0229] Post-treatment period: 28 days.

[0230] A total of 268 subjects were screened, of whom 137 were randomized and 130 started study treatment (Safety Analysis Set or SAS). Efficacy was assessed in a total of 128 subjects constituting the Full Analysis Set or FAS and 118 subjects constituting the Per-Protocol Set or PP. For pharmacokinetic analysis, 55 subjects constituted the PK population (of whom 14 had a BMI > 30 kg / m 2 , 41 had a BMI between 18 and 30 kg / m 2 ).

[0231] 1.3 Test drug, dosage and mode of administration LNG VDS for vaginal administration were used. Each LNG VDS contained about 10 mg of LNG, designed to release at a rate of 75 μg / day, 125 μg / day or 150 μg / day, respectively. Each LNG VDS was intended for use for 28 days.

[0232] 1.4 Duration of treatment The treatment duration was 56 days, i.e. two consecutive treatment cycles (TC1 and TC2), each cycle being 28 days.

[0233] 1.5 Control treatment, dosage and mode of administration Desogestrel (Cerazet) 75 μg film-coated tablets were used as control medication, administered orally for 28 consecutive days in each cycle.

[0234] 2. Evaluation criteria 2.1. Primary efficacy criteria The determination of ovulation inhibition was made by calculating the Hoogland score, which combines the TVU-measured mm-level follicle size and the nmol / L-level bio-pregnane / estradiol serum concentrations. If ovulation was suspected to have occurred in TC1 or TC2 by ultrasound examination, confirmation was made by blood progesterone levels and expressed in the Landgren score.

[0235] Primary endpoint analysis: Ovulation inhibition (yes / no) was analyzed by logistic regression models to compare the effect of ovulation inhibition between the treatment groups, with BMI included as a covariate in the model. Adjusted odds ratios (ORs) and two-sided 95% CIs were calculated. No hypothesis testing was performed.

[0236] 2.2. Secondary efficacy criteria Insler score was assessed in the pre-treatment cycle, TC1, TC2 and post-treatment cycle when follicle diameter was > 13 mm.

[0237] Endometrial thickness was monitored by TVUs in all cycles.

[0238] Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone and SHBG were analyzed.

[0239] Resumption of ovulation was assessed in the post-treatment cycle.

[0240] Secondary endpoint analysis: Secondary efficacy parameters were described by treatment group and cycle using appropriate descriptive statistical methods for dichotomous, categorical or continuous variables. No hypothesis testing was performed.

[0241] 2.3 Safety criteria Vital signs; Laboratory analyses; Adverse event incidence (AEs); Cycle control and incidence of intermenstrual bleeding were assessed by recording the pattern of vaginal bleeding in the diary cards completed daily by the subjects.

[0242] 2.4 PK analysis The correlation of LNG PK with SHBG levels and ovulation inhibition was analyzed in a subset of all randomized subjects receiving LNG. This subset was derived from the total randomized population and included 12 subjects with BMI ≥ 18 and < 30 kg / m 2 and 7 subjects with BMI ≥ 30 kg / m 2 .

[0243] Pharmacokinetic parameters of LNG were determined in a subset of 55 subjects using LNG VDS to analyze the correlation with ovulation inhibition and SHBG levels. This subset included 41 subjects with BMI ≥ 18 and < 30 kg / m² and 14 subjects with BMI ≥ 30 kg / m².

[0244] 3. Statistical methods This study employed exploratory analysis, primarily using descriptive statistical methods. Furthermore, exploratory statistical tests and modeling were used to reveal key characteristics of the data. Descriptive statistics for continuous variables (such as Landgren score, Insler score, endometrial thickness, pituitary hormones, bleeding pattern, demographic and baseline characteristics, and safety parameters) presented at each planned visit included: number of participants (n), mean, median, standard deviation (SD), minimum, maximum, and 1st-3rd quantiles.

[0245] Baseline change, where applicable, is expressed as a 95% confidence interval (CI), calculated as the absolute change in the assessed visit value minus the baseline value. For categorical variables including binary variables, descriptive statistics include the absolute frequency (n), relative frequency (%), and number of missing data for each category at each planned visit.

[0246] 4. Treatment Results and Analysis 4.1. Primary efficacy assessment 4.1.1. Inhibit ovulation Table 5 shows the ovulation suppression results of each treatment group in different treatment cycles in FAS. In TC1, ovulation suppression was observed in 127 subjects (99.2%) across all treatment groups. Only one subject who received Cerazet treatment and had a body mass index (BMI) ≥18 and <30 kg / m² was affected. 2 No ovulation suppression was observed in the subjects in the previous study. In TC2, ovulation suppression was confirmed in all subjects regardless of treatment group or BMI.

[0247] Table 5: Ovulation suppression status by treatment cycle - logistic regression model

[0248] Adjusted odds ratio (95% CI) is not applicable. Note: Logistic regression model parameters with BMI as a covariate were used; ovulation-adjusted odds ratio (OR): yes vs no. Note: The analysis for each treatment cycle uses the highest score result within that cycle.

[0249] [1] Ovulation suppression is defined as a Hoogland score of 1-4 (including the boundary value); [2] %Calculated based on the total number of participants for each factor category; [3] Total includes results from Cycle 1 and Cycle 2. The combined Hoogland score was determined as follows: ovulation was assigned if ovulation occurred in either cycle (regardless of the other cycle result of no ovulation / missing); missing was assigned if both cycle data were missing; and no ovulation was assigned if one cycle had no ovulation and the other cycle data were missing.

[0250] 4.1.2 Hoogland Score vs. Landgren Score Table 6 shows the number and percentage of participants with no ovarian activity, residual ovarian activity, or high ovarian activity in each treatment cycle by treatment group and BMI category in the FAS.

[0251] Table 6: Hoogland Score - Body Mass Index Stratified Sensitivity Analysis by Treatment Cycle (Proportional Odds Model)

[0252] Adjusted odds ratio (95% CI) not applicable Note: Multinomial logistic regression proportional odds model with BMI as a covariate; high ovarian activity (including ovulation) was set as the reference group for Hoogland score.

[0253] Note: The analysis for each treatment cycle used the highest score result within the cycle.

[0254] [1] % calculated by the total number of subjects per factor category; [2] No or minimal ovarian activity: Hoogland score of 1 or 2.

[0255] [3] Residual ovarian activity: Hoogland score of 3 or 4.

[0256] [4] High ovarian activity (including ovulation): Hoogland score of 5 or 6.

[0257] [5] Total includes results from Cycle 1 and Cycle 2. The combined Hoogland score was determined as follows: ovulation was assigned if ovulation occurred in either cycle (regardless of the other cycle result or no ovulation / missing data); missing was assigned if both cycle data were missing; and no ovulation was assigned if one cycle had no ovulation and the other cycle data were missing.

[0258] In TC1, 88 (68.8%) subjects presented with no or minimal ovarian activity (Hoogland score 1 or 2), of which 19 (57.6%), 17 (56.7%), 26 (76.5%) and 26 (83.9%) received Cerazet, LNG VDS 75, 125 and 150, respectively; 39 (30.5%) subjects presented with residual ovarian activity (Hoogland score 3 or 4), of which 3 (39.4%), 3 (43.3%), 8 (23.5%) and 5 (16.1%) received Cerazet, LNG VDS 75, 125 and 150, respectively.

[0259] Only 1 (0.8%) subject using Cerazet presented with high ovarian activity (Hoogland score 5 to 6) in TC1.

[0260] In the ANCOVA model performed, the least square mean (95% CI) difference for the LNG VDS 75, 125 and 150 groups compared to the Cerazet group was -0.2 (0.30) (-0.8; 0.4), -0.6 (0.29) (-1.1; 0.0) and -0.7 (0.29) (-1.3; -0.2), respectively.

[0261] The analysis of Hoogland score by BMI subgroups showed that among subjects with BMI ≥ 18 and < 30 kg / m 2 , 77 (73.3%) presented with no or minimal ovarian activity; among subjects with BMI ≥ 30 kg / m 2 , 11 (47.8%) presented with no or minimal ovarian activity. Among subjects with BMI ≥ 18 and < 30 kg / m 2 , 27 (25.7%) presented with residual ovarian activity and among subjects with BMI ≥ 30 kg / m 2 , 11 (47.8%) presented with residual ovarian activity.

[0262] In the ANCOVA model performed, the least square mean (95% CI) difference for subjects with BMI ≥ 30 kg / m 2 compared to subjects with BMI ≥ 18 and < 30 kg / m 2 was 0.8 (0.27) (0.2; 1.3).

[0263] Among subjects with BMI ≥ 30 kg / m 2In the subgroup of subjects who had a BMI < 30 kg / m2, 74 (71.8%) subjects had no or minimal ovarian activity, 29 (28.2%) subjects had residual ovarian activity, and no subject had high ovarian activity. In the subgroup of subjects who had a BMI ≥ 30 kg / m2, 15 (68.2%) subjects had no or minimal ovarian activity, 7 (31.8%) subjects had residual ovarian activity, and no subject had high ovarian activity.

[0264] In TC2, a total of 89 (71.2%) subjects had no or minimal ovarian activity (Hoogland score of 1 or 2), and 36 (28.8%) subjects had residual ovarian activity (Hoogland score of 3 or 4).

[0265] By treatment group analysis, 15 (48.4%), 19 (63.3%), 28 (84.8%), and 27 (87.1%) subjects who received Cerazet, LNG VDS 75, 125, and 150, respectively, had no or minimal ovarian activity; 16 (51.6%), 11 (36.7%), 5 (15.2%), and 4 (12.9%) subjects, respectively, had residual ovarian activity.

[0266] No subject had high ovarian activity (Hoogland score of 5 to 6) during TC1. In the ANCOVA model performed, the least square mean (95% CI) difference for the LNG VDS 75, 125, and 150 groups compared to the Cerazet group was -0.4 (0.29) (-0.9; 0.2), -0.8 (0.29) (-1.4; -0.3), and -1.0 (0.29) (-1.6; -0.5), respectively.

[0267] The analysis of the Hoogland score by BMI group showed that in subjects with a BMI ≥ 18 and < 30 kg / m2, 74 (71.8%) had no or minimal ovarian activity; in subjects with a BMI ≥ 30 kg / m2, 15 (68.2%) had no or minimal ovarian activity. 2 In subjects with a BMI ≥ 18 and < 30 kg / m2, 29 (28.2%) had residual ovarian activity, and in subjects with a BMI ≥ 30 kg / m2, 7 (31.8%) had residual ovarian activity. 2 2 2

[0268] ​​​In the ANCOVA model performed, the difference in least square mean (95% CI) between the groups was 0.2 (0.27) (-0.4; 0.7) for subjects with BMI < 30 kg / m 2 The group of subjects was the control group, with BMI ≥ 30 kg / m 2 The difference in least square mean (95% CI) between the groups was 0.2 (0.27) (-0.4; 0.7) for subjects with BMI < 30 kg / m

[0269] In subjects with BMI ≥ 30 kg / m 2 Among subjects with BMI ≥ 30 kg / m 2 No subjects with BMI < 30 kg / m

[0270] In the full analysis set (FAS) TC1 and TC2, a total of 43 subjects (33.6% of subjects when their follicle size measured by TVU suggested suspected ovulation) underwent Landgren assessment (10 subjects [33.3%] in the LNG VDS 75 treatment group, 10 subjects [29.4%] in the LNG VDS 125 treatment group, 10 subjects [32.3%] in the LNG VDS 150 treatment group, and 13 subjects [39.4%] in the Cerazet treatment group). However, only 1 subject (0.8%) in the Cerazet treatment group had a positive result for this test. None of the participants who received LNG VDS had a positive result for the Landgren test.

[0271] 4.1.3 Ovarian follicle size Table 4 shows the follicle size in the different treatment cycles for each treatment group. In TC1, the mean (SD) size of the largest follicle was 10.2 (3.8) mm in 117 subjects in the FAS. Numerical differences were observed between the treatment groups: the mean size of the largest follicle was 11.7 (4.6) mm, 11.2 (4.2) mm, 9.4 (3.4) mm and 8.6 (2.1) mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively.

[0272] In TC2, the mean (SD) maximum follicle size was 9.8 (3.2) mm in the 111 subjects in the FAS. Numerical differences were also observed between treatment groups: the mean maximum follicle size was 12.0 (4.1) mm, 10.4 (3.5) mm, 8.7 (1.8) mm and 8.2 (1.3) mm for the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively.

[0273] In subjects with BMI ≥ 30 kg / m 2 (Table 12), the mean (SD) maximum follicle size was 11.5 (4.2) mm in TC1, (14.5 [5.5] mm, 11.0 [4.3] mm, 11.3 [3.2] mm and 9.2 [2.8] mm for the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively), slightly higher than in the overall population. In TC2, the mean (SD) maximum follicle size decreased to 9.8 (3.3) mm (12.5 [4.8] mm, 9.4 [3.1] mm, 8.8 [0.6] mm and 8.3 [0.4] mm for the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively), very close to the values observed in the overall population.

[0274] Table 7: Follicle size by treatment cycle

[0275] N: total number of subjects; n: number of subjects with BMI ≥ 30 4.1.4. Serum progesterone levels Serum progesterone levels were assessed every three days from Day 3 to Day 27 in TC1 and every three days from Day 3 to Day 27 and additionally on Day 29 in TC2. Progesterone levels were assessed by visit and treatment group in the FAS overall, in the subgroup of subjects with BMI ≥ 30 kg / m 2

[0276] ​In TC1, subjects receiving Cerazet treatment had higher serum progesterone levels than subjects receiving any of the three release rate LNG VDS treatments, with this difference being mainly observed on Day 21 (2.3 [8.7] nmol / L, 0.9 [0.5] nmol / L, 0.7 [0.6] nmol / L and 0.6 [0.5] nmol / L for the Cerazet, LNG VDS 75, 125 and 150 groups, respectively) and Day 24 (1.7 [6.1] nmol / L, 0.9 [0.5] nmol / L, 0.8 [0.7] nmol / L and 0.6 [0.5] nmol / L for the Cerazet, LNG VDS 75, 125 and 150 groups, respectively).

[0277] In TC2, the mean progesterone levels were relatively close across the treatment groups at all visit points. In subjects with BMI ≥ 30 kg / m2, although serum progesterone levels were generally lower than in the general population, no significant difference in progesterone levels was observed between the treatment groups of TC1 and TC2 at the study visits. 2 In subjects with BMI ≥ 30 kg / m2, although serum progesterone levels were generally lower than in the general population, no significant difference in progesterone levels was observed between the treatment groups of TC1 and TC2 at the study visits.

[0278] 4.1.5. Serum estradiol levels In TC1, serum estradiol levels were measured every three days from Day 3 to Day 27; in TC2, serum estradiol levels were measured every three days from Day 327 and an additional measurement was performed on Day 29. The results are presented in Table 8.

[0279] Table 8: Estradiol levels in treatment cycles

[0280] N: total number of subjects, n: number of subjects with BMI ≥ 30 In TC1, the mean (SD) estradiol concentration for the FAS was 56.6 (54.6) pg / mL (97.1 (84.3) pg / mL, 59.3 (40.2) pg / mL, 37.3 (21.2) pg / mL and 32.1 (12.1) pg / mL for the Cerazet, LNG VDS 75, 125 and 150 groups, respectively).

[0281] In the overall population, 7 subjects (5.5%) had a mean estradiol concentration <20 pg / mL (0 in the Cerazet group, 0 in the LNG VDS 75 group, 4 in the LNG VDS 125 group, and 3 in the LNG VDS 150 group [0.0%], 0 in the LNG VDS 75 group, 4 in the LNG VDS 125 group, and 3 in the LNG VDS 150 group [9.7%], respectively); another 27 subjects (21.1%) had a mean estradiol concentration ≥20 and <30 pg / mL (1 in the Cerazet group, 2 in the LNG VDS 75 group, 10 in the LNG VDS 125 group, and 14 in the LNG VDS 150 group [45.2%], respectively).

[0282] In TC2, the mean (SD) estradiol concentration was 42.7 (28.7) pg / mL (66.5 (41.6) pg / mL, 48.0 (21.4) pg / mL, 30.4 (10.4) pg / mL, and 26.8 (8.2) pg / mL in the Cerazet, LNG VDS 75, 125, and 150 groups, respectively).

[0283] In the overall population, 12 subjects (9.6%) had a mean estradiol concentration <20 pg / mL (0 in the Cerazet group [0.0%], 0 in the LNG VDS 75 group [0.0%], 4 in the LNG VDS 125 group [12.1%], and 8 in the LNG VDS 150 group [25.8%]); another 36 subjects (28.8%) had a mean estradiol concentration between 20 and 30 pg / mL (2 in the Cerazet group [6.5%], 8 in the LNG VDS 75 group [26.7%], 13 in the LNG VDS 125 group [39.4%], and 13 in the LNG VDS 150 group [41.9%]).

[0284] BMI ≥30 kg / m 2 In the test groups, the mean (SD) estradiol concentration of TC1 was 66.5 (53.1) pg / mL (123.6 (74.9) pg / mL, 58.7 (25.9) pg / mL, 50.2 (17.0) pg / mL, and 33.8 (20.3) pg / mL in the Cerazet, LNG VDS 75, 125, and 150 groups, respectively). No subjects in this group had a mean estradiol concentration <20 pg / mL, and 5 subjects (21.7%) had a mean estradiol concentration ≥20 and <30 pg / mL (0 subjects [0.0%], 0 subjects [0.0%], 0 subjects [0.0%], and 5 subjects [83.3%] in the Cerazet, LNG VDS 75, 125, and 150 groups, respectively).

[0285] The mean (SD) estradiol concentration for TC2 was 46.1 (29.9) pg / mL (75.5 (41.0) pg / mL, 44.6 (26.8) pg / mL, 35.4 (13.3) pg / mL, and 28.4 (8.3) pg / mL for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively). There was 1 subject (4.5%) in this group with a mean estradiol concentration <20 pg / mL (0 [0.0%], 0 [0.0%], 0 [0.0%], and 1 [16.7%] for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively); another 6 subjects (27.3%) had a mean estradiol concentration >20 and <30 pg / mL (1 [16.7%], 2 [50.0%], 0 [0.0%], and 3 [50.0%] for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively).

[0286] Figure 4 The mean estradiol levels for each treatment group by treatment cycle and BMI category are presented. The results show that the mean estradiol levels decreased from TC1 to TC2 for both BMI groups, but the decrease was greater for the BMI <30 kg / m2group than for the BMI >30 kg / m2group in TC1. 2 The serum estradiol levels were higher for subjects with a lower BMI.

[0287] 4.2. Secondary efficacy assessments 4.2.1. Insler score In the PP and FAS, the Insler score results were assessed by treatment group at the pre-treatment cycle, TC1, TC2, and post-treatment cycle visits. A total of 38 participants in the FAS completed the Insler score over the two treatment cycles.

[0288] In TC1, the mean (SD) maximum Insler score obtained was 4.6 (2.1), with 4.4 [1.8], 4.5 [1.8], 5.6 [2.7] and 3.5 [2.4] in the Cerazet, LNG VDS75, 125 and 150 treatment groups, respectively. Nine subjects (23.7%) had a maximum Insler score between 0 and 3, with 3 [20.0%] in the Cerazet, 3 [27.3%] in the LNG VDS 75, 125 and 150 treatment groups, and 1 [25.0%] in the LNG VDS 75, 125 and 150 treatment groups, respectively; 20 subjects (52.6%) had a maximum Insler score between 4 and 6, with 9 [60.0%] in the Cerazet, 6 [54.5%] in the LNG VDS 75, 125 and 150 treatment groups, and 3 [75.0%] in the LNG VDS 75, 125 and 150 treatment groups, respectively.

[0289] In TC2, the mean (SD) maximum Insler score obtained was 4.1 (2.1) points, with 4.2 [1.6], 3.7 [1.8], 5.0 [3.7] and 3.4 [2.7] in the Cerazet, LNG VDS75, 125 and 150 treatment groups, respectively. Thirteen subjects (34.2%) had a maximum score between 0 and 3, with 5 [29.4%] in the Cerazet treatment group, 4 [36.4%] in the LNG VDS 75, 125, and 150 treatment group, and 2 [40.0%] in the LNG VDS 75, 125, and 150 treatment group, respectively. Twenty-three subjects (60.5%) had a maximum score between 4 and 6, with 11 [64.7%] in the Cerazet treatment group, 7 [63.6%] in the LNG VDS 75, 125, and 150 treatment group, and 3 [60.0%] in the LNG VDS 75, 125, and 150 treatment group, respectively.

[0290] Among the 12 individuals with a BMI ≥30 kg / m² 2 Among the subjects (Table 15), the mean (SD) maximum Insler score obtained during TC1 was 5.8 (1.8), with scores of 5.4 [1.5], 4.5 [0.7], 7.3 [1.7], and 4.0 [NA] in the Cerazet, LNG VDS 75, 125, and 150 treatment groups, respectively. There were no subjects with a maximum score between 0 and 3, and 7 subjects (58.3%) had a maximum Insler score between 4 and 6, with 3 [60.0%], 2 [100.0%], 1 [25.0%], and 1 [100.0%] in the Cerazet, LNG VDS 75, 125, and 150 treatment groups, respectively.

[0291] During TC2, only 8 subjects completed the Insler score assessment with a mean (SD) maximum score of 3.6 (2.0) with Cerazet, LNG VDS 75, 125 and 150 treatment groups of 4.8 [0.5], 4.0 [NA], 5.0 [NA] and 0.5 [0.7] respectively. There were 2 subjects (25%) with an Insler score between 0-3 with Cerazet, LNG VDS 75, 125 and 150 treatment groups of 0 [0.0%], 0 [0.0%], 2 [100%] and 0 [0.0%] respectively; there were 6 subjects (75.0%) with an Insler score between 4-6 with Cerazet, LNG VDS 75, 125 and 150 treatment groups of 4 [100%], 1 [100%], 1 [100%] and 0 [0.0%] respectively.

[0292] 4.2.2. Ovulation recovery Ovulation recovery assessment in FAS (Table 9) showed that 104 of 127 subjects (81.9%) showed recovery of ovulation after treatment with Cerazet, LNG VDS 75, 125 and 150 treatment groups of 23 [69.7%], 24 [80.0%], 31 [93.9%] and 26 [83.9%] respectively; BMI ³ 18 and < 30 kg / m 2 of 86 (81.9%) showed recovery of ovulation with Cerazet, LNG VDS 75, 125 and 150 treatment groups of 20 [74.1%], 20 [69.0%], 25 [92.6%] and 21 [84.0%] respectively; of 22 subjects with BMI ³ 30 kg / m 2 of 18 (81.8%) showed recovery of ovulation with Cerazet, LNG VDS 75, 125 and 150 treatment groups of 3 [50.0%], 4 [100%], 6 [100%] and 5 [83.3%] respectively.

[0293] Table 9: Ovulation recovery (Full Analysis Set)

[0294] The same results were observed when assessing ovulation recovery in PP.

[0295] In FAS, the mean serum progesterone concentration (SD) at the post-treatment cycle assessment was 17.3 (15.3) pg / mL at OV+2, with 12.8 [11.0], 16.4 [13.5], 15.5 [12.3] and 24.7 [20.8] pg / mL for the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively, and 29.9 (14.9) pg / mL at OV+4, with 31.0 [13.5], 29.1 [17.7], 26.9 [11.7] and 33.4 [16.2] pg / mL for the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively. Similar results were obtained for the post-treatment cycle progesterone blood concentrations assessed in PP.

[0296] 4.2.3. Endometrial thickness Endometrial thickness was assessed to determine if there were changes in the endometrial layer that were not suitable for implantation. A thickness < 6 mm was considered unsuitable for pregnancy. This measurement was taken by TVUs to measure the double-layer distance of the longitudinal section of the uterus at each visit time point.

[0297] Overall subjects and the group of subjects with BMI ≥ 30 kg / m2were measured by TVU at pre-treatment, TC1, TC2 and at each study visit time point post-treatment, and the mean results at each visit time point and for each treatment group were analysed. 2

[0298] The mean (SD) endometrial thickness at the pre-treatment cycle was 7.8 (2.1) mm (8.2 [2.9], 7.2 [1.8], 7.9 [1.3] and 7.8 [1.9] for the Cerazet, LNG VDS 75, 125 and 150 groups, respectively).

[0299] The mean (SD) endometrial thickness at TC1 was 4.1 (1.1) mm (4.3 [1.3], 3.7 [0.9], 4.1 [0.8] and 4.1 [1.1] for the Cerazet, LNG VDS 75, 125 and 150 groups, respectively).

[0300] The mean (SD) endometrial thickness at TC2 was 3.8 (1.0) mm (3.9 [1.2], 3.3 [0.9], 3.9 [0.9] and 3.9 [1.0] for the Cerazet, LNG VDS 75, 125 and 150 groups, respectively).

[0301] ​The mean (SD) endometrial thickness after treatment was 7.0 (1.6) mm (6.7 [2.0], 6.7 [1.6], 7.3 [1.5] and 7.4 [1.3] for Cerazet, LNG VDS 75, 125 and 150 groups, respectively).

[0302] In the subgroup of subjects with BMI ≥ 30 kg / m 2 The mean (SD) endometrial thickness before treatment was 7.8 (2.1) mm (9.1 [1.7], 7.2 [0.9], 8.0 [1.5] and 9.1 [2.7] for Cerazet, LNG VDS 75, 125 and 150 groups, respectively) in the subgroup of subjects with BMI ≥ 30 kg / m2. In TC1, the mean (SD) thickness was 4.1 (1.1) mm (5.6 [1.7], 3.6 [0.7], 4.0 [0.6] and 4.6 [1.2] for Cerazet, LNG VDS 75, 125 and 150 groups, respectively). In TC2, the mean (SD) thickness was 3.8 (1.0) mm (4.9 [1.1], 3.9 [1.5], 3.6 [0.6] and 3.8 [1.4] for Cerazet, LNG VDS 75, 125 and 150 groups, respectively). After treatment (Table 20), the mean (SD) thickness was 7.0 (1.6) mm (6.9 [1.5], 6.9 [0.6], 6.4 [1.8] and 6.9 [1.7] for Cerazet, LNG VDS 75, 125 and 150 groups, respectively).

[0303] 4.2.4. Bleeding pattern Subjects were required to record daily vaginal bleeding in the diary cards. The results of the analysis of the presence or absence of bleeding and bleeding events for all participants are presented below.

[0304] In TC1, only 1 (0.8%) subject (from the LNG VDS 75 treatment group) had no bleeding throughout the cycle. The mean (SD) number of days of bleeding (of any type) was 12.0 (6.0) days (10.7 (4.9), 11.5 (6.4), 11.6 (6.4), and 11.3 (6.3) for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively). The mean (SD) number of days of spotting was 6.2 (4.7) days (5.5 (4.4), 6.8 (5.6), 5.9 (4.0), and 6.9 (5.0) for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively). The mean (SD) number of days of minor bleeding was 3.4 (2.8) days (3.2 (2.4), 2.8 (2.1), 4.6 (3.9), and 2.8 (1.8) for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively).

[0305] In TC2, a total of 22 (17.6%) subjects had no bleeding (3 [9.7%], 8 [26.7%], 8 [24.2%], and 3 [9.7%] for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively). The mean (SD) number of days of bleeding was 14.1 (8.9) days (12.5 (6.7), 13.0 (8.2), 17.9 (9.7), and 13.2 (10.2) for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively). The mean (SD) number of days of spotting was 9.2 (7.1) days (7.4 (5.1), 9.3 (8.1), 10.3 (6.8), and 9.7 (8.1) for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively). The mean (SD) number of days of minor bleeding was 5.8 (4.7) days (5.1 (4.0), 3.3 (2.3), 8.0 (5.2), and 6.3 (5.6) for the Cerazet, LNG VDS 75, 125, and 150 groups, respectively).

[0306] 5. Efficacy conclusion FAS enrolled a total of 128 participants.

[0307] The primary endpoint analysis showed that all subjects who received LNG VDS treatment exhibited ovulation suppression in both TCs. Except for 1 subject with a BMI of 18-30 kg / m 2All subjects receiving Cerazet treatment also showed ovulation suppression during both treatment cycles, except for subjects in the TC1 range who ovulated outside the TC1.

[0308] In TC1, ovarian activity results measured by Hoogland score showed that 69% of subjects had no or only very slight ovarian activity, with this proportion being as high as 84% for the group of subjects receiving LNG VDS 150 treatment; 31 % of subjects showed residual ovarian activity, with this proportion being higher for subjects receiving LNG VDS 75 treatment (43%). Also, more subjects with a BMI ≥ 30 kg / m 2 2 compared to subjects with a BMI ≥ 18 and < 30 kg / m 2 2 but this proportion was higher if subjects with a BMI ≥ 30 kg / m 2 compared to subjects with a BMI ≥ 18 and < 30 kg / m 2 During TC2, the proportion of participants with no or minimal ovarian activity was higher in the overall population compared to TC1 (71 % vs 68%) and also higher in participants with a body mass index ≥ 30 kg / m 2 compared to subjects with a BMI ≥ 18 and < 30 kg / m 2

[0309] ANCOVA models showed that there was a statistically significant difference between subjects receiving LNG VDS 150 treatment and subjects receiving Cerazet treatment with a difference of 1 point in Hoogland score during TC2 (1.8 vs 2.8, respectively), and a difference of 0.7 points in Hoogland score between subjects receiving LNG VDS 125 treatment and subjects receiving Cerazet treatment (2.1 vs 2.8, respectively).

[0310] Landgren score results confirmed that only 1 subject receiving Cerazet treatment ovulated in TC1.

[0311] In TC1, the mean (SD) size of the largest follicle was 10.2 (3.8) mm, with subjects receiving Cerazet treatment and subjects receiving LNG VDS 75 treatment having higher values (11.7 [4.6] and 11.2 [4.2] mm, respectively) than subjects receiving LNG VDS 125 and 150 treatment (9.4 [3.4] and 8.6 [2.1] mm, respectively). The same trend was observed in TC2, with similar results.

[0312] In subjects with a BMI ≥ 30 kg / m 2In subjects with a BMI ≥ 30 kg / m

[0313] In the later visits of TC1, serum progesterone concentrations were higher in subjects treated with Cerazet than in the LNG VDS treatment groups; in TC2, there were no significant differences in serum progesterone concentrations between the treatment groups.

[0314] In subjects with a BMI ≥ 30 kg / m 2 In subjects with a BMI ≥ 30 kg / m

[0315] For mean estradiol concentrations, the overall value in TC1 was 56.6 (54.6) pg / mL, but the value in the Cerazet treatment group (97.1 [84.3] pg / mL) was higher than in the LNG VDS 75, 125, and 150 groups (59.3 [40.2], 37.3 [21.2], and 32.1 [12.1] pg / mL, respectively). The same trend was observed in TC2, but estradiol concentrations were lower in all groups than in TC1. Notably, the proportion of subjects with estradiol concentrations < 20 pg / mL and < 30 pg / mL was significantly higher in the LNG VDS 125 and 150 treatment groups than in the LNG VDS 75 group and the Cerazet group. The same trend was observed in subjects with a BMI ≥ 30 kg / m 2

[0316] The maximum mean Insler score obtained in TC1 and TC2 was 4.6 and 4.1, respectively. In both periods, subjects treated with LNG VDS 150 had the lowest maximum score (3.5 in TC1 and 3.4 in TC2) of the four treatment groups. In both treatment periods, no subject had a cervical mucus condition that was favorable for sperm penetration (maximum Insler score 10-12); only 1 subject (treated with Cerazet) had a condition that was moderately favorable for sperm penetration (maximum Insler score 7-9) in treatment period 2. In subjects with a BMI ≥ 30 kg / m 2 The maximum Insler score in TC1 (5.8) was higher than in the overall population, and no subject had a mean score between 0-3. In this subgroup, no subject had a maximum Insler score of 10-12 in either treatment period; only 3 subjects treated with LNG VDS 125 and 2 treated with Cerazet had an Insler score of 7-9 in TC1.​

[0317] After treatment, more than 80% of subjects resumed ovulation (resumption rates were 80.8%, 93.9% and 83.9% for the LNG VDS 75, 125 and 150 treatment groups, respectively, and 69.7% for the Cerazet treatment group).

[0318] Pharmacokinetic evaluation In a subset of 55 subjects using LNG VDS, pharmacokinetic parameters of LNG and SHBG levels were determined; 41 subjects had a BMI between 18-30 kg / m 2 (LNG VDS 75, 125 and 150 treatment groups had 15, 14 and 12 subjects, respectively) and 14 subjects had a BMI ≥ 30 kg / m 2 (LNG VDS 75, 125 and 150 treatment groups had 3, 7 and 4 subjects, respectively).

[0319] Figure 2 and Figure 3 show the mean concentration-time profiles of LNG and SHBG for subjects in the LNG VDS 75, 125 and 150 treatment groups, respectively; Figure 4 and Figure 5 show the same parameters (mean concentration-time profiles of LNG and SHBG) categorized by BMI.

[0320] 5.1. Pharmacokinetics of levonorgestrel in LNG VDS 75, 125 and 150 treatment groups Plasma levonorgestrel concentrations were detected at the first sampling point (2 hours after insertion) in all subjects, all cycles, and all dose levels after insertion of LNG VDS releasing doses of 75, 125 and 150 μg / day.

[0321] In TC1, Tmax values were observed at 116, 123 and 113 hours after dosing for the 75, 125 and 150 μg / day dose groups, respectively. In subjects with a BMI ≥ 18 and < 30 kg / m 2 , Tmax values observed after the 75, 125 and 150 μg / day doses were 115, 110 and 98.667 hours, respectively; in subjects with a BMI ≥ 30 kg / m 2 , Tmax values observed after the 75, 125 and 150 μg / day doses were 120, 150 and 156 hours, respectively.

[0322] After reaching peak plasma concentrations of LNG at Tmax, plasma levels remained elevated with minimal peak-to-trough fluctuation, representing a long-acting release of LNG in TC1 at all dose levels and all BMI categories.

[0323] In TC1, the total maximum plasma concentrations (Cmax) observed in the 75, 125, and 150 μg / day dose groups were 0.950, 1.548, and 1.426 ng / mL, respectively. This was observed in individuals with a BMI ≥18 and <30 kg / m². 2 In the subjects with a BMI ≥30 kg / m², the Cmax values ​​were 1.011, 1.829, and 1.539 ng / mL, respectively; in the subjects with a BMI ≥30 kg / m², the Cmax values ​​corresponding to the 75, 125, and 150 μg / day dose groups were 0.647, 0.987, and 1.090 ng / mL, respectively.

[0324] In TC1, the AUC(0-t) observed in the 75, 125, and 150 μg / day dose groups were 340, 571, and 468 h*ng / mL, respectively. In the BMI ≥18 and <30 kg / m² category, the AUC(0-t) values ​​were 357, 662, and 490 h*ng / mL, respectively; in subjects with a BMI ≥30 kg / m², the AUC(0-t) values ​​for the 75, 125, and 150 μg / day dose groups were 253, 389, and 403 h*ng / mL, respectively.

[0325] In TC1, the overall clearance values ​​measured after extravascular administration of 75, 125, and 150 μg / day of LNG VDS were 76.383, 96.103, and 106.000 mL / h, respectively. In subjects with a BMI ≥18 and <30 kg / m², the clearance values ​​were 66.816, 84.964, and 101 mL / h, respectively; and in subjects with a BMI ≥30 kg / m², the clearance values ​​were 119, 125, and 123 mL / h, respectively.

[0326] In TC1, the apparent volumes of distribution (VDCs) of 75, 125, and 150 μg / day of LNG VDS administered via extravascular route were 101, 96.294, and 103 L, respectively. In subjects with a BMI ≥18 and <30 kg / m², the apparent VDCs were 99.117, 85.227, and 94.116 L, respectively; and in subjects with a BMI ≥30 kg / m², the apparent VDCs were 111.991, 124.941, and 140.244 L, respectively.

[0327] In TC2, the overall Tmaxobserved for levonorgestrel was 283, 192 and 192 hours after dosing for the 75, 125 and 150 pg / day dose groups, respectively. In subjects with BMI > 18 and < 30 kg / m2, the Tmaxvalues observed were 269, 156 and 199 hours for the 75, 125 and 150 pg / day dose groups, respectively. In subjects with BMI > 30 kg / m2, the Tmaxvalues observed were 352, 276 and 174 hours for the 75, 125 and 150 pg / day dose groups, respectively.

[0328] After the Tmax, the plasma concentration of LNG reached a peak, and then the plasma drug concentration of all dose levels and all BMI categories of subjects remained elevated throughout the second treatment cycle (TC2) with minimal peak-to-trough fluctuation, which represents the sustained release characteristics of levonorgestrel throughout the cycle.

[0329] In TC2, the overall maximum plasma concentration observed was 0.654, 0.987 and 0.925 ng / mL for the 75, 125 and 150 pg / day dose groups, respectively. In subjects with BMI > 18 and < 30 kg / m2, the Cmaxvalues were 0.695, 1.085 and 0.995 L, respectively; in subjects with BMI > 30 kg / m2, the Cmaxvalues observed for the 75, 125 and 150 pg / day dose groups were 0.449, 0.757 and 0.842 ng / mL, respectively.

[0330] In TC2, the overall AUC(0-t) observed was 363, 538 and 505 h*ng / mL for the 75, 125 and 150 pg / day dose groups, respectively. In subjects with BMI > 18 and < 30 kg / m2, the AUC(0-t) values were 382, 584 and 517 h*ng / mL, respectively; in subjects with BMI > 30 kg / m2, the AUC(0-t) values observed for the 75, 125 and 150 pg / day dose groups were 269, 432 and 473 h*ng / mL, respectively.

[0331] In TC2, the overall clearance values observed after extravascular administration of the 75, 125 and 150 pg / day LNG VDS were 25.705, 75.382 and 62.028 mL / h, respectively. In subjects with BMI > 18 and < 30 kg / m2, the clearance values were 25.449, 57.623 and 52.200 mL / h, respectively; in subjects with BMI > 30 kg / m2, the clearance values observed were 27.240, 116.821 and 91.512 mL / h, respectively.

[0332] In TC2, the apparent volumes of distribution (VDCs) of 75, 125, and 150 μg / day of LNG VDS administered via extravascular route were 138, 140, and 172 L, respectively. In subjects with a BMI ≥18 and <30 kg / m², the apparent VDCs were 131, 118, and 167 L, respectively; in subjects with a BMI ≥30 kg / m², the apparent VDCs were 177, 1912, and 187 L, respectively.

[0333] While terminal elimination half-life values ​​were reported in TC1 and TC2, these values ​​do not represent the true elimination kinetics of LNG because levonorgestrel was continuously released from LNG VDS during the sampling period, resulting in a constant drug input. Therefore, these half-life values ​​are not interpreted or discussed.

[0334] In summary, within TC1, an increasing trend in exposure (determined by Cmax and AUC(0-t)) was observed over the dose range; while for BMI ≥ 18 and < 30 kg / m², the trend was different. 2 Compared to participants with a BMI ≥ 30 kg / m², 2 Participants showed lower levels of exposure.

[0335] In TC2, an overall increasing trend in exposure (determined by Cmax and AUC(0-t)) was observed between dose levels of 75 μg / day and 125 μg / day; however, no clear overall difference was observed between dose levels of 125 μg / day and 150 μg / day. (This is in contrast to BMI ≥18 and <30 kg / m².) 2 Compared to other subjects, those with a BMI ≥30 kg / m² tended to exhibit lower exposure (determined by Cmax and AUC(0-t)), lower clearance, and larger apparent volume of distribution. As observed in all participants and in both BMI categories, there was no significant difference in exposure between the 125 μg / day and 150 μg / day dose levels. Plasma clearance observed in TC2 appeared to differ between dose levels, with both BMI categories showing lower clearance at the 75 μg / day dose compared to the 125 and 150 μg / day doses.

[0336] Example 3 A multicenter, phase 2, dose-exploratory, double-blind, randomized clinical trial was conducted to evaluate the efficacy and safety of levonorgestrel (LNG) vaginal delivery system (VDS) administered at doses of 75 mcg / day and 125 mcg / day for 28 consecutive days, after 4 cycles of treatment, for moderate to severe endometriosis-related pain, compared with placebo.

[0337] Study design: This is a multicenter clinical trial involving female participants aged ≥18 years and ≤45 years who have undergone surgery to confirm endometriosis and whose endometriosis-associated pelvic pain (EAPP) score is ≥3 on the Numerical Rating Scale (NRS) within the past 3 months. The clinical trial includes a screening period (maximum 100 days), a treatment period (including 4 placebo-controlled, double-blind drug treatment cycles), and a follow-up period.

[0338] Subjects will be randomly assigned to receive LVDS 75 mcg / day, LVDS 125 mcg / day, or a placebo vaginal ring. The vaginal ring will be placed at follow-up 1b and replaced every 28 days (on day 29). Subjects will then return for follow-up 2 on day 20 (+6) of the first treatment cycle. A treatment termination visit (visit 3) will be conducted 1–3 days after the end of the fourth treatment cycle (theoretically day 29 (+2) of the fourth cycle); alternatively, if a subject terminates treatment early, an early termination visit will be conducted 1–3 days after the last day of vaginal ring placement.

[0339] Study objectives: Main objectives: This study aimed to demonstrate the efficacy of two levonorgestrel vaginal delivery systems (LVDS) at doses of 75 mcg / day and 125 mcg / day compared with placebo in the treatment of endometriosis-associated pelvic pain (EAPP), with efficacy assessed using a numerical rating scale (NRS).

[0340] Primary endpoint Population: Premenopausal women aged ≥18 years and ≤45 years who were surgically diagnosed with endometriosis and had an EAPPNRS score ≥3 within at least 3 months were randomly assigned to receive LVDS 0.075 mg / day, LVDS 0.125 mg / day, or placebo. Analysis was conducted on participants who had received at least one dose of the corresponding LVDS and had at least one post-baseline assessment of the primary efficacy endpoint (modified intention-to-treat set [mITT] set).

[0341] Variables: After 16 weeks of treatment (4 treatment cycles), the change in endometriosis-related pelvic pain (EAPP) score from baseline was assessed using subject-reported digital rating scale (NRS) pain scores.

[0342] Concurrent Events (ICEs) and their handling strategies: Changes in the use of rescue drugs during the 16-week treatment period (4 cycles of drug therapy) compared to baseline.

[0343] Treatment adherence was poor (<80% or >120%).

[0344] Discontinue treatment (due to poor efficacy, adverse events (AEs), or safety issues).

[0345] Population-level summary: Compare the mean change in EAPP score from baseline at week 16 (i.e., after 4 cycles of drug treatment) among the treatment groups (LVDS 0.075 mg / day, LVDS 0.125 mg / day, placebo) (for those who discontinued treatment early, the score data from their last cycle of drug treatment was used).

[0346] Secondary objectives Compared with the placebo group, after 16 weeks of treatment with LVDS 0.075mcg / day and LVDS 0.125mcg / day, the proportion of patients meeting the criteria for dysmenorrhea relief and the dysmenorrhea NRS score decreased by an average of 50% from baseline.

[0347] Compared with the placebo group, after 16 weeks of treatment with LVDS 0.075mcg and LVDS 0.125mcg, the proportion of patients meeting the criteria for relief of nonmenstrual pelvic pain (NMPP) and the NRS score for nonmenstrual pelvic pain decreased by an average of 50%.

[0348] Functional benefits were determined by measuring the pain domain of the Endometriosis Health Scale-30.

[0349] Functional benefits were determined by measuring the non-pain domain of the Endometriosis Health Scale-30.

[0350] Determine the benefit in terms of average EAPP NRS score.

[0351] Determine the benefit in terms of NRS scores for dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia.

[0352] Determine the benefits in patients with dysmenorrhea, NMPP, overall pain severity, and overall assessment (PGA) of functional impairment.

[0353] Determine changes in patients’ overall impressions of dysmenorrhea, NMPP, and dyspareunia (PGIC).

[0354] Determine changes in the use of emergency medications.

[0355] Secondary endpoint Changes in pain domain scores of the Endometriosis Health Scale-30 from baseline to week 16.

[0356] Change in endometriosis-associated quality of life score as measured by EHP-30 non-pain domains from baseline to Week 16.

[0357] Change in mean NRS scores for dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia from baseline to Weeks 4, 8, 12, and 16.

[0358] Change in mean EAPP NRS scores from baseline to Weeks 4, 8, 12, and 16.

[0359] Patient global assessment (PGA) of dysmenorrhea, NMPP, and functional impairment, and current pain over the past 4 weeks at Week 16.

[0360] Patient global impression change (PGIC) in dysmenorrhea, NMPP, and dyspareunia from start of treatment to Week 16.

[0361] Change in use of rescue medication compared to baseline at Week 4 and Week 16 (every 24 hours).

[0362] Dosage and route of administration: Trial drug: 75 mcg / day levonorgestrel vaginal delivery system (LVDS).

[0363] 125 mcg / day levonorgestrel vaginal delivery system (LVDS).

[0364] Control drug: Placebo vaginal ring identical in shape, size, and color to the LVDS.

[0365] Each LVDS contains approximately 10 mg of LNG and is designed to release a dose of 75 mcg / day and 125 mcg / day, respectively.

[0366] Duration of treatment: 4 treatment cycles, each cycle of 28 days.

[0367] Subjects will be placed with the vaginal ring on the day of Visit lb and will use it for 28 consecutive days. After 28 days, subjects will change the vaginal ring (remove the currently used vaginal ring and immediately place the next vaginal ring with no interval period in between).

[0368] The investigator will need to inform the subject that the vaginal ring must not be removed for more than 3 hours within 24 hours.

[0369] Statistical methods The primary endpoint will be analyzed using analysis of covariance (ANCOVA). All secondary endpoints will be analyzed using the appropriate method.

[0370] Efficacy analyses will be based on the modified intent-to-treat set (mITT set). This data set is defined as all randomized patients who have received at least one dose of the randomized study medication unless otherwise noted in the statistical analysis plan. The randomization ratio for the three treatment groups will be 1 : 1 : 1 : LVDS 75 mcg / day.

[0371] LVDS 125 mcg / day.

[0372] Placebo.

[0373] The primary endpoint of this study is defined as follows: To demonstrate the efficacy of LVDS 75 mcg / day and LVDS 125 mcg / day compared to placebo in the treatment of endometriosis-associated pelvic pain (EAPP) as assessed by the numerical rating scale (NRS).

[0374] EAPP includes dysmenorrhea, NMPP, and if applicable, sexual pain. The mean EAPP score at baseline will be calculated using the EAPP scores recorded in the eDiary for the last 28 days prior to Visit 1b.

[0375] The secondary endpoints of this study are defined as follows: The proportion of patients who achieve the dysmenorrhea relief criteria after 12 weeks of treatment with LVDS 75 mcg / day and LVDS 125 mcg / day compared to placebo.

[0376] The proportion of patients who achieve the non-menstrual pelvic pain (NMPP) relief criteria after 12 weeks of treatment with LVDS 75 mcg / day and LVDS 125 mcg / day compared to placebo.

[0377] The baseline pain assessment will be based on the mean of the values recorded during the baseline period, up to the day before the first dose of the randomized study medication.

[0378] A responder (defined for dysmenorrhea and NMPP, respectively) must meet the following criteria: the patient has not increased the use of analgesic medication and has a reduction in pain of more than the following defined threshold compared to the baseline pain assessment period in the 35 days prior to the last dose of study medication in the Week 12 / EOT pain assessment period: For dysmenorrhea: a 50% reduction in the mean NRS score from baseline; For non-menstrual pelvic pain: a 50% reduction in the mean NRS score from baseline; Patients who have been treated for less than 5 weeks in the treatment period will be considered non-responders for both the dysmenorrhea and non-menstrual pelvic pain assessments.

[0379] For patients on treatment for a cycle of at least 5 weeks, responder status for dysmenorrhea and non-menstrual pelvic pain will be determined according to the following rules: For dysmenorrhea: The use of analgesics will be taken into account and at least 2 days of dysmenorrhea NRS scores will be required to be recorded in the e-diary. The mean will then be calculated and used for the assessment of dysmenorrhea responder status. The requirement of at least 2 days of dysmenorrhea scores is justified as the typical menstrual bleeding days are between 3-7 days.

[0380] For non-menstrual pelvic pain: The use of analgesics will be taken into account and at least 14 days of non-menstrual pelvic pain scores will be required to be recorded in the e-diary. The mean non-menstrual pelvic pain score will then be calculated and used for the assessment of non-menstrual pelvic pain responder status. The requirement of at least 14 days of scores is justified as this corresponds to at least half of the non-menstrual days in a typical 28-day menstrual cycle.

[0381] The expected response rate in the placebo group is between 30-35%.

[0382] Example 4 A single center, phase 2, open-label clinical trial to assess the effect of a levonorgestrel (LNG) vaginal drug system (VDS) on ovulation inhibition in a group of women with a BMI > 30 kg / m 2 Ovulation inhibition in women, with details as follows: 1. Study design 1.1. Study objectives Primary objectives: To assess the effect of a levonorgestrel (LNG) vaginal drug system (VDS) on ovulation inhibition (measured by ovarian activity, using Hoogland and Skouby scoring) in a group of women with a BMI > 30 kg / m2 in treatment cycles 1 and 2.

[0383] Secondary objectives: To assess luteal function in the post-ovulatory / unruptured follicle syndrome (LUF) according to Landgren criteria.

[0384] To assess the effect of the LNG VDS on cervical mucus, endometrial thickness, and follicular-like structures (FLS) diameter.

[0385] To assess the effect of the LNG VDS on pituitary hormones (FSH, LH) and ovarian hormones (E2, P) and sex hormone binding globulin (SHBG) serum concentrations.

[0386] To assess the safety and tolerability of the LNG VDS.

[0387] Exploratory objectives: To assess the impact of body mass index (BMI) and SHGB levels on the pharmacokinetic (PK) characteristics of LNG and its ovulation-suppressing effect.

[0388] 1.2. Methods This was a single-center, open-label, phase 2 clinical trial designed to assess the ovulation-suppressing effect (measured by ovarian activity) of a levonorgestrel (LNG) vaginal delivery system (VDS) in healthy female subjects aged 18-35 years with a BMI ≥ 30 kg / m 2

[0389] 1.3. Test drug, dosage, and administration The LNG VDS was used for vaginal administration. Each LNG VDS contained approximately 1 mg of LNG with a release rate of 75 pg of LNG per day. Each LNG VDS could be used for 28 days.

[0390] 1.4. Duration of treatment Treatment was conducted for 2 treatment cycles, each cycle lasting 28 days, for a total of 56 consecutive days.

[0391] 2. Efficacy results 2.1. Primary efficacy objectives The primary efficacy measure, "ovulation suppression," was defined as HSS ≤ 4, and "non-suppressed ovulation" was defined as HSS ≥ 5.

[0392] Analysis of this measure was performed for the entire treatment period and for each treatment cycle separately, and all 30 subjects were included in the FAS. To detect potential BMI-related differences, additional analyses of "ovulation suppression" were performed by BMI subgroup: BMI subgroup 1 (30 ≤ BMI < 35) included 13 subjects, and BMI subgroup 2 (BMI ≥ 35) included 17 subjects.

[0393] Table 10: Ovulation suppression based on HSS Ovulation suppression based on HSS score - overall frequency analysis, including 95% CI-PPS by BMI subgroup (subgroup 1: 30 ≤ BMI < 35; subgroup 2: BMI ≥ 35) and overall population (TOTAL) - PPS

[0394] *BMI subgroup 2: Subject 1018 was excluded from efficacy evaluation due to abnormal LNG and SHBG values. Therefore, This evaluation did not take into account subjects.

[0395] ​Ovalation inhibition was achieved in all subjects throughout the treatment phase. No differences were observed between the two BMI subgroups and between treatment cycle 1 and treatment cycle 2.

[0396] All sensitivity analyses performed, i.e. per cycle analysis and analysis for PPS throughout the treatment phase, were consistent with the results of the primary analysis.

[0397] As a supportive analysis, the frequency of HSS scores was statistically analyzed for all subjects and analyzed separately by BMI subgroups: in most treatment cycles, the HSS score was 4, and the frequency of HSS 4 was higher in BMI subgroup 2, with a slight increase in frequency over the course of treatment (BMI subgroup 1 : 61.54% in cycle 1 and 69.23 in cycle 2; BMI subgroup 2: 82.35 in cycle 1 and 88.24 in cycle 2). Correspondingly, HSS scores of 3, 2 and 1 only occurred in individual cycles; due to the small number, no association with BMI could be detected.

[0398] Table 11: Maximum HSS score categories Maximum HSS category - frequency analysis by BMI subgroups (BMI subgroup 1 : 30 < BMI < 35; BMI subgroup 2: BMI > 35) and overall population (TOTAL) - full analysis set (FAS)

[0399] The maximum HSS score in a treatment cycle was categorized as "no / minimal ovarian activity" (scores 1 / 2), "residual ovarian activity" (scores 3 / 4) and "high ovarian activity (including ovulation)" (scores 5 / 6). In BMI subgroup 1 and subgroup 2, respectively, 84.62% and 88.24% of the subjects observed "residual ovarian activity".

[0400] Summary: Ovulation inhibition was successfully achieved in all subjects throughout the treatment phase, with no statistically significant differences between the two BMI subgroups. The majority of subjects still showed residual ovarian activity during treatment, with an HSS score of 4. In treatment cycle 2, the frequency of HSS-4 values increased, and the incidence was slightly higher in BMI subgroup 2.

[0401] 2.2 Secondary efficacy objectives 2.2.1 Effect on cervical mucus At each visit, if the follicle diameter was observed to be >13 mm, the effect of LVDS on cervical mucus was assessed using the Insler score. The maximum Insler score during LNG treatment was slightly lower than the pre-treatment cycle, indicating a slight decrease in sperm penetration due to progesterone administration. The values ​​(±SD) obtained from the two BMI subgroups were comparable, with mean scores of 6.8 (±3.0) and 7.6 (±1.8) for subgroup 1 and subgroup 2, respectively.

[0402] 2.2.2 Effect on the diameter of dominant follicle-like structures The impact of LVDS on the diameter of dominant follicle-like structures was assessed using TVUS at different study visit sites. In pre-treatment cycles, assessment was performed only before ovulation.

[0403] Specifically, in treatment cycle 1, the arithmetic mean (±SD) of MFD in BMI subgroup 1 was 22.16 ± 9.43 mm, and in BMI subgroup 2 it was 23.69 ± 9.08 mm. In treatment cycle 2, the arithmetic mean (±SD) of MFD in BMI subgroup 1 was 20.94 ± 8.40 mm, and in BMI subgroup 2 it was 25.46 ± 8.52 mm. These values ​​remained stable throughout the treatment period, and no ovulation was observed.

[0404] During the trial, endometrial thickness (ET) was measured using TVUS to monitor endometrial proliferation.

[0405] The combined assessment results of the two treatment cycles showed that the ETmax values ​​of both BMI subgroups decreased to a similar degree during treatment (7.98 ± 1.5 mm in BMI subgroup 1; 8.66 ± 1.47 mm in BMI subgroup 2). When assessed separately for each treatment cycle, the arithmetic mean of ETmax in treatment cycle 2 decreased further, and the trend was consistent in both BMI subgroups.

[0406] In summary, LNG treatment inhibited endometrial proliferation, and the degree of inhibition did not differ between the two BMI subgroups. Endometrial proliferation inhibition is a known effect of continuous progestin therapy, which may affect embryo implantation.

[0407] 2.2.3 Pituitary and Ovarian Hormones Regarding pituitary and ovarian hormones, the following key results were obtained: Table 12: Maximum FSH concentration [U / L] for each period Maximum FSH [U / L] concentration by period - by analyte, BMI subgroup (subgroup 1: 30 ≤ BMI < 35; subgroup 2: BMI ≥ 35) and total population (TOTAL) - FAS

[0408] The maximum follicle-stimulating hormone serum (FSH) concentration of each subject remained essentially stable during treatment, with only slight fluctuations in both BMI subgroups.

[0409] Table 13: Maximum LH concentration [U / L] per cycle Maximum LH [U / L] concentration by cycle - by analyte, BMI subgroup (Subgroup 1 : 30 < BMI < 35; Subgroup 2: BMI > 35) and total population (TOTAL) - FAS

[0410] The maximum luteinizing hormone (LH) serum concentration of each subject was affected by the suppression of ovulation, i.e. no LH peak occurred. The results were comparable for both BMI subgroups: the arithmetic mean (± SD) for BMI Subgroup 1 was 5.272 ± 1.952 U / L in Treatment Cycle 1 and 5.432 ± 2.182 U / L in Treatment Cycle 2; the arithmetic mean (± SD) for BMI Subgroup 2 was 6.629 ± 2.529 U / L in Treatment Cycle 1 and 5.506 ± 2.248 U / L in Treatment Cycle 2. All individual values remained below 12 U / L.

[0411] Summary: The LNG treatment suppressed the occurrence of LH peaks, so that the LH values for both BMI subgroups remained at a low level, which was significantly below 20 U / L.

[0412] Table 14: Maximum E2 concentration [pg / mL] per cycle Maximum E2 [pg / mL] concentration by cycle - by analyte, BMI subgroup (Subgroup 1 : 30 < BMI < 35; Subgroup 2: BMI > 35) and total population (TOTAL) - FAS

[0413] The maximum E2 concentration for each subject showed a decreasing trend from Cycle 1 to Cycle 2 during treatment. E2 concentrations were slightly higher in BMI Subgroup 2 than in BMI Subgroup 1 : the arithmetic mean (± SD) of the maximum E2 concentration for individuals in BMI Subgroup 1 was 170.538 ± 130.587 pg / ml in treatment Cycle 1 and 87.538 ± 77.954 pg / ml in treatment Cycle 2, and for BMI Subgroup 2, the values were 208.353 ± 150.904 pg / ml and 141.235 ± 116.740 pg / ml, respectively. Individual maximum E2 levels for subjects showed large variability. The mean values for maximum E2 indicated that LNG administration did not consistently suppress E2 concentrations, which is consistent with the observed follicular activity results.

[0414] Table 15: Maximum E2 concentration category by cycle Maximum E2 category by cycle frequency analysis by BMI subgroup; BMI Subgroup (Subgroup 1 : 30 < BMI < 35; Subgroup 2: BMI > 35) and Total Population (TOTAL) - FAS

[0415] Note: Maximum E2 < 20 pg / ml; Category 2: 20 < maximum E2 < 30 pg / ml; Category 3: 30 < maximum E2 < 50 pg / ml; Category 4: 20 > = 50 pg / ml Maximum E2 concentrations were categorized into different categories. The maximum E2 concentration for the majority of subjects fell in Category 4, with concentrations > 50 pg / ml, in both BMI subgroups and both treatment cycles. For BMI Subgroup 1, the frequency of Category 4 was 76.92% in Cycle 1 and 61.54% in Cycle 2. For BMI Subgroup 2, the frequency of Category 4 was higher in both cycles, at 88.24% and 76.47%, respectively. No cases of Category 1 (< 20 pg / ml) occurred, and only one case of Category 2 (< 30 pg / ml) occurred in Subgroup 1 in one treatment cycle, with the remaining 13 cycles falling in Category 3 (> 30 and < 50 pg / ml).

[0416] Table 16: Mean E2 concentration [pg / ml] by cycle Mean E2 [pg / mL] concentration by cycle by analyte, BMI subgroup (Subgroup 1 : 30 < BMI < 35; Subgroup 2: BMI > 35) and Total Population (TOTAL) - FAS

[0417] The mean serum estradiol (E2) concentration in all subjects also showed a decreasing trend during treatment, with higher values ​​in BMI subgroup 2: In treatment cycle 1, the arithmetic mean of BMI subgroup 1 and subgroup 2 was 81.27 ± 56.06 pg / ml and 86.54 ± 46.00 pg / ml, respectively. In treatment cycle 2, the arithmetic mean of BMI subgroup 1 and subgroup 2 was 38.78 ± 16.92 pg / ml and 60.51 ± 31.71 pg / ml, respectively. Throughout the treatment period, the mean E2 concentrations in BMI subgroup 1 and subgroup 2 were 60.52 ± 33.17 pg / ml and 73.62 ± 35.16 pg / ml, respectively. The mean and median mean E2 concentrations in both BMI subgroups were significantly higher than 30 pg / ml, a threshold considered the lower limit that does not lead to accelerated bone loss.

[0418] Table 17: Maximum P [nmol / L] concentration for each period.

[0419] Average P [nmol / L] concentration by period - by analyte, BMI subgroup (subgroup 1: 30 ≤ BMI < 35; subgroup 2: BMI ≥ 35) and total population (TOTAL) - FAS

[0420] Maximum serum progesterone (P) concentrations were comparable across the two treatment cycles and throughout the entire treatment period. The arithmetic means (±SD) of the two BMI subgroups were also similar: BMI subgroup 1 was 0.959 ± 0.452 nmol / L in treatment cycle 1 and 0.758 ± 0.445 nmol / L in cycle 2; BMI subgroup 2 was 0.849 ± 0.333 nmol / L in cycle 1 and 0.733 ± 0.393 nmol / L in cycle 2. All individual values ​​were ≤ 2.0 nmol / L. In summary, serum progesterone concentrations remained at low levels due to ovulation suppression during treatment.

[0421] The effect of LVDS on sex hormone-binding globulin (SHBG) serum concentrations was assessed by comparing them with baseline values ​​obtained at the pre-treatment cycle. Prior to the start of treatment, the mean serum SHBG concentrations in the two BMI subgroups were similar (see [link to study]. Figure 10 ).

[0422] SHBG levels decreased significantly during LNG treatment. Mean profiles for both BMI subgroups showed a similar degree of sharp decrease in SHBG levels during the first half of cycle 1. SHBG concentrations continued to decrease during the second half of cycle 1, but the rate of decrease slowed thereafter. In cycle 2, mean serum concentration-time profiles showed a relatively flat trend throughout the cycle.

[0423] Baseline change assessment results were consistent with serum concentration-time profile trends: SHBG levels decreased significantly during LNG treatment for both BMI subgroups, and to a similar degree: at the D55 visit (i.e., after 55 ± 1 days of LNG treatment), SHBG levels decreased to approximately 45% of baseline for BMI subgroup 1 (from 52.24 nmol / L to 23.54 nmol / L) and to 48.74% of baseline for BMI subgroup 2 (from 54.88 nmol / L to 26.75 nmol / L).

[0424] These results are fully consistent with literature data showing a 50% decrease in SHBG levels during treatment with LNG.

[0425] 2.2.4 Pharmacokinetic results Pharmacokinetic evaluation of LNG was performed in this clinical trial to explore the effect of BMI on LNG pharmacokinetics, which was an exploratory trial objective (see Figure 11 ).

[0426] Mean plasma concentration-time profiles obtained for all subjects following LVDS multiple dosing showed a relatively flat trend throughout the treatment phase. Plasma concentrations showed a slight, continuous decrease from the concentration at the start of cycle 1 (466 pg / mL) to the lowest concentration at the last visit of cycle 2 (382 pg / mL).

[0427] Mean profiles by BMI subgroups were generally consistent with the above and similar in shape. However, throughout the treatment, LNG plasma concentrations were consistently higher for BMI subgroup 1 than for BMI subgroup 2. This observation is highly consistent with literature data reporting lower LNG plasma concentrations for subjects with higher BMI.

[0428] Mean pharmacokinetic parameter results for LNG were consistent with the trends shown by plasma concentration-time profiles.

[0429] The arithmetic mean of the mean plasma concentrations of LNG throughout the treatment period was 452 pg / mL (± 86.5 pg / mL) in BMI Subgroup 1 and 374 pg / mL (± 101 pg / mL) in BMI Subgroup 2, confirming the observed difference between the two subgroups (i.e. there was about a 17.26% difference between BMI Subgroup 1 and Subgroup 2).

[0430] The arithmetic mean ranged from 428 pg / mL (Treatment Period 2) to 476 pg / mL (Treatment Period 1) in BMI Subgroup 1 and was 374 pg / mL in both Period 1 and Period 2 in BMI Subgroup 2.

[0431] Similar trends were observed for the geometric mean of the area under the curve calculated throughout the treatment period (AUCo-56,ss): the AUCo-56,ss values were 24900 day*pg / mL and 20900 day*pg / mL for BMI Subgroup 1 and Subgroup 2, respectively (i.e. there was about a 16.06% difference between BMI Subgroup 1 and Subgroup 2). The geometric mean ranged from 11800 day*pg / mL (Treatment Period 2) to 13100 day*pg / mL (Treatment Period 1) in BMI Subgroup 1 and was 10100 day*pg / mL in both Period 1 and Period 2 in BMI Subgroup 2.

[0432] Linear regression analysis of AUCo-56,ss and Cav,ss,56 supported the conclusions drawn from the analysis of variance: for both parameters, the regression lines showed a decrease in their values with increasing BMI values. These evaluations clearly indicated that BMI had an impact on the total exposure observed during the dosing interval and that the maximum exposure showed a decreasing trend with increasing BMI.

[0433] 3. Conclusion Based on the results of this trial, the following conclusions were drawn: Treatment at a dose of 75 pg / day achieved complete inhibition of ovulation in the BMI < 30 kg / m 2 study population.

[0434] Ovarian activity was not completely suppressed in most subjects; in both BMI subgroups, the HSS value was 4 in most subjects. This feature is expected with simple progestin therapy to avoid low-estrogen-related side effects.

[0435] Despite the fact that ovarian activity was not completely suppressed, treatment with LNG at 75 pg / day was sufficient to effectively prevent the occurrence of LH peaks, thus completely inhibiting normal ovulation, which can lead to pregnancy.

[0436] E2 mean plasma concentrations were suppressed during treatment, but remained well above the accepted threshold for clinically significant bone density loss, and thus there were no safety concerns due to E2 suppression.

[0437] SHBG levels decreased significantly during levonorgestrel treatment in both BMI subgroups, and to a similar extent.

[0438] Pharmacokinetic assessments clearly demonstrated an impact of BMI on the total exposure observed over the dosing interval, and a trend for decreasing maximum exposure with increasing BMI (i.e. the arithmetic mean Cav was approximately 17.26% lower, and the geometric mean AUCo-56ss was approximately 16.06% lower, for Subgroup 2 compared to Subgroup 1).

[0439] Comparison of pharmacodynamic parameters (HSS, E2 concentrations) between the two BMI subgroups showed a slightly lower degree of ovarian suppression in the higher BMI subgroup, but with greater variability in the data, and no statistically significant difference in HSS scores.

[0440] LVDS was well tolerated.

[0441] The incidence of adverse events related to LNG VDS was comparable between the two BMI subgroups.

[0442] References (1) Merck Sharp & Dohme Limited. Cerazet® 75 IJg (desogestrel). Ficha técnica (SmPC Febrero 2019). Agencia Española del Medicamento y Productos Sanitarios (AEMPS). Available from: https: / / cima.aemps.es / cima / dochtml / p / 62285 / P_62285.html (2) Rice C, Killick S, Hickling D, Coelingh Bennink H. Ovarian activity and vaginal bleeding patterns with a desogestrel-only preparation at three different doses. Hum Reprod 1996; 11: 737-40. (3) Rice CF, Killick SR, Dieben T, Coelingh Bennink H. A comparison of the inhibition of ovulation achieved by desogestrel 75 μg and levonorgestrel 30 μg daily. Hum Reprod 1999; 14: 982-5. (4) Duijkers IJM, Heger-Mahn D, Drouin D, Skouby S. A randomised study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24 / 4 regimen. Eur J Contracept Reprod Health Care 2015; 20: 419-27 (5) McCann MF, Potter LS. Progestin-only oral contraception: a comprehensive review. Contraception 1994; 50 (Suppl 1): S9-195. (6) Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill. A double-blind study comparing the contraceptive efficacy acceptability and safety of two progestogen-only pills containing desogestrel 75 μg / day or levonorgestrel 30 μg / day. Eur J Contracept Reprod Health Care 1998; 3: 169-78. (7) Ingrid J. M. Duijkers, Christine Klipping, Tanja Rautenberg, Barbara S. Schug, Prithi S. Kochhar, Hermann Osterwald, Michael Oettel, Effect on ovarian activity and ovulation inhibition of different oral dosages of levonorgestrel Contraception (2022) doi: https: / / doi.org / 10.1016 / j.contraception.2022.01.018 (8) Sivin I. 1984. Five-year clinical studies of Norplant implants. In: The Norplant Subdermal Contraceptive System. M. M. Shaaban (ed.). Assiut Egypt: Assiut University pp. 74-75. (9) Milsom I, Korver T. Ovulation incidence with oral contraceptives: a literature review. BMJ Sexual & Reproductive Health. 2008;34:237-246. (10) V. Brache F. Alvarez & A. Faundes (2001) Mechanism of action of levonorgestrel contraceptive implants Gynecological Endocrinology 15:sup2 14-20 DOI: 10.1080 / gye.15.s2.14.20 (11) Meirik et al (2003) "Implantable Contraceptive for women". Human Reproduction Update 9(1): 49-59. (12) Glacier (2016) Anna Glasier Chapter 134 - Contraceptio Editor(s): J. Larry Jameson, Leslie J De Groot, David M. de Kretser, Linda C. Giudice, Ashley B. Grossman, Shlomo Memed, John T. Potts, Gordon C. weir, Endocrinology: Adult and Pediatric (Seventh Edition) I.B. Saunders 2016 Pages 2297-2309. e2. (13) Barbieri (1992). "Hormone treatment of endometriosis: the estrogen threshold hypothesis". Am J Obstet Gynecol. 1992 Feb; 166(2): 740-5. doi: 10.1016 / 0002-9378(92)91706-g. (14) Schindler AE (2011). "Dienogest in long-term treatment of endometriosis." Int J womens Health 3: 175-184. (15) 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, Thomas, JW, Jain, RI, and Chwalisz K (2017). "Treatment of Endometriosis-Associated Pain with Elagolixan Oral GnRH Antagonist." N Engl J Med 377(1): 28-40. (16) Vercellini, P, Viganò, P, Somigliana, E and Fedele, L (2014). "Endometriosis: pathogenesis and treatment." Nature Reviews Endocrinology 10(5): 261-275. (17) Paolo Vercellini, M.D. Laura Buggio, M.D. Maria Pina Frattaruolo, M.D. Alessandra Borghi, M.D. Dhouha Dridi, M.D. Edgardo Somigliana, M.D. (2018) "Medical treatment of endometriosis related pain" Best Practice & Research Clinical Obstetrs & Gynaecology. 51 68-91. (18) Casper, RF (2017). "Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills." Fertil Steril 107(3): 533-536. (19) Caruso et al (2019). "Randomized study on the effectiveness of nomegestrol acetate plus 17β-estradiol oral contraceptive versus dienogest oral pill in women with suspected endometriosis-associated chronic pelvic pain". BMC Women's Health. 2022 May 10;22(1):146. doi:10.1186 / s12905-022-01737-7. (20) Vercellini P Bracco B Mosconi P Roberto A Alberico, D Dhouha, D and Somigliana E (2016). "Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study." Fertil Steril 105(3): 734-743.e733. (21) Bulu, Yang et al. (2002): "Estrogen production and Metabolism in Endometriosis" Annals New York Academy of Sciences 2002 pp 75-85 (22) Brosens and Gellersen (2012): "The uterus under hormonal control - cycling for life" Molecular and Cellular Endocrinology 358 (2012) 145.

Claims

1. Levonorgestrel for use in a method of providing contraception to a female subject, comprising the sustained administration of levonorgestrel to the subject, wherein, The daily dosage of levonorgestrel is about 60-100 μg per day, wherein the route of administration is vaginal administration.

2. Levonorgestrel for use in a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in a female subject, comprising the sustained administration of levonorgestrel to the subject, wherein the daily dosing amount of levonorgestrel is about 60-160 pg / day, wherein, The route of administration is vaginal administration.

3. Levonorgestrel for use in a method of treatment of endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea according to claim 2, wherein, The treatment has a simultaneous contraceptive effect.

4. Use of levonorgestrel as a contraceptive, comprising administering to a female subject levonorgestrel at a dose of about 60-200 μg / day continuously, wherein, The route of administration is vaginal administration.

5. Levonorgestrel for use in a method according to claims 1-3, or levonorgestrel for use as a contraceptive according to claim 4, wherein, No other contraceptive component, preferably no estrogen, is administered to the female subject at the same time.

6. Levonorgestrel for use according to any one of claims 1 to 3, or use of levonorgestrel according to claim 4 or 5, wherein, The administration of the levonorgestrel also induces amenorrhea.

7. A drug delivery device comprising: (a) a core layer comprising a polymer, preferably a polyurethane; (b) a sheath layer substantially or completely surrounding the core layer, the sheath layer comprising a polymer, preferably a polyethylene-co-vinyl acetate copolymer having a vinyl acetate content of about 10-40% w / w; and (c) levonorgestrel dissolved or dispersed in the core layer and / or the sheath layer, wherein the total amount of levonorgestrel present in the core layer and / or the sheath layer is between about 9 mg and 11 mg.

8. The drug delivery device of claim 7, having a drug release profile characterized by, when the device is tested in-vitro in 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, (i) releases no more than about 150 μg of levonorgestrel over the initial 24 hour release period, and (ii) releases about 60-90 μg of levonorgestrel per day over at least 27 days after the initial 24 hour release period.

9. The drug delivery device of claim 7, having a drug release profile characterized by, when the device is tested in-vitro in 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, (i) releases no more than about 250 μg of levonorgestrel over the initial 24 hour release period, and (ii) releases about 90-150 μg of levonorgestrel per day over at least 27 days after the initial 24 hour release period.

10. The drug delivery device of claim 7, wherein, The device has a drug release profile characterized in that, when the device is tested in-vitro in 0.2 M sodium acetate buffer, pH adjusted to 4.2, containing 1.0% sodium lauryl sulfate (SLS) surfactant, (i) releases no more than about 300 μg of levonorgestrel over the initial 24 hour release period, and (ii) releases about 110-180 μg of levonorgestrel per day over at least 27 days after the initial 24 hour release period.

11. The drug delivery device of claims 7-10, wherein, provides a mean Cmax value of less than 1 ng / ml of levonorgestrel after one treatment cycle of 28 days, a mean Cmax value of less than 0.7 ng / ml of levonorgestrel after two treatment cycles of 28 days each; provides a mean AUC (0-t) value of less than 350 h*ng / ml of levonorgestrel after one treatment cycle of 28 days; provides a mean AUC (0-t) value of less than 370 h*ng / ml of levonorgestrel after two treatment cycles of 28 days each.

12. The drug delivery device of any of claims 7-10, wherein, The device provides a mean Cmax value of less than 1.6 ng / ml of levonorgestrel after one treatment cycle of 28 days, a mean Cmax value of less than 1 ng / ml of levonorgestrel after two treatment cycles of 28 days each; a mean AUC (0-t) value of less than 580 h*ng / ml of levonorgestrel after one treatment cycle of 28 days; a mean AUC (0-t) value of less than 540 h*ng / ml of levonorgestrel after two treatment cycles of 28 days each after the device is placed intravaginally in the body of a subject.

13. The drug delivery device of any of claims 7-12, wherein, The device does not comprise any additional contraceptive ingredient, preferably the device does not comprise any estrogen.

14. The drug delivery device according to any one of claims 7-13, wherein: (i) the concentration of levonorgestrel present in the core layer is about 0.20-1.00 wt% based on the total weight of the core layer; and / or (ii) the thickness of the sheath layer is about 5-500 μm, preferably about 50-200 μm.

15. The drug delivery device of any of claims 7-14, wherein, The drug delivery device has a shape selected from the group consisting of a spiral shape or a ring shape, preferably the drug delivery device has a ring shape, more preferably the device is a vaginal ring.

Images