Methods and devices for providing effective contraception

Abstract

The present invention relates to levonorgestrel used in a method of providing contraception in a female subject, comprising continuous intravaginal administration of approximately 60 μg / day to approximately 100 μg / day of levonorgestrel. Furthermore, the present invention relates to levonorgestrel used in a method of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea, comprising continuous administration of approximately 60 μg / day to approximately 160 μg / day of levonorgestrel. A delivery device, preferably an intravaginal ring, for carrying out these methods is also envisioned.

Description

[Technical Field]

[0001] This invention relates to the field of women's health, and more specifically to levonorgestrel used in a method of providing contraception while simultaneously providing optimal estrogen suppression. Methods for treating endometriosis and endometriosis-related diseases are also envisioned, as well as drug delivery devices, such as vaginal rings, suitable for implementing these methods. [Background technology]

[0002] Levonorgestrel (LNG) is a synthetic progestin that exhibits no significant estrogenic activity but high progesterone activity. Levonorgestrel inhibits follicular stimulation and ovulation and reduces sperm penetration through cervical mucus. Levonorgestrel is used as a progestogen in numerous contraceptive products registered worldwide. Levonorgestrel is currently one of the most widely used progestogens in mixed oral contraceptive (COC) products. Cerazet® is an effective progestin-only pill (POP) containing a desogestrel 75 μg film-coated tablet (1). Its mechanism of action focuses on inhibiting ovulation. Traditionally, POPs work by thickening cervical mucus, slowing egg transport, and providing an endometrium unsuitable for implantation. Cerazet® has been shown to inhibit ovulation with comparable efficacy to COC pills. While a POP dose containing desogestrel 0.075 mg is high enough to inhibit ovulation in at least 98% of cycles, LNG 0.030 mg inhibits ovulation in only 72% of cycles (2, 3, 4). Due to consistent ovulation inhibition, which is probably considered the most potent mechanism of action of POPs, the contraceptive efficacy of desogestrel 0.075 mg is higher than that of LNG 0.030 mg and other low-dose POPs, and is comparable to the efficacy of COC (5, 6). Although Cerazet® is a widely used product with an extensive safety database, adverse drug reactions such as irregular bleeding have been reported in subjects treated with this therapy. Therefore, there is a need for alternative progestin-only contraceptives.

[0003] Long-term implants containing only LNG have also been proven to be an effective form of contraception. For example, in a multicenter clinical study of the Jadelle® implant involving 1,393 women, eight pregnancies occurred within five years of placement (8, 9).

[0004] Ovulation inhibition is directly related to the steady-state plasma concentration of levonorgestrel. However, the minimum threshold level of circulating LNG required for contraceptive effectiveness remains unknown. Based on initial studies of the subcutaneous contraceptive implant Norplant® (Wyeth, Pfizer, NY), a plasma LNG concentration of 0.3 ng / mL to 0.4 ng / mL is often cited as the threshold level, with contraceptive effectiveness decreasing below this level. Several weeks after implant insertion, the average plasma LNG level stabilized between 0.3 ng / mL and 0.4 ng / mL, gradually decreasing to an average level of 0.28 ng / mL after 5 years of use, and reaching approximately 0.22 ng / mL (ranging from 0.02 ng / mL to 0.35 ng / mL) by 8 years. Thus, the LNG concentration associated with unwanted pregnancies was reported to be 0.21 ± 0.06 ng / mL.

[0005] Regarding ovulation inhibition caused by levonorgestrel implants, ovulation is inhibited in over 85% of cycles during the first year of use, when the levonorgestrel release rate is highest (10). The percentage of ovulation inhibition decreases to nearly 65% ​​of cycles in the second and third years, while luteal activity occurs in almost 50% of cycles during the last two years of use. Throughout the five-year period of Norplant use, mean serum estradiol levels were similar to those of the control group, approximately 400 pmol / L to 500 pmol / L (109 pg / mL to 136 pg / mL).

[0006] Levonorgestrel implants exert their contraceptive effect by causing changes in cervical mucus, inhibiting ovulation, and promoting ovulatory abnormalities. If contraception fails, pregnancies occurring with levonorgestrel implants are more likely to be ectopic than pregnancies conceived with other contraceptives. Due to the high contraceptive efficacy of levonorgestrel implants, the absolute rate of ectopic pregnancies among Jadelle® (a new brand name for Norplant®) users is very low.

[0007] To develop an estrogen-free contraceptive with high contraceptive reliability and an acceptable bleeding pattern, higher-dose LNG-POP was tested (7). Investigational doses were 0.095 mg, 0.115 mg, and 0.135 mg of levonorgestrel per day, administered to three groups of 30 patients for 56 days. It was concluded that 0.115 mg of levonorgestrel per day was the minimum effective dose for consistent ovulation inhibition. Levonorgestrel, when administered orally, is completely absorbed after oral administration, resulting in near 100% bioavailability, and is known not to undergo first-pass metabolism, as demonstrated for commercially available COCs (Seasonique®) containing levonorgestrel and ethinylestradiol, for example.

[0008] A multicenter, open-label, single-arm study (NCT02403401) was conducted to investigate the contraceptive efficacy and safety of LNG (40 μg / day) delivered via an intravaginal ring (IVR). The LNG release rate and dose for the IVR in this study were selected to achieve exposure levels similar to those of approved low-dose LNG POPs (NorgestonVR / MicrolutVR, 30 μg / day) and LNG implants (Norplant IIVR / JadelleVR) after a two-year insertion period. However, due to a high number of pregnancies, the study was terminated prematurely after reaching approximately one-third of the planned exposure.

[0009] Therefore, although the safety profile of LNG is well-characterized and there is experience with various doses, formulations, and delivery systems, the contraceptive effectiveness of LNG as monotherapy administered via vaginal delivery systems remains unclear to date.

[0010] Another problem associated with progestogen-only contraceptives is menstrual irregularities due to insufficient estrogen intake. In fact, this is the most common reason for discontinuing levonorgestrel implants (45%) (11).

[0011] Although the bleeding mechanisms associated with progestogen-only contraceptives are still not well understood, the bleeding patterns associated with progestin-only contraceptives are known to depend on the degree of suppression of ovarian activity. Generally, when normal ovulation occurs consistently, women will experience menstrual bleeding at a frequency characteristic of a normal cycle. If both ovulation and follicular development are completely suppressed, amenorrhea may occur. If ovulation or follicular development (and therefore sufficient estrogen secretion to stimulate endometrial growth) occurs irregularly, bleeding becomes irregular and unpredictable (12).

[0012] Therefore, there is a need for a progestogen-only contraceptive that exhibits high contraceptive efficacy by inhibiting ovulation while simultaneously providing a favorable bleeding profile.

[0013] Increasing the dosage of levonorgestrel in the formulation will result in consistent ovulation inhibition; however, it is desirable to achieve complete ovulation inhibition to enhance contraceptive effectiveness while administering the minimum dose of the drug to avoid or reduce side effects.

[0014] One of the main side effects is estrogen suppression caused by the administration of progestogen monotherapy, which can lead to undesirable hypoestrogenic side effects, particularly bone loss. Although tissue sensitivity to estradiol varies, an average estradiol concentration between 30 pg / ml and 45 pg / ml is assumed to be sufficient to prevent bone loss (13).

[0015] A decrease in plasma estradiol levels is associated with the improvement of other conditions such as premenstrual syndrome and menorrhagia, as well as other estrogen-dependent pathologies such as uterine fibroids and subserosal endometrial polyps.

[0016] 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 trigger a chronic inflammatory response, which can lead to the formation of scar tissue and adhesions. Women with endometriosis frequently experience symptoms of dysmenorrhea, premenstrual pain, painful intercourse, and chronic fatigue (14), as well as less common symptoms such as ovulation pain, constipation, and painful urination (15). Furthermore, the presence of extrauterine endometrium can lead to infertility, which can occur in up to 50% of women with endometriosis (16). Conventional techniques suggest estradiol levels of approximately 40 pg / ml to 60 pg / ml for the treatment of endometriosis.

[0017] Currently, there is no cure for endometriosis. Women with endometriosis still need continuous, collaborative, and supportive management of their condition, as well as an understanding of the significant impact the condition can have on their quality of life. The main goals of treatment are to alleviate pain and other symptoms, reduce endometrial lesions, and improve the quality of life for affected individuals.

[0018] Current hormonal therapies for pain associated with endometriosis focus on systemic or local estrogen suppression, inhibition of tissue proliferation and inflammation, or both. Mixed oral contraceptives (COCs) are widely used as the first-line treatment for dysmenorrhea or chronic pelvic pain, particularly in adolescents with endometriosis, regardless of whether endometriosis is suspected or not (17). Nevertheless, estrogen has a stimulating effect on the metabolic activity of the endometrium. Therefore, COC administration may lead to estrogen dominance, potentially increasing the risk of disease progression (18).

[0019] Progestin monotherapy is also used as a first-line treatment for pelvic pain associated with endometriosis and to reduce the severity of endometrial lesions. One of the progestins approved by the FDA for the treatment of endometriosis, secondary amenorrhea, and abnormal uterine bleeding is norethisterone acetate (NETA) (5 mg tablets). In principle, NETA can provide ovulation inhibition starting at a dose of 0.35 mg / day when administered continuously for 28 days, but the high doses required to treat endometriosis (5 mg / day to 15 mg / day) are more than 10 times the dose required for ovulation inhibition (0.35 mg / day), and it is not approved for contraceptive use. Treatment may be maintained at this high dose level for up to 6 to 9 months, or until breakthrough bleeding requests temporary discontinuation of treatment. Furthermore, at such high doses, NETA may cause androgenic side effects such as acne, hirsutism, weight gain, and, in some women, slightly more severe voice changes.

[0020] Another approved progestin, dienogest (DNG), is a synthetic progestin currently used in Europe for the clinical treatment of endometriosis at a daily dose of 2 mg (Visanne® 2 mg tablets). DNG, lacking androgenic activity, is more tolerable than NETA. While 2 mg of DNG per day inhibits ovulation, it does not completely suppress ovarian activity and is therefore not approved as a contraceptive (19). Consequently, users are advised to employ barrier contraception or other non-hormonal alternatives when using DNG for the treatment of endometriosis (20).

[0021] Currently approved treatments for endometriosis-related pain do not include contraception. Furthermore, the combined use of some FDA or European-approved endometriosis medications (e.g., GnRH antagonists such as the recently approved product Elagolix, or progestins as dienogest) with hormonal contraceptives is not permitted. The need for barrier contraception may limit compliance with these products and increase discontinuation rates. Therefore, there is a critical need for treatments for endometriosis-related pelvic pain (EAPP) in women seeking hormonal contraception. [Overview of the project] [Problems that the invention aims to solve]

[0022] Therefore, one object of the present invention was to provide a contraceptive with very high ovulation inhibitory efficacy while limiting estrogen suppression to an optimal level, such as a level corresponding to the early follicular phase, thereby avoiding the well-known side effects caused by conventional contraceptives containing levonorgestrel as an active ingredient.

[0023] A further object of the present invention is to provide a contraceptive that has very high ovulation-inhibiting efficacy and is also suitable for the treatment of endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea, and other related estrogen-dependent disorders. [Means for solving the problem]

[0024] Accordingly, the present invention relates to levonorgestrel used in a method for providing contraception in a female subject, wherein the method comprises administering levonorgestrel to the subject in a continuous manner, the daily dose of levonorgestrel administered is approximately 60 μg / day to approximately 100 μg / day, and the route of administration is vaginal.

[0025] In another embodiment, the present invention relates to levonorgestrel used in a method for providing contraception in a female subject, wherein the method comprises administering levonorgestrel to the subject in a series of doses, the average daily dose of levonorgestrel administered is about 75 μg / day, and the route of administration is vaginal.

[0026] In another embodiment, the present invention relates to levonorgestrel used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, wherein the method comprises administering levonorgestrel to the subject in a continuous manner, the daily dose of levonorgestrel administered being about 60 μg / day to about 160 μg / day, and preferably the route of administration being vaginal.

[0027] In one embodiment, the present invention relates to levonorgestrel used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, wherein the method comprises administering levonorgestrel to the subject continuously, the average daily dose of levonorgestrel administered is about 75 μg / day to about 150 μg / day, and the route of administration is preferably vaginal.

[0028] In one embodiment, the present invention relates to levonorgestrel used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, comprising administering levonorgestrel to the subjects continuously, wherein the average daily dose of levonorgestrel administered is about 75 μg / day, about 125 μg / day, or about 150 μg / day, and preferably the route of administration is vaginal.

[0029] The above treatment relates to levonorgestre used in methods of treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea as described above, which also provide contraception.

[0030] In one embodiment of the method of the present invention, no further contraceptive components are administered to the female subject at the same time, preferably no estrogen is administered to the female subject at the same time.

[0031] In one preferred embodiment of the method of the present invention, female subjects are not simultaneously administered any further antiviral agents.

[0032] In one preferred embodiment of the method of the present invention, tenofovir is not administered to female subjects simultaneously.

[0033] In one embodiment of the method of the present invention, amenorrhea is also induced by the administration of levonorgestrel.

[0034] In a further embodiment, the present invention relates to the use of levonorgestrel as a contraceptive, comprising administering levonorgestrel to female subjects in a continuous dose of approximately 60 μg / day to approximately 200 μg / day, with the route of administration being vaginal.

[0035] In one embodiment of the above-described aspect, the present invention relates to the use of levonorgestrel as a contraceptive, comprising continuously administering levonorgestrel to a female subject at an average dose of approximately 75 μg / day to approximately 150 μg / day, preferably via vaginal administration.

[0036] In one embodiment of the above-described aspect, the present invention relates to the use of levonorgestrel as a contraceptive, comprising continuously administering levonorgestrel to a female subject at an average dose of about 75 μg / day, about 125 μg / day, or about 150 μg / day, preferably via vaginal administration.

[0037] In a preferred embodiment, the route of administration is via the mucous membrane, preferably the vaginal route.

[0038] In a further embodiment of the use of the present invention, female subjects are not simultaneously administered any additional contraceptive component, preferably estrogen.

[0039] In one embodiment of the use of the present invention, amenorrhea is also induced by the administration of levonorgestrel.

[0040] In one embodiment of the use of the present invention, female subjects are not simultaneously administered any further antiviral agents.

[0041] In one embodiment of the use of the present invention, tenofovir is not administered to female subjects at the same time.

[0042] In a further embodiment, the present invention is (a) A core containing a polymer, (b) A sheath substantially or completely surrounding the core, comprising a polymer, (c) Levonorgestrel dissolved or dispersed in the core and / or sheath, The present invention relates to a drug delivery device comprising the above-mentioned core / or sheath, wherein the total amount of levonorgestrel present in the core / or sheath is between approximately 9 mg and approximately 11 mg.

[0043] In a preferred embodiment, the total amount of levonorgestrel present in the core / or sheath is approximately 10 mg.

[0044] In one embodiment, the core polymer is polyurethane, and the sheath polymer is ethylene-vinyl acetate copolymer.

[0045] In one embodiment, the ethylene-vinyl acetate copolymer of the sheath contains a vinyl acetate content of 10% (weight / weight) to 40% (weight / weight), preferably 15% (weight / weight) to 30% (weight / weight).

[0046] In a further embodiment, the delivery device is (a) A core containing polyurethane, (b) A sheath substantially or completely surrounding the core, comprising an ethylene-vinyl acetate copolymer having a vinyl acetate content of about 10% (weight / weight) to 40% (weight / weight), preferably about 15% (weight / weight) to 30% (weight / weight), (c) Levonorgestrel dissolved or dispersed in the core and / or sheath, This includes, where the total amount of levonorgestrel present in the core / or sheath is approximately 10 mg.

[0047] In a further embodiment, the delivery device is (a) A core containing polyurethane, (b) A sheath substantially or completely surrounding the core, comprising an ethylene-vinyl acetate copolymer having a vinyl acetate content of about 18% (by weight / by weight), (c) Levonorgestrel dissolved or dispersed in the core and / or sheath, This includes, where the total amount of levonorgestrel present in the core / or sheath is approximately 10 mg.

[0048] In one embodiment of the drug delivery device described above, the device, after being administered to a female subject, releases levonorgestrel at a constant rate over a period of 28 days.

[0049] In one embodiment, the present invention relates to a drug delivery device containing levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2. During the initial 24-hour release period, approximately 150 μg or less, preferably approximately 130 μg or less of levonorgestrel is released. The present invention relates to a drug delivery device characterized by releasing approximately 60 μg to 90 μg of levonorgestrel per day for at least 27 days following an initial 24-hour release period.

[0050] In one embodiment, the present invention relates to a drug delivery device containing levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2. During the initial 24-hour release period, approximately 70 μg to approximately 150 μg, preferably approximately 70 μg to approximately 130 μg of levonorgestrel is released, and, The present invention relates to a drug delivery device characterized by releasing approximately 60 μg to 90 μg, preferably approximately 60 μg to approximately 80 μg, of levonorgestrel per day for at least 27 days following an initial 24-hour release period.

[0051] In some embodiments, the average daily release of levonorgestrel over a 28-day treatment cycle, including an initial 24-hour release period followed by 27 days, is approximately 60 μg to 100 μg per day, preferably 70 μg to 80 μg, and more preferably 75 μg.

[0052] In one embodiment, the daily release of levonorgestrel over a 28-day treatment cycle, including the initial 24-hour release period followed by 27 days, is not less than approximately 56 μg per day on any given day.

[0053] In a further embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2. During the initial 24-hour release period, approximately 250 μg or less of levonorgestrel is released. The present invention relates to a drug delivery device characterized by releasing approximately 90 μg to 150 μg of levonorgestrel per day for at least 27 days following an initial 24-hour release period.

[0054] In a further embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2. During the initial 24-hour release period, approximately 100 μg to 200 μg, preferably 110 μg to 170 μg, of levonorgestrel is released. The present invention relates to a drug delivery device characterized by releasing approximately 90 μg to 150 μg, preferably approximately 90 μg to 140 μg, of levonorgestrel per day for at least 27 days following an initial 24-hour release period.

[0055] In some embodiments, the average daily release of levonorgestrel over a 28-day treatment cycle, including an initial 24-hour release period followed by 27 days, is approximately 90 μg to 160 μg per day, preferably 105 μg to 140 μg, and more preferably 125 μg.

[0056] In one embodiment, the daily release of levonorgestrel over a 28-day treatment cycle, including the initial 24-hour release period followed by 27 days, is not less than approximately 87 μg per day on any given day.

[0057] In a further embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2. During the initial 24-hour release period, approximately 300 μg or less of levonorgestrel is released. The present invention relates to a drug delivery device characterized by releasing approximately 110 μg to 180 μg of levonorgestrel per day for at least 27 days after the initial 24-hour release period.

[0058] In one embodiment, when the device was subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2, During the initial 24-hour release period, approximately 250 μg or less, preferably approximately 170 μg to approximately 220 μg of levonorgestrel is released. Levonorgestrel is released at a rate of 110 μg to 180 μg per day, preferably about 120 μg to about 170 μg, for at least 27 days following the initial 24-hour release period.

[0059] In one embodiment, the average daily release of levonorgestrel over a 28-day treatment cycle, including an initial 24-hour release period followed by 27 days, is approximately 120 μg to approximately 200 μg per day, preferably approximately 150 μg.

[0060] In one embodiment, the daily release of levonorgestrel over a 28-day treatment cycle, including the initial 24-hour release period followed by 27 days, is not less than approximately 105 μg per day on any given day.

[0061] In one embodiment, the release of levonorgestrel from the delivery device described herein follows a zero-order rate equation after the initial 24-hour release period, i.e., the amount of levonorgestrel released each day is constant.

[0062] In a preferred embodiment, after the delivery device is placed in the subject, levonorgestrel is administered continuously over 28 days via the delivery device.

[0063] In a preferred embodiment, the delivery device according to the present invention does not contain any further active ingredients.

[0064] In a preferred embodiment, the delivery device according to the present invention does not contain any further contraceptive components.

[0065] In one preferred embodiment, the delivery device according to the present invention does not contain an antiviral agent.

[0066] In one preferred embodiment, the delivery device according to the present invention does not contain tenofovir.

[0067] In another preferred embodiment, the delivery device does not contain estrogen.

[0068] In one embodiment of the drug delivery device of the present invention, levonorgestrel is present in the core at a concentration of 0.20% to 1.00% by weight relative to the total weight of the core.

[0069] In a further embodiment, the sheath has a thickness ranging from 5 μm to 500 μm, preferably from 50 μm to 200 μm.

[0070] In one embodiment, the drug delivery device of the present invention, after being placed vaginally in a female subject, yields in the subject an average Cmax value of less than 1 ng / ml for levonorgestrel after one 28-day treatment cycle, and an average Cmax value of less than 0.7 ng / ml for levonorgestrel after two 28-day treatment cycles, and an average AUC(0.-t) value of less than 350 h·ng / ml after one 28-day treatment cycle, and an average AUC(0.-t) value of less than 370 h·ng / ml after two 28-day treatment cycles.

[0071] In another embodiment, the drug delivery device of the present invention, after being placed vaginally in a female subject, yields in the subject a mean Cmax value of less than 1.6 ng / ml for levonorgestrel after one 28-day treatment cycle, and a mean Cmax value of less than 1 ng / ml for levonorgestrel after two 28-day treatment cycles, and a mean AUC(0-t) value of less than 580 h·ng / ml after one 28-day treatment cycle, and a mean AUC(0-t) value of less than 540 h·ng / ml after two 28-day treatment cycles.

[0072] In another embodiment, the drug delivery device of the present invention yields an average Cmax value for levonorgestrel of less than 1.5 ng / ml after one 28-day treatment cycle, and an average Cmax value for levonorgestrel of less than 1 ng / ml after two 28-day treatment cycles, and yields an average AUC(0-t) value of less than 480 h·ng / ml after one 28-day treatment cycle, and an average AUC(0-t) value of less than 540 h·ng / ml after two 28-day treatment cycles.

[0073] In one embodiment, the drug delivery device of the present invention has a shape selected from a spiral shape or a ring shape, and preferably the drug delivery device has a ring shape. In a preferred embodiment, the device is a vaginal ring. [Brief explanation of the drawing]

[0074] [Figure 1] This figure shows the in vitro elution profile of the levonorgestrel vaginal drug delivery system 75 μg / day. [Figure 2] This figure shows the in vitro elution profile of the levonorgestrel vaginal drug delivery system 125 μg / day. [Figure 3] This figure shows the in vitro elution profile of the levonorgestrel vaginal drug delivery system 150 μg / day. [Figure 4]This figure shows estradiol levels by hospital visit and by body mass index. It shows the average estradiol levels for all treatment groups in each treatment cycle and by BMI category. [Figure 5] This figure shows the pharmacokinetic parameters for LNG. It displays the mean concentration-time profiles of LNG from participants in the LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups. [Figure 6] This figure shows the pharmacokinetic parameters for SHBG. It displays the mean concentration-time profiles of LNG and SHBG for participants from the LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups. [Figure 7] This figure shows pharmacokinetic parameters for LNG by body mass index. It displays the mean concentration-time profiles of LNG from participants in the LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, categorized by BMI. [Figure 8] This figure shows the pharmacokinetic parameters for SHBG by body mass index. It displays the mean concentration-time profiles of LNG and SHBG for participants from the LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, categorized by BMI. [Figure 9] This diagram shows schematic diagrams of two shapes of drug delivery devices: A) ring shape and B) spiral shape. [Figure 10] This figure shows the mean SHBG concentration versus time curves (linear plots) for each BMI subgroup (BMI subgroup 1: 30 ≤ BMI ≥ 35, BMI subgroup 2: BMI ≥ 35) after vaginal administration of the levonorgestrel vaginal delivery system (LVDS) over two 28-day treatment cycles (release rate of 75 μg / day). [Figure 11]This figure shows the mean plasma concentration versus time curves (linear plot, PPS) for each BMI subgroup (BMI subgroup 1: 30 ≤ BMI ≥ 35, N=12; BMI subgroup 2: BMI ≥ 35, N=16) after vaginal administration of the levonorgestrel vaginal delivery system (LVDS) over two 28-day treatment cycles (release rate of 75 μg / day). [Modes for carrying out the invention]

[0075] As described above, the object of the present invention was to provide a contraceptive that has very high ovulation-inhibiting efficacy while simultaneously limiting estrogen suppression to an optimal level such as that corresponding to the early follicular phase, thereby avoiding the well-known side effects caused by conventional contraceptives containing levonorgestrel as an active ingredient.

[0076] Therefore, the inventors embarked on developing a delivery device with the desired properties and conducted a multicenter, open-label, randomized phase 2 clinical trial to evaluate the ovulation inhibition of levonorgestrel (LNG) released in a continuous manner over 28 days from an LNG vaginal delivery system (LNG VDS) at three different dosing strengths (75 μg / day, 125 μg / day, and 150 μg / day) in healthy female subjects aged 18 to 35 years, compared to orally administered desogestrel (Cerazet®).

[0077] This study consisted of four stages: a screening phase of a minimum of 4 weeks, and up to 8 weeks if a washout cycle was required; a 28-day pre-treatment cycle; a treatment cycle (TC) consisting of 56 treatment days (two cycles of TC1 and TC2, each of 28 days); and a 28-day post-treatment cycle.

[0078] Ovulation inhibition was measured by assessing ovarian activity in patients by studying follicular growth, serum estradiol concentration, and serum progesterone concentration.

[0079] Furthermore, this study assessed the effects of LNG VDS on cervical mucus, endometrial thickness, resumption of ovulation in the post-treatment cycle, the effects of LNG VDS on blood levels of sex hormones, and the safety and tolerability of LNG VDS.

[0080] A total of 268 subjects were screened, of which 137 were randomized, and 130 were initiated into the study treatment. Efficacy was assessed in the maximum analysis population, i.e., the 128 participants comprising the FAS, and in the protocol-compliant population, i.e., the 118 participants comprising the PP. In the PK / PD analysis, 55 participants constituted the PK group (of which 14 had a 30 kg / m² pharmacokinetic). 2 Of those with a BMI above this level, 41 had a BMI of 18 kg / m². 2 More than 30kg / m 2 (Having a BMI between [number] and [number].

[0081] We were able to reveal that a total of 127 out of 128 participants (99.2%) showed ovulation inhibition during TC1. The only participant who did not show ovulation inhibition was 18 kg / m². 2 More than 30kg / m 2 They belonged to the group with a BMI of less than 5 and were treated with Cerazet. Surprisingly, during TC2, all participants generally experienced ovulation inhibition (125 out of 125 [100%]).

[0082] The number and percentage of participants (Hoogland score 1–2) showing no ovarian activity or minimal ovarian activity were 19 (57.6%), 17 (56.7%), 26 (76.5%), and 26 (83.9%) in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups in TC1, and 15 (48.4%), 19 (63.3%), 28 (84.8%), and 27 (87.1%) in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups in TC2, respectively. The number and percentage of participants showing residual ovarian activity (Hoogland score 3-4) were 13 (39.4%), 13 (43.3%), 8 (23.5%), and 5 (16.1%) in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group in TC1, and 16 (51.6%), 11 (36.7%), 5 (15.2%), and 4 (12.9%) in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group in TC2, respectively.

[0083] In TC1, only one participant (0.8%) had a positive result on the Landgren test. This participant was treated with Cerazet. No positive results on the Landgren score were observed in either group during TC2.

[0084] In summary, these clinical trial data convincingly demonstrate that levonorgestrel administered via the delivery device according to the present invention effectively inhibited ovulation at all three release rates, namely 75 μg / day, 125 μg / day, and 150 μg / day, regardless of the subject's BMI.

[0085] Furthermore, the safety profile of LNG VDS was acceptable, and no serious study-treatment adverse events were observed during the study.

[0086] Accordingly, the present invention relates to levonorgestrel used in a method for providing contraception in a female subject, wherein the method comprises administering levonorgestrel to the subject in a continuous manner, the daily dose of levonorgestrel administered is approximately 60 μg / day to approximately 100 μg / day, and the route of administration is vaginal.

[0087] In one embodiment, the average daily dose of levonorgestrel administered is approximately 75 μg / day, and the route of administration is vaginal.

[0088] As mentioned above, previous studies have shown that when administered orally, levonorgestrel 115 μg / day is the minimum effective dose for consistent ovulation inhibition. Levonorgestrel is known to be completely absorbed after oral administration, resulting in nearly 100% bioavailability and not undergoing first-pass metabolism.

[0089] Surprisingly, it has now been found that even a very low dose of levonorgestrel, 75 μg / day, administered vaginally, completely or almost completely inhibits ovulation.

[0090] Ovarian suppression is dose-dependent, and it is known that higher doses of LNG lead to greater ovarian suppression and lower estradiol levels. Surprisingly, even lower doses of levonorgestrel, such as 75 μg / day, resulted in 30 kg / m² estradiol levels. 2 In all study groups, including those with the above BMI, 100% ovulation inhibition was observed. Thus, administering low doses of levonorgestrel is highly advantageous because it is expected to have fewer side effects.

[0091] As described above, one of the main side effects is estrogen suppression caused by the administration of progestogen monotherapy, which can lead to undesirable hypoestrogenic side effects, particularly bone loss. Although tissue sensitivity to estradiol varies, an average estradiol concentration between 30 pg / ml and 45 pg / ml is assumed to be sufficient to suppress bone loss (13).

[0092] Therefore, in order to avoid the undesirable side effect of decreased bone density, it is essential to maintain estradiol levels within a certain safety level, thus ensuring a good balance between estrogen suppression and contraceptive effect.

[0093] The estrogen suppression induced by administering approximately 75 μg / day of LNG after two treatment cycles was found to be above the desired safety range, i.e., 30 pg / ml.

[0094] Clinical trial data revealed that the mean (SD) estradiol concentrations in TC1 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 in the Cerazet-treated group, LNG VDS 75-treated group, LNG VDS 125-treated group, and LNG VDS 150-treated group, respectively, and in TC2, they were 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-treated group, LNG VDS 75-treated group, LNG VDS 125-treated group, and LNG VDS 150-treated group, respectively.

[0095] Serum estradiol levels observed after two cycles of administration for the three doses of levonorgestrel IVR resulted in lower doses of levonorgestrel (LNG) of 75 μg / day after two treatment cycles being associated with less estrogen suppression and therefore a lower impact on bone loss compared to higher doses of 125 μg / day and 150 μg / day.

[0096] In another embodiment, a decrease in plasma estradiol levels is associated with the improvement of other conditions such as premenstrual syndrome and menorrhagia, as well as other estrogen-dependent pathologies such as uterine fibroids and subserosal endometrial polyps.

[0097] In particular, estrogen suppression is directly related to the improvement of endometriosis. Estrogen plays an important role in the pathophysiology of endometriosis because it promotes the implantation of endometrial tissue into the peritoneum, exerts proliferative and anti-apoptotic effects on endometrial cells, and stimulates local and systemic inflammation (21, 22). Barbieri explained that estradiol levels should be approximately 40 pg / ml to 60 pg / ml to treat endometriosis (13).

[0098] The estrogen suppression caused by administering approximately 75 μg / day of LNG after two treatment cycles was found to be within the desirable range for the treatment of endometriosis, i.e., 40 pg / ml to 60 pg / ml as described above.

[0099] definition As used herein, the term “amenorrhea” refers to the absence of bleeding / trace bleeding in female subjects, preferably women of reproductive age, for at least 56 days or two administration cycles.

[0100] As used herein, the term “burst release” refers to the rate of release of a pharmaceutically active ingredient over time, which is not uniform and generally increases over a given period, typically immediately after a device containing the pharmaceutically active ingredient is implanted in tissue.

[0101] Where used herein, the term “complete ovulation inhibition” refers to 100% ovulation inhibition in a subject. The term “near-complete ovulation inhibition” should be understood as 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% ovulation inhibition in a subject.

[0102] As used herein, “method of contraception” or “method of providing contraception” means a method of preventing pregnancy.

[0103] As used herein, the term “dysmenorrhea” refers to a medical term relating to the painful menstrual period caused by uterine contractions. Primary dysmenorrhea refers to recurrent pain, while secondary dysmenorrhea is caused by a disorder of the reproductive system.

[0104] As used herein, the term “dispersed” means that one or more pharmaceutically active ingredients form a dispersion in a core polymer or sheath polymer, and therefore they are partially or completely present in a solid granular form suspended in or surrounded by a continuous phase.

[0105] As used herein, the term “dissolved” means that one or more pharmaceutically active ingredients form a solution within the core polymer or sheath polymer, so that they are distributed within the core polymer or sheath polymer and form a homogeneous phase.

[0106] As used herein, the terms “endometriosis” and “endometriosis-associated pelvic pain (EAPP)” refer to estrogen-dependent chronic diseases characterized by the formation of extrauterine endometrial lesions, including those in the ovaries and other pelvic structures, and one of its most common symptoms, reported as pelvic pain, respectively. All subtypes of endometriosis are included, including superficial, cystic, deeply invasive, abdominal wall, and catamenial endometriosis. The effectiveness of managing endometriosis-associated pelvic pain (EAPP) can be assessed using different rating scales, such as visual analog scales (VAS) or numerical rating scales (NRS), which are well known to those skilled in the art (see, for example, Gerlinger et al. (2010) and Breivik et al. (2008)). Depending on the rating scale, for example, on an NRS scale of 0 to 10, a difference from placebo of at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, or at least 3.0 can already be considered clinically significant and to provide a real benefit to the patient.

[0107] As used herein, the term “estrogen” refers to a group of steroid hormones that promote the development and maintenance of female physical characteristics. Synthetic estrogens are well known and commonly used in oral contraceptives or for the treatment of menopausal and menstrual disorders.

[0108] As used herein, "levonorgestrel" or "LNG" refers to levonorgestrel itself, i.e., the chemical entity identified by CAS Registry No. 797-63-7, the solvates of levonorgestrel, and derivatives or prodrugs of levonorgestrel.

[0109] As used herein, the terms “post-treatment cycle” or “post-treatment” refer to the 28 days after TC, beginning on day 1 after removal of LNG VDS or day 1 without oral administration of Cerazet.

[0110] As used herein, “progestogen-only contraceptive” or “progestogen-only pill” (also known as “POP”) means a pill or contraceptive containing progestogen as the sole contraceptive active ingredient and containing no estrogen whatsoever.

[0111] As used herein, “therapeutic dose” means the amount of medication and duration effective in achieving one or more desirable therapeutic outcomes, such as a significant delay in the onset or progression of a disease, or a significant reduction in the severity of one or more symptoms. A therapeutic dose is also typically the amount in which the therapeutically beneficial effect outweighs any toxic or adverse effects of the active ingredient or pharmaceutical composition.

[0112] As used herein, the term “treatment cycle” (TC) refers to a total of 56 consecutive treatment days. Treatment cycle 1 (TC1) refers to a first cycle consisting of 28 days, and treatment cycle 2 (TC2) refers to a second cycle consisting of 28 days.

[0113] As used herein, “treatment,” “to treat,” or “to treat” means (i) preventing or delaying the onset of a disease, disorder, or condition in a subject who is susceptible to a disease, disorder, or condition but has not yet been diagnosed with the disease; (ii) inhibiting a disease, disorder, or condition, i.e., stopping or delaying its onset or progression; and / or (iii) alleviating a disease, disorder, or condition, i.e., causing a regression of the disease, disorder, or condition. In certain embodiments, such terms mean improvement or elimination of a disease or symptoms associated with a disease.

[0114] In this specification, the terms "vaginal administration" and "intravaginal administration" may be used interchangeably. These terms refer to the administration of a compound, preferably levonorgestrel, through the vaginal mucosa. It should be understood that "vaginal administration" does not include intrauterine administration via devices inserted into the uterus, such as intrauterine devices (IUDs). Vaginal administration may be performed via devices such as intravaginal rings (IVRs) placed within the vaginal canal.

[0115] As used herein, “zero-order” or “near-zero-order” means that a nearly constant or constant amount of drug per unit time is released over a given period of time. For the purposes of this invention, the term “nearly constant amount” is defined by Higuchi’s formula; see Pharmaceutical Sciences 1963, vol. 52, 1145–1149.

[0116] Method of the present invention The present invention relates to levonorgestrel used in a method for providing contraception to a female subject, wherein the method comprises administering levonorgestrel to the subject in a continuous manner, and the daily dose of levonorgestrel administered is approximately 60 μg / day to approximately 100 μg / day.

[0117] In one embodiment, the present invention relates to levonorgestrel used in a method for providing contraception to a female subject, wherein the method comprises administering levonorgestrel to the subject continuously, the average daily dose of levonorgestrel administered is about 75 μg / day, and the route of administration is vaginal.

[0118] Surprisingly, we were able to demonstrate that an average dose of 75 μg / day administered vaginally resulted in complete or near-complete inhibition of ovulation. At the same time, the 75 μg / day dose administered vaginally resulted in less estrogen suppression than the higher doses tested after two administration cycles, thus reducing undesirable side effects caused by estrogen suppression, such as bone loss.

[0119] The estrogen suppression caused by administering an average of approximately 75 μg / day of LNG after two treatment cycles was found to be within the desirable range for the treatment of endometriosis, i.e., 40 pg / ml to 60 pg / ml as described above.

[0120] Accordingly, the present invention relates to levonorgestrel used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in a female subject, wherein the method comprises administering levonorgestrel to the subject in a continuous manner, the daily dose of levonorgestrel administered being about 60 μg / day to about 160 μg / day, and preferably the route of administration being vaginal.

[0121] In one embodiment, the present invention relates to levonorgestrel used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, wherein the method comprises administering levonorgestrel to the subject in a continuous manner, the average daily dose of levonorgestrel administered being approximately 75 μg / day to approximately 150 μg / day.

[0122] In one embodiment, the present invention relates to levonorgestrel used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, wherein the method comprises administering levonorgestrel to the subject continuously, the average daily dose of levonorgestrel administered is about 75 μg / day, about 125 μg / day, or about 150 μg / day, and preferably the route of administration is vaginal.

[0123] In one embodiment, the average daily dose of levonorgestrel administered is approximately 75 μg / day to approximately 125 μg / day.

[0124] In a further preferred embodiment, the above treatment also provides contraception. As described in more detail above, administration of all three dosages used in the clinical trials resulted in complete or near-complete inhibition of ovulation.

[0125] In a preferred embodiment of the method of the present invention, the route of administration is via the mucous membrane, preferably via the vaginal route.

[0126] In a further embodiment of the method of the present invention, no further contraceptive components are administered to the female subject at the same time.

[0127] In a preferred embodiment of the method of the present invention, estrogen is not administered to female subjects at the same time.

[0128] In one embodiment of the method of the present invention, amenorrhea is also induced by the administration of levonorgestrel as described herein.

[0129] In another embodiment, the present invention relates to levonorgestrel used in a method for treating uterine fibroids and other estrogen-dependent pathologies such as subserosal endometrial polyps.

[0130] use In a further embodiment, the present invention relates to the use of levonorgestrel as a contraceptive, comprising administering levonorgestrel to female subjects in a continuous dose of approximately 60 μg / day to approximately 200 μg / day, with the route of administration being vaginal.

[0131] In one embodiment of the above-described aspect, the present invention relates to the use of levonorgestrel as a contraceptive, comprising continuously administering levonorgestrel to a female subject at an average dose of approximately 75 μg / day to 150 μg / day, wherein the route of administration is vaginal.

[0132] In one embodiment of the above-described aspect, the present invention relates to the use of levonorgestrel as a contraceptive, comprising continuously administering levonorgestrel to female subjects at an average dose of approximately 75 μg / day, approximately 125 μg / day, or approximately 150 μg / day, with the route of administration being vaginal.

[0133] In a further embodiment of the use of the present invention, female subjects are not simultaneously administered any additional contraceptive component, preferably estrogen.

[0134] In one embodiment of the use of the present invention, amenorrhea is also induced by the administration of levonorgestrel as described above.

[0135] In one preferred embodiment of the method, or the use of levonorgestrel, ovulation is restored in more than 80% of female subjects within 28 days of post-treatment. In contrast, in the Cerazet treatment group, ovulation is restored in only 69.7% of female subjects within 28 days of post-treatment.

[0136] device In a further embodiment, the present invention is (a) A core containing a polymer, (b) A sheath substantially or completely surrounding the core, comprising a polymer, (c) Levonorgestrel dissolved or dispersed in the core and / or sheath, The present invention relates to a drug delivery device comprising the above-mentioned core / or sheath, wherein the total amount of levonorgestrel present in the core / or sheath is between approximately 9 mg and approximately 11 mg.

[0137] In one embodiment, the total amount of levonorgestrel present in the core / or sheath is approximately 10 mg.

[0138] In one embodiment of the above-described model, the polymer is selected from low-density polyethylene, ethylene-vinyl acetate copolymer, styrene-butadiene-styrene copolymer, polyurethane, poly(dimethylsiloxane), or silicone polyetheramide copolymer, silicone, silicone-poly(carbonate urethane), poly(carbonate urethane), and silicone-poly(ether urethane), or a combination thereof.

[0139] In one embodiment, the core polymer is polyurethane, and the sheath polymer is ethylene-vinyl acetate copolymer.

[0140] In one embodiment, the ethylene-vinyl acetate copolymer of the sheath contains a vinyl acetate content of 10% (weight / weight) to 40% (weight / weight), preferably 15% (weight / weight) to 30% (weight / weight).

[0141] In one embodiment, the present invention is (a) A core containing polyurethane, (b) A sheath substantially or completely surrounding the core, comprising an ethylene-vinyl acetate copolymer (EVA) having a vinyl acetate content of 10% (weight / weight) to 40% (weight / weight), preferably 15% (weight / weight) to 30% (weight / weight), (c) Levonorgestrel dissolved or dispersed in the core and / or sheath, The present invention relates to a drug delivery device comprising, wherein the total amount of levonorgestrel present in the core / or sheath is approximately 10 mg.

[0142] In a further embodiment, the delivery device is (a) A core containing polyurethane, (b) A sheath substantially or completely surrounding the core, comprising an ethylene-vinyl acetate copolymer having a vinyl acetate content of about 18% (by weight / by weight), (c) Levonorgestrel dissolved or dispersed in the core and / or sheath, This includes, where the total amount of levonorgestrel present in the core / or sheath is approximately 10 mg.

[0143] The device core contains polyurethane. Polyurethane (PU) is a polymer composed of chains of organic units linked by carbamate (urethane) linkages. Suitable polyurethanes that can be used as core polymers 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), thermoplastic silicone polyether polyurethanes, thermoplastic silicone polycarbonate polyurethanes, and hydrophilic thermoplastic polyurethane elastomers, or combinations thereof. Suitable commercially available polyurethanes include, but are not limited to, Tecophilic®, Tecoflex®, Tecothane®, Carbothane®, Chronothane®, Elasthane®, Pursil®, Hydrothane®, and PATHWAY®. Preferred materials are the polyurethanes Hydrothane® AL25 80A and PATHWAY® PY-PT80AE25.

[0144] PATHWAY PY-PT80AE25 is an aliphatic polyether-based thermoplastic polyurethane offered by LUBRIZOL.

[0145] Hydrothane® AL25 80A is disclosed in U.S. Patent No. 9,872,829.

[0146] In one embodiment, the core polymer contains at least 50% polyurethane. In one embodiment, the core contains at least 60% polyurethane. In one embodiment, the core contains at least 70% polyurethane. In one embodiment, the core contains at least 80% polyurethane. In one embodiment, the core contains at least 90% polyurethane. In one embodiment, the core contains at least 95% polyurethane. In one embodiment, the core is essentially made of polyurethane, i.e., the core contains 50% to 100%, more specifically 75% to 100% polyurethane. The above percentages refer to weight percentages (weight of polyurethane relative to weight of core).

[0147] The core may further contain one or more of the following additives: release modifiers (including, but not limited to, polyethylene glycerol, glucose, glycine, ascorbic acid, hydroxyethylcellulose, croscarmellose, and lactose), fillers (including, but not limited to, high-surface-area fumed silica and precipitated silica, clay 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-tertiary butyl-4-hydroxyphenyl)-propionate (Irganox®), ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), citric acid (CA), butylated hydroxytoluene) A combination thereof may include cyanisol (BHA), tertiary butylhydroquinone (TBHQ), and propyl 30 gallate (PG) and α-tocopherol; lubricants (but not limited to irgawax, talc, aerosil, and stearates such as magnesium stearate); and additives (but not limited to water-soluble polysaccharides or water-swellable polysaccharides such as croscarmellose (cross-linked carboxymethylcellulose) or hydroxyethylcellulose, glucose, lactose, or other monosaccharides or disaccharides, or their water-soluble salts, proteins such as gelatin, nonionic surfactants, bile salts, ethoxydiglycol, polyethylene glycol, and organic solvents such as fatty acid esters).

[0148] As used herein, the expression “substantially surrounding the core” means that at least 90%, more specifically 95%, and more specifically 100% of the core’s surface area is surrounded by the sheath. In a preferred embodiment, the ethylene-vinyl acetate copolymer sheath completely surrounds the core.

[0149] As described above, the device sheath contains an ethylene-vinyl acetate (EVA) copolymer. EVA is a semicrystalline copolymer of an ethylene monomer and a vinyl acetate (VA) monomer. The specific ethylene-vinyl acetate copolymer used for the sheath will depend on the desired drug permeation flux and can be any commercially available ethylene-vinyl acetate copolymer. In one embodiment, in arbitrary combination with one or more features of the various embodiments described above or below, the sheath contains an EVA copolymer having a vinyl acetate (VA) content of 1% (weight / weight) to 50% (weight / weight), more specifically 10% (weight / weight) to 40% (weight / weight), and even more specifically 15% (weight / weight) to 30% (weight / weight). In a preferred embodiment, the EVA sheath copolymer has a vinyl acetate content of 15% (weight / weight) to 20% (weight / weight), more preferably about 18% (weight / weight).

[0150] For the purposes of this invention, "vinyl acetate content" refers to the weight content of vinyl acetate relative to the total weight of the ethylene-vinyl acetate copolymer.

[0151] Suitable commercially available ethylene-vinyl acetate copolymers include those available under the trade names Elvax®, VitalDose®, Evatane®, Lupolen V®, Movriton®, Ultrathene®, Ateva®, Vestypar®, Dupont 760, Equistar UE637-000, Huntsman PE1903, and F 100309 (Exxon Mobil).

[0152] In one embodiment, the sheath contains 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 is essentially made of ethylene-vinyl acetate, i.e., the sheath contains 50% to 100%, more specifically 75% to 100% ethylene-vinyl acetate. The above percentages refer to weight percentages (weight of ethylene-vinyl acetate relative to the weight of the sheath).

[0153] The sheath may further contain one or more of the following additives: release modifiers (including, but not limited to, polyethylene glycerol, glucose, glycine, ascorbic acid, hydroxyethylcellulose, croscarmellose, and lactose), fillers (including, but not limited to, high surface area fumed silica and precipitated silica, clay 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-tertiary butyl-4-hydroxyphenyl)-propionate (Irganox®), ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), citric acid (CA), butyric acid A combination of the following: hydroxyanisole hydroxylated (BHA), tertiary butylhydroquinone (TBHQ), propyl 30 gallate (PG), and α-tocopherol; lubricants (but not limited to irga wax, talc, aerosil, and stearates such as magnesium stearate); and additives (but not limited to croscarmellose (cross-linked carboxymethylcellulose) or hydroxyethylcellulose, or other water-soluble polysaccharides or water-swellable polysaccharides, glucose, lactose, or other monosaccharides or disaccharides, or their water-soluble salts, proteins such as gelatin, nonionic surfactants, bile salts, ethoxydiglycol, polyethylene glycol, and organic solvents such as fatty acid esters).

[0154] In a particular embodiment, in arbitrary combination with one or more features of the various embodiments described above or below, the core weight accounts for 70% to 95% of the total device weight, the sheath weight accounts for 5% to 30% of the total device weight, and the total device weight is 100%.

[0155] In a preferred embodiment, LNG is present in the core. In a more preferred embodiment, LNG is present in the core at a concentration lower than its saturation concentration at 25°C.

[0156] The inventors have found that levonorgestrel is highly soluble in the core polymer, particularly at the concentrations listed below. Therefore, since LNG is present at concentrations below its saturation concentration, there is no tendency for LNG to crystallize over time at any practical temperature. As a result, the device of the present invention remains stable even when stored at room temperature for extended periods, particularly for at least six months. This has the advantage that the device does not require costly storage and transportation below room temperature.

[0157] In a preferred embodiment of the drug delivery device of the present invention, the core comprises a hydrophilic thermoplastic polyurethane, preferably PATHWAY® PY-PT80AE25, and a polymer sheath of EVA having concentrations of 0.46% (weight / weight) and 0.51% (weight / weight) of levonorgestrel and a vinyl acetate content of 18% (weight / weight).

[0158] The inventors have found that when the devices of the present invention, particularly the devices described above, are exposed to tissue or an in vitro release medium, levonorgestrel is eluted in zero-order or near-zero-order manner, thereby minimizing potential peak / trough fluctuations and side effects, while maximizing the amount of time the drug concentration remains within the treatment window (efficacy). In this specification, “zero-order” or “near-zero-order” means that approximately constant or constant amounts of the drug per unit time are released over a given period. For the purposes of the present invention, the term “approximately constant amount” is defined by Higuchi’s formula; see Pharmaceutical Sciences 1963, vol. 52, 1145–1149.

[0159] Furthermore, the devices described above also exhibit low initial burst release. The term "burst release" refers to the rate of release of the active ingredient over time, which is not uniform and generally increases throughout a given period, typically immediately after a device containing the active ingredient is implanted in tissue.

[0160] In one embodiment, the present invention relates to a drug delivery device containing levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2. During the initial 24-hour release period, approximately 150 μg or less, preferably approximately 130 μg or less of levonorgestrel is released. The present invention relates to a drug delivery device characterized by releasing approximately 60 μg to 90 μg of levonorgestrel per day for at least 27 days following an initial 24-hour release period.

[0161] In one embodiment, the present invention relates to a drug delivery device containing levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2. During the initial 24-hour release period, approximately 70 μg to 150 μg, preferably approximately 70 μg to 130 μg, of levonorgestrel is released. The present invention relates to a drug delivery device characterized by releasing approximately 60 μg to 90 μg, preferably approximately 60 μg to 80 μg, of levonorgestrel per day for at least 27 days following an initial 24-hour release period.

[0162] In one embodiment, when the device was subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2, During the initial 24-hour release period, approximately 90 μg to 140 μg of levonorgestrel is released. Levonorgestrel is released at a rate of approximately 65 μg to 80 μg per day for at least 27 days following the initial 24-hour release period.

[0163] In one embodiment of the above-described model, at least 56 μg, preferably about 56 μg to about 90 μg of levonorgestrel is released on day 28.

[0164] In one embodiment of the preferred embodiment described above, the daily release of levonorgestrel over a 28-day treatment cycle, including an initial 24-hour release period followed by 27 days, is no less than approximately 56 μg per day.

[0165] Furthermore, the average daily release of levonorgestrel over a 28-day treatment cycle, including the initial 24-hour release period followed by the 27 days after the initial 24-hour release period, is preferably about 60 μg to about 100 μg per day, preferably about 70 μg to about 80 μg, and more preferably about 75 μg.

[0166] In a preferred embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2. During the initial 24-hour release period, release less than 250 μg of levonorgestrel. The present invention relates to a drug delivery device characterized by releasing approximately 90 μg to 150 μg of levonorgestrel per day for at least 27 days following an initial 24-hour release period.

[0167] In a further embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH 4.2 medium. During the initial 24-hour release period, approximately 100 μg to 200 μg, preferably 110 μg to 170 μg, of levonorgestrel is released. The present invention relates to a drug delivery device characterized by releasing approximately 90 μg to 150 μg, preferably approximately 90 μg to 140 μg, of levonorgestrel per day for at least 27 days following an initial 24-hour release period.

[0168] In a preferred embodiment, when the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2, During the initial 24-hour release period, release less than 220 μg of levonorgestrel. Levonorgestrel is released at a rate of approximately 105 μg to 135 μg per day for at least 27 days following the initial 24-hour release period.

[0169] In one embodiment of the preferred embodiment described above, levonorgestrel is released on day 28 in amounts exceeding approximately 85 μg up to 95 μg.

[0170] In one embodiment of the preferred embodiment described above, the daily release of levonorgestrel over a 28-day treatment cycle, including an initial 24-hour release period followed by 27 days after the initial 24-hour release period, is no less than approximately 87 μg per day.

[0171] Furthermore, the average daily release of levonorgestrel over a 28-day treatment cycle, including the initial 24-hour release period followed by 27 days, is preferably about 90 μg to about 160 μg per day, preferably about 105 μg to about 140 μg, and more preferably about 125 μg.

[0172] In a preferred embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2. During the initial 24-hour release period, release less than 300 μg of levonorgestrel. The present invention relates to a drug delivery device characterized by releasing approximately 110 μg to 180 μg of levonorgestrel per day for at least 27 days after the initial 24-hour release period.

[0173] In a preferred embodiment, when the device is subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2, During the initial 24-hour release period, levonorgestrel is released in an amount of 250 μg or less, preferably about 170 μg to about 220 μg. Levonorgestrel is released at a rate of approximately 110 μg to 180 μg per day, preferably approximately 120 μg to 170 μg per day, for at least 27 days following the initial 24-hour release period.

[0174] In one embodiment of the preferred embodiment described above, levonorgestrel is released on day 28 in an amount exceeding approximately 100 μg up to 110 μg, preferably exceeding approximately 105 μg.

[0175] In one embodiment, the daily release of levonorgestrel over a 28-day treatment cycle, including an initial 24-hour release period followed by 27 days, is not less than approximately 105 μg per day on any given day.

[0176] Furthermore, the average daily release of levonorgestrel over a 28-day treatment cycle, including the initial 24-hour release period followed by the 27 days after the initial 24-hour release period, is preferably about 120 μg to about 200 μg per day, preferably about 150 μg.

[0177] In a preferred embodiment, the release of levonorgestrel from the delivery device described herein follows a zero-order rate equation after the initial 24-hour release period, i.e., the amount of levonorgestrel released each day is constant.

[0178] In one embodiment, constant release means that the amount of levonorgestrel released per day can vary by up to 20% to 25%.

[0179] In a preferred embodiment, the vaginal ring according to the present invention does not contain any further active ingredients.

[0180] In one embodiment of the drug delivery device of the present invention, levonorgestrel is present in the core at a concentration of about 0.20% to 1.00% by weight relative to the total weight of the core.

[0181] In a further embodiment, the sheath has a thickness ranging from about 5 μm to 500 μm, preferably from about 50 μm to 200 μm.

[0182] In one embodiment, the drug delivery device of the present invention, after being placed vaginally in a female subject, yields in the subject an average Cmax value of less than 1 ng / ml for levonorgestrel after one 28-day treatment cycle, and an average Cmax value of less than 0.7 ng / ml for levonorgestrel after two 28-day treatment cycles, and an average AUC(0.-t) value of less than 350 h·ng / ml after one 28-day treatment cycle, and an average AUC(0.-t) value of less than 370 h·ng / ml after two 28-day treatment cycles.

[0183] In another embodiment, the drug delivery device of the present invention, after being placed vaginally in a female subject, yields in the subject a mean Cmax value of less than 1.6 ng / ml for levonorgestrel after one 28-day treatment cycle, and a mean Cmax value of less than 1 ng / ml for levonorgestrel after two 28-day treatment cycles, and a mean AUC(0-t) value of less than 580 h·ng / ml after one 28-day treatment cycle, and a mean AUC(0-t) value of less than 540 h·ng / ml after two 28-day treatment cycles.

[0184] In another embodiment, the drug delivery device of the present invention yields a mean Cmax value for levonorgestrel less than 1.5 ng / ml after one 28-day treatment cycle, and a mean Cmax value for levonorgestrel less than 1 ng / ml after two 28-day treatment cycles, and yields a mean AUC(0-t) value of less than 480 h·ng / ml after one 28-day treatment cycle, and a mean AUC(0-t) value of less than 540 h·ng / ml after two 28-day treatment cycles.

[0185] In one embodiment, the drug delivery device of the present invention has a shape selected from a spiral shape (helical shape) or a ring shape, and preferably the drug delivery device has a ring shape. Various shapes are shown in Figures 9A) and B). In a preferred embodiment, the device is a vaginal ring. More specifically, the ring-shaped device has an outer diameter in the range of 50 mm to 60 mm, more specifically 52 mm to 56 mm, and an inner diameter in the range of 40 mm to 48 mm, more specifically 44 mm to 48 mm, and a cross-sectional diameter in the range of 2.5 mm to 8 mm, preferably 4 mm.

[0186] Preferably, this dosage form shall contain no estrogen whatsoever, which may be beneficial for contraception but potentially harmful to certain estrogen-induced disorders.

[0187] Any feature described herein may be optionally combined with any embodiment of any medical or contraceptive use, composition, kit, method of contraception, treatment method, or method of manufacture of the present invention, and it is intended that any embodiment considered herein may be carried out in any of these. Specific embodiments described herein are provided as examples, not as limitations of the present invention.

[0188] All publications and patent applications constitute part of this Spec. by reference, as is indicated by each individual publication or patent application that they constitute part of this Spec.

[0189] The use of the words "a" or "an" can mean "one," but it can also mean "one or more," "at least one," and "one or two or more." The use of the term "another" can refer to one or more. The use of the term "or" in a claim is used to mean "and / or" unless it refers only to substitutes or explicitly states that the substitutes are mutually exclusive.

[0190] Where used herein and in the claims (which may be more), the words “comprising” (and any form of “comprising,” such as “comprise” and “comprises”), “having” (and any form of “having,” such as “have” and “has”), “including” (and any form of “including,” such as “includes” and “include”), or “containing” (and any form of “containing,” such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, undeclared elements or process steps. The term “comprises” also includes and expressly discloses the terms “consists of” and “consists essentially of.” Where used herein, the phrase “consists essentially of” limits the scope of the claim to the specified materials or processes and does not materially affect the basic and novel characteristics of the invention described in the claim. As used herein, the phrase "consisting only of" excludes any elements, processes, or components not explicitly stated in the claims, other than, for example, impurities that normally accompany an element or limitation.

[0191] As used herein, the term “or any combination thereof” means any rearrangement and combination of the listed items preceding this term. For example, “A, B, C, or any combination thereof” is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and also intended to include BA, CA, CB, CBA, BCA, ACB, BAC, or CAB, where the order is important in particular circumstances. Following this example, expressly included are combinations that involve the repetition of one or more items or terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc. A person skilled in the art will understand that, unless otherwise particularly evident from the context, there is typically no limit to any combination of the number of items or terms.

[0192] Where used herein, but not limited to, approximants such as “about,” “around,” and “approximately” are understood not necessarily absolute or perfect when modified in this way, and refer to a state that is considered to be close enough to guarantee to a person skilled in the art that the state exists. The degree to which the description may differ depends on how significant the change may be and whether a person skilled in the art can be convinced that the modified function still possesses the characteristics and capabilities required of the original function. Generally, given the preceding discussion, numerical values ​​in this specification modified with approximants such as “about” may differ from the stated value by ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%. Therefore, the term “about” may mean ±5% of the indicated value, preferably ±2%, and most preferably “about” may mean exactly the indicated value (±0%).

[0193] The following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the present invention. [Examples]

[0194] Example 1: The vaginal delivery system (VDS) contains the following components: [Table 1]

[0195] Manufacturing process: VDS was manufactured by a process that included the following steps:

[0196] 1) Drying of the polymer: The thermoplastic polyurethane elastomer PY-PT80AE25 is dried in an air dryer at 80°C for at least 6 hours.

[0197] 2) Blending: The materials were homogenized using a GlenMills T2F Turbulent Mixer. The following materials were added to the bottle in the following order: a) fraction A of thermoplastic polyurethane elastomer, b) pulverized levonorgestrel, c) fraction B of thermoplastic polyurethane elastomer, and blended at 13 rpm for 30 minutes.

[0198] 3) Formulation: LNG was blended into a thermoplastic polyurethane elastomer using a Leistritz ZSE18 twin-screw extruder. The dry-blended LNG and polymer were fed into the extruder by a gravimetric feeder and extruded through a strand die equipped with a circular orifice. The extruder's processing zone was set to 130°C to 150°C, and the screw speed was set to 120 rpm to 180 rpm. The extruded strands were cooled in a water bath and fed directly into a pelletizing unit.

[0199] 4) Strand pelletization: Cooled fibers were directly drawn out by a pelletization unit and pelletized into 3.0 mm long pellets.

[0200] 5) Drying of pellets: The API-loaded polymer pellets were dried in an air dryer at 80°C for at least 4 hours.

[0201] 6) Blending: The dry pellets were mixed at 13 rpm for 5 minutes.

[0202] 7) Co-extrusion: Polymer pellets loaded with API were used as the core material, and ethylene-vinyl acetate copolymer (VA content 18% (wt / wt)) pellets were used as the skin material. These were further extruded through a coaxial extrusion apparatus. The coaxial extrusion apparatus consisted of two extruders, two melt pumps, a co-extrusion die, and connecting tubes. The process temperature of the core extruder was set to 130°C to 150°C. The output of the core material was controlled by a melt pump set to 42%. The process temperature of the skin extruder was set to 120°C to 150°C. The output of the skin material was controlled by a melt pump set to 30 rpm. The core-sheath fibers were discharged from the co-extrusion die and cooled in a vertical water bath. The water temperature was set to 9°C.

[0203] 8) Strand cutting: The fibers were pulled out at 3.8 m / min by a tension conveyor and then cut into 157 mm segments / strands. The 4 mm fiber diameter was continuously controlled by a laser gauge.

[0204] 9) Welding: The ends of the two strands were joined by heat. When the ends of the 157 mm strands were joined in the welding equipment, the fibers were forced to take on a torus structure, thus obtaining a core-sheath vaginal ring with an outer diameter of 54 mm, an inner diameter of 46 mm, and a cross-sectional diameter of 4 mm.

[0205] Figures 1, 2, and 3, as well as Tables 2 to 4 below, show the daily in vitro elution profiles for the levonorgestrel vaginal rings at 75 μg / day, 125 μg / day, and 150 μg / day. The in vitro release rate of levonorgestrel in Example 1 was determined by immersing the sample in 200 mL (day 1) and 100 mL (days 2-28) of 0.2 M sodium acetate buffer aqueous solution containing 1.0% sodium lauryl sulfate (SLS) surfactant, and adjusting the pH to 4.2 at 37°C while continuously stirring at 60 rpm. Levonorgestrel concentration was determined daily by HPLC using a Waters XBridge C18 column, a flow rate of 1.0 ml / min, and an injection volume of 25 μL. Detection was performed by UV detection at 240 nm.

[0206] [Table 2]

[0207] [Table 3]

[0208] [Table 4]

[0209] Example 2: A multicenter, open-label, randomized phase 2 clinical trial was conducted to evaluate the ovulation inhibition of three levonorgestrel (LNG) vaginal delivery systems (VDS) with three different potencies, released in a continuous manner over 28 days, compared to desogestrel (Cerazet®), as further detailed below in this specification:

[0210] 1. Research Design 1.1. Purpose Main purpose: The inhibition of ovulation by levonorgestrel (LNG) vaginal delivery system (VDS) in treatment cycles (TC) 1 and TC2, as measured by ovarian activity (follicular growth, serum estradiol concentration, and serum progesterone concentration), will be evaluated compared to desogestrel (Cerazet).

[0211] Secondary purpose: The effects of LNG VDS on cervical mucus and endometrial thickness will be evaluated. The effect of LNG VDS on blood levels of sex hormones will be assessed. The safety and tolerability of LNG VDS, as well as the resumption of ovulation in the post-treatment cycle, will be evaluated.

[0212] 1.2.Methodology A multicenter, open-label, randomized phase 2 clinical trial evaluating the ovulation inhibition of LNG VDS at three different dosage levels (75 μg / day, 125 μg / day, and 150 μg / day) released in a continuous pattern over 28 days, compared to desogestrel (Cerazet), in healthy female subjects aged 18 to 35 years.

[0213] This study consists of four stages: Screening phase (minimum 4 weeks, up to 8 weeks if a washout cycle is required). Pre-treatment cycle (28 days) and randomization. A treatment cycle consisting of 56 treatment days (2 cycles, 28 days per cycle). Post-treatment cycle (28 days).

[0214] A total of 268 subjects were screened, of which 137 were randomized, and 130 were initiated into the study treatment (safety analysis population, i.e., SAS). Efficacy was assessed in the maximum analysis population, i.e., the FAS, consisting of a total of 128 participants, and in the protocol-compliant population, i.e., the PP, consisting of 118 participants. In the PK / PD analysis, 55 participants constituted the PK group (of which 14 had a 30 kg / m² urinary tract). 2 Of those with a BMI above this level, 41 had a BMI of 18 kg / m².2 with a BMI below 30 kg / m 2 (had).

[0215] 1.3. Test article, dosage, and administration method LNG VDS for vaginal administration was used. Each LNG VDS contained approximately 10 mg of LNG, which was designed to release 75 μg / day, 125 μg / day, or 150 μg / day of LNG. One LNG VDS was to last continuously for 28 days.

[0216] 1.4. Duration of treatment The treatment was carried out over 56 days, i.e., two consecutive treatment cycles (TC1 and TC2) of 28 days each.

[0217] 1.5. Reference therapy, dosage, and administration method As a reference, desogestrel (Cerazet) 75 μg film-coated tablets were used and orally administered continuously for 28 days in each cycle.

[0218] 2. Evaluation criteria 2.1. Primary efficacy Inhibition of ovulation was determined by calculating the Hoogland score combining the measurement of follicle size (mm) by TVU and the progesterone / estradiol serum concentration (nmol / L) (if ovulation was suspected by ultrasound examination during TC1 or TC2, this was confirmed by the blood progesterone level and reflected by the Landgren score).

[0219] Analysis of the primary assessment item: Inhibition of ovulation (yes, no) was analyzed through a logistic regression model comparing the inhibition of ovulation between treatment groups with BMI included as a covariate. Their two-sided 95% CIs were calculated together with the adjusted odds ratio (OR). No hypothesis testing was performed.

[0220] 2.2. Secondary efficacy When the follicles had a diameter exceeding 13 mm, the Insler score was evaluated before the cycle, in TC1 and TC2, and in the post-treatment cycle. The endometrial thickness was followed by TVU throughout the cycles. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, and SHBG were analyzed. Resumption of ovulation was evaluated in the post-treatment cycle.

[0221] Secondary assessment item analysis: Secondary efficacy parameters were described using appropriate descriptive statistics for binary variables, categorical variables, or continuous variables by treatment group and cycle. No hypothesis testing was performed.

[0222] 2.3. Safety Vital signs Laboratory analysis Incidence of adverse events (AE) The vaginal bleeding pattern was evaluated by daily diary entries by the subjects and thus by assessment of cycle control and occurrence of breakthrough bleeding.

[0223] 2.4. PK analysis The PK parameters of LNG were correlated with SHBG levels and inhibition of ovulation within a subgroup of subjects receiving LNG from the overall randomized population consisting of 12 subjects with a BMI less than 18 kg / m 2 to 30 kg / m 2 or more and 7 subjects with a BMI of 30 kg / m 2 or more.

[0224] The pharmacokinetic parameters of LNG were determined and these were correlated with inhibition of ovulation and SHBG levels in a subgroup of 55 subjects who had used the LNG VDS, including 41 subjects with a BMI less than 18 kg / m 2 to 30 kg / m 2 2]or more and 14 subjects with a BMI of 30 kg / m 2 or more.

[0225] 3. Statistical methods The analysis in this study was exploratory and primarily employed descriptive statistical methods. Furthermore, exploratory statistical tests and modeling were used to reveal interesting aspects of the data. For continuous variables (Landgren score, Insler score, endometrial thickness, pituitary hormones, bleeding patterns, demographic and baseline characteristics, and safety parameters), the descriptive statistics presented were the number of subjects (n), mean, median, standard deviation (SD), minimum and maximum values ​​(max), and quantiles (1st to 3rd) at each scheduled visit.

[0226] Changes from baseline are shown, along with 95% confidence intervals (CIs) where applicable, and are calculated as absolute changes by subtracting baseline values ​​from assessed visit values. For categorical variables, including binary variables, the absolute frequency (n) and relative frequency (%), as well as the number of missing data points, are summarized for each category at each scheduled visit.

[0227] 4. Results and analysis of effectiveness 4.1. Primary efficacy assessment 4.1.1. Inhibition of ovulation Table 5 shows the results obtained for ovulation inhibition by treatment cycle and treatment group for FAS. In TC1, 127 participants (99.2%) in all treatment groups showed ovulation inhibition, and those treated with Cerazet (18 kg / m²) showed inhibition. 2 More than 30kg / m 2 Only one participant with a BMI below a certain level did not show ovulation inhibition. In TC2, ovulation inhibition was observed in all participants, regardless of treatment group or BMI.

[0228] [Table 5] TIFF2026511005000006.tif65170

[0229] 4.1.2. Hoogland score and 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 and BMI group in the FAS.

[0230] [Table 6] TIFF2026511005000008.tif146170

[0231] In TC1, a total of 88 participants (68.8%) showed no ovarian activity or minimal ovarian activity (Hoogland score of 1 or 2), corresponding to 19 participants (57.6%), 17 participants (56.7%), 26 participants (76.5%), and 26 participants (83.9%) treated with Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150, respectively. Additionally, 39 participants (30.5%) showed residual ovarian activity (Hoogland score of 3 or 4), corresponding to 3 participants (39.4%), 13 participants (43.3%), 8 participants (23.5%), and 5 participants (16.1%) treated with Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150, respectively.

[0232] Only one participant (0.8%) treated with Cerazet showed high ovarian activity (Hoogland score of 5-6) during TC1.

[0233] In the ANCOVA model implemented, the LS mean (95% CI) of the difference when Cerazet was considered as the reference group was -0.2 (0.30) (-0.8; 0.4) for LNG VDS 75, -0.6 (0.29) (-1.1; 0.0) for LNG VDS 125, and -0.7 (0.29) (-1.3; -0.2) for LNG VDS 150.

[0234] Based on the Hoogland score assessment by BMI group, 18 kg / m² 2 More than 30kg / m2 77 participants (73.3%) had a BMI of less than 30 kg / m². 2 In each of the 11 participants (47.8%) with a BMI of 18 kg / m² or higher, ovarian activity was either absent or minimal, and ovarian activity was observed. 2 More than 30kg / m 2 27 participants (25.7%) had a BMI of less than 30 kg / m² and 30 kg / m². 2 In each of the 11 participants (47.8%) with the above BMI, residual ovarian activity was observed.

[0235] In the ANCOVA model implemented, 18 kg / m 2 More than 30kg / m 2 The mean LS (95% CI) difference considering the group of participants with a BMI less than 30 kg / m² is 30 kg / m². 2 For participants with the above BMI, the figures were 0.8 (0.27) (0.2; 1.3).

[0236] 30 kg / m 2 In the group of participants with the above BMI, 1 (16.7%), 2 (50.0%), 3 (42.9%), and 5 (83.3%) of participants treated with Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 showed no ovarian activity or minimal ovarian activity, while 5 (83.3%), 2 (50.0%), 4 (57.1%), and 1 (16.7%) of participants treated with Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150, respectively, showed residual ovarian activity. 30 kg / m² during TC1 2 None of the participants with the above BMI reported high ovarian activity.

[0237] In TC2, a total of 89 patients (71.2%) showed no ovarian activity or minimal ovarian activity (Hoogland score of 1 or 2), and 36 patients (28.8%) showed residual ovarian activity (Hoogland score of 3 or 4).

[0238] Among the treatment groups, 15 (48.4%), 19 (63.3%), 28 (84.8%), and 27 (87.1%) participants treated with Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150, respectively, showed no ovarian activity or minimal ovarian activity, and 16 (51.6%), 11 (36.7%), 5 (15.2%), and 4 (12.9%) participants treated with Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150, respectively, showed residual ovarian activity.

[0239] There were no participants who showed high ovarian activity (Hoogland score of 5 - 6) during TC1. In the ANCOVA model performed, the LS mean (95% CI) of the differences when considering Cerazet as the reference group was -0.4 (0.29) (-0.9; 0.2) for LNG VDS 75, -0.8 (0.29) (-1.4; -0.3) for LNG VDS 125, and -1.0 (0.29) (-1.6; -0.5) for LNG VDS 150.

[0240] By rating the Hoogland score according to BMI groups, in each of the 74 (71.8%) participants with a BMI of 18 kg / m 2 or more and less than 30 kg / m 2 and 15 (68.2%) participants with a BMI of 30 kg / m 2 or more, no ovarian activity or minimal ovarian activity was observed, and in each of the 29 (28.2%) participants with a BMI of 18 kg / m 2 or more and less than 30 kg / m 2 and 7 (31.8%) participants with a BMI of 30 kg / m 2 or more, residual ovarian activity was clearly observed.

[0241] In the ANCOVA model performed, for a BMI of 18 kg / m 2 or more and less than 30 kg / m 2The mean LS (95% CI) difference considering the group of participants with a BMI less than 30 kg / m² is 30 kg / m². 2 For participants with the above BMI, the values ​​were 0.2 (0.27) (-0.4 to 0.7).

[0242] 30 kg / m 2 In the group of participants with the above BMI, 2 (33.3%), 3 (75.0%), 5 (83.3%), and 5 (83.3%) participants treated with Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 showed no ovarian activity or minimal ovarian activity, while 4 (66.7%), 1 (25.0%), 1 (16.7%), and 1 (16.7%) participants treated with Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150, respectively, showed residual ovarian activity. 30 kg / m² during TC1 2 None of the participants with the above BMI reported high ovarian activity.

[0243] Landgren assessments were performed in 43 (33.6%) participants with FAS in TC1 and TC2 (when ovulation was suspected based on follicular size measured by TVU) (10 participants [33.3%] in the LNG VDS 75 treatment group, 10 participants [29.4%] in the LNG VDS 125 group, 10 participants [32.3%] in the LNG VDS 150 group, and 13 participants [39.4%] in the Cerazet treatment group). However, this test was positive in only one participant (0.8%) in the Cerazet treatment group. No participants treated with LNG VDS reported a positive Landgren test.

[0244] 4.1.3. Follicle size Follicle size was assessed for each treatment cycle in each treatment group (Table 4). During TC1, the mean (SD) size of the largest follicle assessed in 117 participants from FAS was 10.2(3.8) mm. Differences in values ​​were observed among the treatment groups: 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, LNG VDS 125, and LNG VDS 150 treatment groups, respectively.

[0245] During TC2, the mean (SD) size of the largest follicle, as assessed by 111 participants from FAS, was 9.8(3.2) mm. Differences in values ​​were also observed among the treatment groups: 12.0(4.1) mm, 10.4(3.5) mm, 8.7(1.8) mm, and 8.2(1.3) mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively.

[0246] 30 kg / m 2 Among participants with the above BMI (Table 12), the mean (SD) maximum follicular size during TC1 was 11.5 (4.2) mm (14.5 [5.5] mm, 11.0 [4.3] mm, 11.3 [3.2] mm, and 9.2 [2.8] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively), which was slightly higher than the overall population. During TC2, the mean (SD) maximum follicular 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[1.4] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively), which was very similar to the values ​​obtained in the overall population.

[0247] [Table 7]

[0248] 4.1.4. Serum progesterone levels Serum progesterone levels were assessed every three days from day 3 to day 27 during TC1, and every three days from day 3 to day 27 during TC2, as well as on day 29. Progesterone levels for each hospital visit and treatment group were assessed at 30 kg / m² for the entire FAS. 2 The assessment was conducted not only among participants with the above BMI levels, but also within the PP target group.

[0249] During TC1, participants treated with Cerazet showed higher serum progesterone levels compared to participants treated with LNG VDS at any of the three release rates, mainly 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 in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 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 in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 groups, respectively).

[0250] During TC2, mean progesterone levels were similar across treatment groups at all visits. 30 kg / m² 2 In participants with the above BMI, serum progesterone levels were generally lower than those observed in the general population; however, no significant variability was observed between treatment groups in either TC1 or TC2, depending on the study visit.

[0251] 4.1.5. Serum Estradiol Levels Serum estradiol levels were assessed every three days from day 3 to day 27 during TC1, and every three days from day 3 to day 27 during TC2, as well as on day 29 (see Table 8).

[0252] [Table 8] TIFF2026511005000011.tif245170TIFF2026511005000012.tif65170

[0253] During TC1, the mean (SD) estradiol concentration in 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 in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0254] In the overall population, 7 participants (5.5%) had an average estradiol concentration of less than 20 pg / mL (0 participants [0.0%], 0 participants [0.0%], 4 participants [11.8%], and 3 participants [9.7%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively), and 27 participants (21.1%) had an average estradiol concentration of 20 pg / mL or more but less than 30 pg / mL (1 participant [3.0%], 2 participants [6.7%], 10 participants [29.4%], and 14 participants [45.2%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively).

[0255] During 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, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0256] In the overall population, 12 participants (9.6%) had an average estradiol concentration of less than 20 pg / mL (0 participants [0.0%], 0 participants [0.0%], 4 participants [12.1%], and 8 participants [25.8%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively), and 36 participants (28.8%) had an average estradiol concentration of 20 pg / mL or more but less than 30 pg / mL (2 participants [6.5%], 8 participants [26.7%], 13 participants [39.4%], and 13 participants [41.9%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively).

[0257] 30 kg / m 2 In the group of participants with the above BMI, the mean (SD) estradiol concentration at 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-treated group, LNG VDS 75-treated group, LNG VDS 125-treated group, and LNG VDS 150-treated group, respectively). No participants had an average estradiol concentration of less than 20 pg / mL, while five participants (21.7%) had an average estradiol concentration of 20 pg / mL or more but less than 30 pg / mL (0 participants [0.0%], 0 participants [0.0%], 0 participants [0.0%], and 5 participants [83.3%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively).

[0258] During TC2, the mean (SD) estradiol concentration was 46.1(29.9) pg / mL (75.5[41.0]pg / mL, 44.6[26.8]pg / mL, 35.4[3.3]pg / mL, and 28.4[8.3]pg / mL in the Cerazet-treated, LNG VDS 75-treated, LNG VDS 125-treated, and LNG VDS 150-treated groups, respectively). One participant (4.5%) had an average estradiol concentration of less than 20 pg / mL (0 participants [0.0%], 0 participants [0.0%], 0 participants [0.0%], and 1 participant [16.7%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively), and six participants (27.3%) had an average estradiol concentration of 20 pg / mL or more but less than 30 pg / mL (1 participant [16.7%], 2 participants [50.0%], 0 participants [0.0%], and 3 participants [50.0%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively).

[0259] Figure 4 shows the mean estradiol levels for each treatment cycle and by BMI category for all treatment groups. This figure shows a level of 30 kg / m³ during TC1. 2 Among participants with the above BMIs, serum levels were higher compared to participants with lower BMIs, but this shows how estradiol levels decreased from TC1 to TC2 in both BMI groups.

[0260] 4.2. Assessment of secondary efficacy 4.2.1. Insler score Insler scores obtained at each visit between pre-treatment, TC1, TC2, and post-treatment were assessed for each treatment group in the PP target population and FAS. Insler scores were assessed for 38 participants from FAS during both TCs.

[0261] During TC1, the mean (SD) maximum score obtained was 4.6 (2.1) (4.4[1.8], 4.5[1.8], 5.6[2.7], and 3.5[2.4] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively). Nine participants (23.7%) had a maximum Insler score between 0 and 3 (3 [20.0%], 3 [27.3%], 2 [25.0%], and 1 [25.0%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively), and 20 participants (52.6%) had a maximum Insler score between 4 and 6 (9 [60.0%], 6 [54.5%], 2 [25.0%], and 3 [75.0%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively).

[0262] During TC2, the mean (SD) maximum Insler score obtained was 4.1 (2.1) (4.2[1.6], 3.7[1.8], 5.0[3.7], and 3.4[2.7] in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively). Thirteen individuals (34.2%) had the highest score between 0 and 3 (5 individuals [29.4%], 4 individuals [36.4%], 2 individuals [40.0%], and 2 individuals [40.0%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively), and 23 individuals (60.5%) had the highest score between 4 and 6 (11 individuals [64.7%], 7 individuals [63.6%], 2 individuals [40.0%], and 3 individuals [60.0%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively).

[0263] 30 kg / m 2Among the 12 participants with the above BMI (Table 15), the mean (SD) Insler score obtained during TC1 was 5.8 (1.8) (5.4[1.5], 4.5[0.7], 7.3[1.7], and 4.0[NA] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively). None of these participants had a maximum score between 0 and 3, and 7 participants (58.3%) had a maximum Insler score between 4 and 6 (3[60.0%], 2[100.0%], 1[25.0%], and 1[100.0%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively).

[0264] During TC2, the mean (SD) maximum score, as assessed by only eight participants, was 3.6 (2.0) (4.8[0.5], 4.0[NA], 5.0[NA], and 0.5[0.7] in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively). Two participants (25%) had an Insler score between 0 and 3 (0[0.0%], 0[0.0%], 2[100%], and 0[0.0%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively), and six participants (75.0%) had an Insler score between 4 and 6 (4[100%], 1[100%], 1[100%], and 0[0.0%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively).

[0265] 4.2.2. Resumption of ovulation Based on the FAS assessment of ovulation resumption (Table 9), 104 out of 127 participants (81.9%) showed ovulation resumption during post-treatment (23 [69.7%], 24 [80.0%], 31 [93.9%], and 26 [83.9%] in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively): 18 kg / m² 2 More than 30kg / m 2 Among 105 participants with a BMI of less than 30 kg / m², 86 (81.9%) (20 [74.1%], 20 [6.9%], 25 [92.6%], and 21 [84.0%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively) and 30 kg / m² 2 Of the 22 participants with the above BMI, 18 (81.8%) were affected (3 [50.0%], 4 [100%], 6 [100%], and 5 [83.3%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively).

[0266] [Table 9]

[0267] The same results were observed when the resumption of ovulation was assessed in the PP target population. The mean (SD) progesterone serum levels (FAS) assessed during the post-treatment cycle were 17.3(15.3) pg / mL in OV+2 (12.8[11.0]pg / mL, 16.4[13.5]pg / mL, 15.5[12.3]pg / mL, and 24.7[20.8]pg / mL in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively), and 29.9(14.9) pg / mL in OV+4 (Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups). In the 150 treatment groups, the levels were 31.0[13.5]pg / mL, 29.1[17.7]pg / mL, 26.9[11.7]pg / mL, and 33.4[16.2]pg / mL, respectively. Similar results were obtained in the assessment of progesterone serum levels during the post-treatment cycle in the PP target population.

[0268] 4.2.3. Endometrial thickness Endometrial thickness was assessed to determine any changes in the endometrial bed that were inappropriate for implantation. An endometrial thickness of less than 6 mm was considered unsuitable for pregnancy. Endometrial thickness was measured as the bilayer distance in the longitudinal section of the uterus by TVU at each visit.

[0269] Endometrial thickness was measured by TVU at each study visit during pre-treatment, TC1, TC2, and post-treatment. The average results obtained at each visit and for each treatment group were used for the entire population and for 30 kg / m². 2 We analyzed the group of participants with the above BMI values.

[0270] In the pretreatment regimen, the mean (SD) endometrial thickness was 7.8(2.1) mm (8.2[2.9] mm, 7.2[1.8] mm, 7.9[1.3] mm, and 7.8[1.9] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0271] During TC1, the mean (SD) endometrial thickness was 4.1(1.1) mm (4.3[1.3] mm, 3.7[0.9] mm, 4.1[0.8] mm, and 4.1[1.1] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0272] During TC2, the mean (SD) endometrial thickness was 3.8(1.0) mm (3.9[1.2] mm, 3.3[0.9] mm, 3.9[0.9] mm, and 3.9[1.0] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0273] In post-treatment, the mean (SD) endometrial thickness was 7.0(1.6) mm (6.7[2.0] mm, 6.7[1.6] mm, 7.3[1.5] mm, and 7.4[1.3] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0274] 30 kg / m 2In the group of participants with the above BMI, the mean (SD) endometrial thickness in the pretreatment group was 7.8(2.1) mm (9.1[1.7] mm, 7.2[0.9] mm, 8.0[1.5] mm, and 9.1[2.7] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively). In TC1, the mean (SD) endometrial thickness was 4.1(1.1) mm (5.6[1.7] mm, 3.6[0.7] mm, 4.0[0.6] mm, and 4.6[1.2] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively). In TC2, the mean (SD) endometrial thickness was 3.8(1.0) mm (4.9[1.1] mm, 3.9[1.5] mm, 3.6[0.6] mm, and 3.8[1.4] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively). In post-treatment (Table 20), the mean (SD) endometrial thickness was 7.0(1.6) mm (6.9[1.5] mm, 6.9[0.6] mm, 6.4[1.8] mm, and 6.9[1.7] mm in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0275] 4.2.4. Bleeding Patterns Vaginal bleeding was recorded daily in the participants' diaries. The presence or absence of bleeding and the outcome of bleeding episodes are shown for all participants.

[0276] In TC1, one participant (0.8%) did not show bleeding throughout the entire cycle (in the LNG VDS 75 treatment group). The mean (SD) days with some bleeding was 11.2 (6.0) days (10.7 [4.9] days, 11.5 [6.4] days, 11.6 [6.4] days, and 11.3 [6.3] days in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively), and the mean (SD) days with spotting was 6.2 (4.7) days (Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups). In the 150 treatment groups, the average duration of bleeding was 5.5[4.4] days, 6.8[5.6] days, 5.9[4.0] days, and 6.9[5.0] days, respectively. The mean (SD) duration of mild bleeding was 3.4(2.8) days (3.2[2.4] days, 2.8[2.1] days, 4.6[3.9] days, and 2.8[1.8] days in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0277] In TC2, 22 participants (17.6%) did not experience bleeding (3 [9.7%], 8 [26.7%], 8 [24.2%], and 3 [9.7%] in the Cerazet treatment group, LNG VDS 75 treatment group, LNG VDS 125 treatment group, and LNG VDS 150 treatment group, respectively). The mean (SD) days with some form of bleeding was 14.1 (8.9) days (12.5 [6.7] days, 13.0 [8.2] days, 17.9 [9.7] days, and 13.2 [10.2] days in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively), and the mean (SD) days with spotting was 9.2 (7.1) days (Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups). In the 150 treatment groups, the average duration of bleeding was 7.4[5.1] days, 9.3[8.1] days, 10.3[6.8] days, and 9.7[8.1] days, respectively. The mean (SD) duration of bleeding was 5.8(4.7) days (5.1[4.0] days, 3.3[2.3] days, 8.0[5.2] days, and 6.3[5.6] days in the Cerazet, LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0278] 5. Conclusion on effectiveness FAS included a total of 128 participants.

[0279] Analysis of the primary assessment parameters revealed that all participants treated with LNG VDS showed inhibition of ovulation in both TCs. In addition, all participants treated with Cerazet showed inhibition of ovulation in one participant (18 kg / m²) who ovulated during TC1. 2 More than 30kg / m 2 Except for BMI below a certain level, both TCs showed inhibition of ovulation.

[0280] Ovarian activity, as measured by the Hoogland score during TC1, revealed that 69% of participants showed no ovarian activity or minimal ovarian activity (this percentage was 84% ​​among participants treated with LNG VDS 150), and 31% showed residual ovarian activity (this percentage was higher among participants treated with LNG VDS 75 (43%)). Similarly, 18 kg / m³ 2 More than 30kg / m 2 Participants with a BMI below 30 kg / m² 2 Compared to participants with a BMI above the above (48%), more participants showed no ovarian activity or minimal ovarian activity (73%), and this percentage was higher (83%) when such participants were treated with LNG VDS 150. In TC2, compared to TC1, the percentage of participants showing no ovarian activity or minimal ovarian activity was not only higher in the overall population (71% vs. 68%), but also 30 kg / m² 2 Among participants with the above BMI, the percentage was higher (68% vs. 48%).

[0281] The ANCOVA model statistically demonstrated that during TC2, participants treated with LNG VDS 150 and those treated with Cerazet differed in Hoogland scores by 1 point (1.8 vs. 2.8, respectively), and participants treated with LNG VDS 125 differed by 0.7 points (2.1 vs. 2.8, respectively).

[0282] Based on the Landgren score, it was confirmed that only one participant treated with Cerazet ovulated in TC1.

[0283] In TC1, the mean (SD) maximum follicle size was 10.2(3.8) mm, which was larger in participants treated with Cerazet and LNG VDS 75 (11.7[4.6] mm and 11.2[4.2] mm, respectively) compared to participants treated with LNG VDS 125 and LNG VDS 150 (9.4[3.4] mm and 8.6[2.1] mm, respectively). The same trend was observed in TC2, yielding similar results.

[0284] 30 kg / m 2 In participants with the above BMI, similar differences were observed between the treated arms, and larger follicle sizes were achieved, but the values ​​obtained in TC2 were very similar to those observed in the general population.

[0285] In participants treated with Cerazet at their final visit to TC1, serum progesterone levels were higher in TC1 compared to those observed in the LNG VDS-treated group, whereas no significant changes were observed during TC2 regardless of treatment group.

[0286] 30 kg / m 2 In participants with the above BMI, serum progesterone levels were generally lower than those observed in the general population; however, no significant variability was observed between treatment groups in either TC1 or TC2, depending on the study visit.

[0287] Regarding the mean estradiol concentration, the value obtained in TC1 was 56.6(54.6) pg / mL, which was higher in the Cerazet-treated group (97.1[84.3]pg / mL) compared to LNG VDS 75, LNG VDS 125, and LNG VDS 150 (59.3[40.2]pg / mL, 37.3[21.2]pg / mL, and 32.1[12.1]pg / mL, respectively). A similar trend was observed in TC2, but these values ​​were lower compared to TC1. It is important to note that among patients treated with LNG VDS 125 and LNG VDS 150, the percentage of participants with estradiol concentrations less than 20 pg / mL and less than 30 pg / mL was significantly higher compared to LNG VDS 75 and Cerazet. 30 kg / m 2 In participants with the above BMI, the same trend was observed, although serum estradiol concentrations were higher compared to the overall population in all treatment arms in both TCs.

[0288] The maximum mean Insler score obtained was 4.6 in TC1 and 4.1 in TC2. In both TCs, participants treated with LNG VDS 150 showed lower maximum scores (3.5 in TC1 and 3.4 in TC2) compared to the other three treatment groups. In neither of the two TCs, no participants had a good sperm elevation (maximum Insler score of 10-12), and in TC2, only one participant (treated with Cerazet) had a moderate sperm elevation (maximum Insler score of 7-9). 30 kg / m 2 Among participants with the above BMI, the maximum Insler score in TC1 was higher than the overall population (5.8), and no participants had an average score between 0 and 3. Of these, no participants in any TC had a maximum Insler score of 10-12, and only in TC1 did three participants treated with LNG VDS 125 and two with Cerazet, respectively, reach a maximum Insler score of 7-9.

[0289] In post-treatment, ovulation was restored in over 80% of participants (69.7% in the Cerazet treatment group, compared to 80.8%, 93.9%, and 83.9% in the LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively).

[0290] Pharmacokinetic evaluation In a subgroup of 55 participants, pharmacokinetic parameters for LNG and SHBG levels were determined using LNG VDS, and 41 of them had a level of 18 kg / m². 2 From the above, 30 kg / m 2 Participants had a BMI between 30 kg / m² (15, 14, and 12 participants in the LNG VDS 75, LNG VDS 125, and LNG VDS 150 treatment groups, respectively), and 14 of them had a BMI of 30 kg / m². 2 The participants had the above BMI (3 participants in the LNG VDS 75 treatment group, 7 participants in the LNG VDS 125 treatment group, and 4 participants in the LNG VDS 150 treatment group, respectively).

[0291] Figures 2 and 3 show the mean concentration-time profiles of LNG and SHBG for participants from the LNG VDS 75 treatment group, the LNG VDS 125 treatment group, and the LNG VDS 150 treatment group, respectively. Figures 4 and 5 show the same parameters (mean concentration-time profiles of LNG and SHBG) categorized by BMI.

[0292] 5.1. LNG Pharmacokinetics of the LNG VDS 75 Treatment Group, LNG VDS 125 Treatment Group, and LNG VDS 150 Treatment Group After inserting LNG VDS at dose levels of 75 μg / day, 125 μg / day, and 150 μg / day, plasma LNG concentrations were determined in all subjects from the first sample collection (2 hours after insertion) through all cycles and at all dose levels.

[0293] In TC1, overall maximum concentrations were observed 116 hours, 123 hours, and 113 hours after administration of 75 μg / day, 125 μg / day, and 150 μg / day, respectively. 18 kg / m² 2 More than 30kg / m 2 In the BMI category below 30 kg / m², after insertion with 75 μg / day, 125 μg / day, and 150 μg / day, respectively, the observed Tmax values ​​were 115 hours, 110 hours, and 98.667 hours, respectively. 2 In participants with the above BMI, the observed Tmax values ​​after administration of 75 μg / day, 125 μg / day, and 150 μg / day, respectively, were 120 hours, 151 hours, and 156 hours.

[0294] Following the peak plasma concentration of LNG at Tmax, plasma levels remained elevated with minimal peak-to-trough fluctuation, representing a long-term release of LNG across TC1 at all dose levels and all BMI categories.

[0295] In TC1, after administration of 75 μg / day, 125 μg / day, and 150 μg / day, the overall maximum plasma concentrations observed were 0.950 ng / mL, 1.548 ng / mL, and 1.426 ng / mL. These concentrations were observed after administration of 75 μg / day, 125 μg / day, and 150 μg / day, respectively, at 18 kg / m². 2 More than 30kg / m 2 In participants with a BMI of less than 30 kg / m², the Cmax values ​​were 1.011 ng / mL, 1.829 ng / mL, and 1.539 ng / mL, respectively. 2 In participants with the above BMI, the Cmax values ​​were 0.647 ng / mL, 0.987 ng / mL, and 1.090 ng / mL.

[0296] The exposure levels assessed by the overall AUC(0-t) observed in TC1 were 340 h·ng / mL, 571 h·ng / mL, and 468 h·ng / mL after administration of 75 μg / day, 125 μg / day, and 150 μg / day, respectively.2 More than 30kg / m 2 In the BMI category below 30 kg / m², the AUC(0-t) values ​​were 357 h·ng / mL, 662 h·ng / mL, and 490 h·ng / mL, respectively. 2 In participants with the above BMI, the AUC(0-t) values ​​were 253 h·ng / mL, 389 h·ng / mL, and 403 h·ng / mL.

[0297] In TC1, after extravascular administration of LNG VDS at 75 μg / day, 125 μg / day, and 150 μg / day, the clearance values ​​measured were 76.383 mL / h, 96.103 mL / h, and 106 mL / h, respectively, and 18 kg / m². 2 More than 30kg / m 2 Among participants with a BMI below 30 kg / m², the values ​​were 66.816 mL / h, 84.964 mL / h, and 101 mL / h, respectively. 2 In the above cases, the determined values ​​were 119 mL / h, 125 mL / h, and 123 mL / h.

[0298] The volume of distribution (TC1) measured after extravascular administration of LNG VDS at 75 μg / day, 125 μg / day, and 150 μg / day was 101 L, 96.294 L, and 103 L, respectively, corresponding to 18 kg / m³. 2 More than 30kg / m 2 Among participants with a BMI below 30 kg / m², the values ​​were 99.117 L, 85.227 L, and 94.116 L, respectively. 2 In the above cases, the determined values ​​were 111.991L, 124.941L, and 140.244L.

[0299] In TC2, the maximum overall LNG concentration was observed 283 hours, 192 hours, and 192 hours after administration of 75 μg / day, 125 μg / day, and 150 μg / day, respectively. 18 kg / m³ 2 More than 30kg / m 2In participants with a BMI of less than 30 kg / m², the observed Tmax values ​​after insertion at 75 μg / day, 125 μg / day, and 150 μg / day, respectively, were 269 hours, 156 hours, and 199 hours. 2 In participants with the above BMI, the observed Tmax values ​​after administration of 75 μg / day, 125 μg / day, and 150 μg / day, respectively, were 352 hours, 276 hours, and 174 hours.

[0300] Following the peak plasma concentration of LNG at Tmax, plasma levels remained elevated with minimal peak-to-trough fluctuation, representing a long-term release of LNG across TC2 at all dose levels and all BMI categories.

[0301] In TC2, the maximum plasma concentrations observed overall were 0.654 ng / mL, 0.987 ng / mL, and 0.925 ng / mL after administration of 75 μg / day, 125 μg / day, and 150 μg / day, respectively. 2 More than 30kg / m 2 In participants with a BMI below 30 kg / m², the Cmax values ​​were 0.695 ng / mL, 1.085 ng / mL, and 0.995 ng / mL, respectively. 2 In participants with the above BMI, the Cmax values ​​were 0.449 ng / mL, 0.757 ng / mL, and 0.842 ng / mL.

[0302] In TC2, the exposure levels assessed by the overall observed AUC(0-t) were 363 h·ng / mL, 538 h·ng / mL, and 505 h·ng / mL after administration of 75 μg / day, 125 μg / day, and 150 μg / day, respectively. 2 More than 30kg / m 2 In participants with a BMI of less than 30 kg / m², the AUC(0-t) values ​​were 382 h·ng / mL, 584 h·ng / mL, and 517 h·ng / mL, respectively. 2In participants with the above BMI, the AUC(0-t) values were 269 h·ng / mL, 432 h·ng / mL, and 473 h·ng / mL.

[0303] In TC2, the clearance values measured after extravascular administration of LNG VDS at 75 μg / day, 125 μg / day, and 150 μg / day were 25.705 mL / h, 75.382 mL / h, and 62.028 mL / h, respectively, for participants with a BMI of 18 kg / m 2 to above 30 kg / m 2 In participants with a BMI less than 30 kg / m, the values were 25.449 mL / h, 57.623 mL / h, and 52.200 mL / h, and when the BMI was 30 kg / m 2 or above, the determined values were 27.240 mL / h, 116.821 mL / h, and 91.512 mL / h.

[0304] In TC2, the values of the volume of distribution measured after extravascular administration of LNG VDS at 75 μg / day, 125 μg / day, and 150 μg / day were 138 L, 140 L, and 172 L, respectively, for participants with a BMI of 18 kg / m <000009​​​​​​​​​​​​​​​​​​It was lower in participants with a BMI below.

[0307] Overall in TC2, an increase in exposure (determined by Cmax and AUC(0-t)) was observed at dose levels between 75 μg / day and 125 μg / day, but no clear overall difference occurred at dose levels between 125 μg / day and 150 μg / day. 30 kg / m 2 In participants with a BMI of 18 kg / m 2 or higher and 30 kg / m 2 There was a tendency to show lower exposure (determined by Cmax and AUC(0-t)), lower clearance, and larger volume of distribution compared to those observed in participants with a BMI below 18 kg / m. Overall, no clear difference in exposure was observed at dose levels between 125 μg / day and 150 μg / day, as observed overall and in both BMI categories. The plasma clearance observed in TC2 appears to vary by dose level, where lower clearance was observed for both BMI categories at 75 μg / day compared to dosing at 125 μg / day and 150 μg / day.

[0308] Example 3: A multi-center, concurrent, Phase 2, dose-finding, double-blind, randomized clinical trial to evaluate the efficacy and safety of a levonorgestrel (LNG) vaginal delivery system (VDS) that continuously releases at 75 mcg / day and 125 mcg / day over 28 days in a continuous fashion compared to placebo after 4 drug treatment cycles for the management of moderate to severe pain associated with endometriosis.

[0309] Study design: A multi-center, concurrent clinical trial in female subjects 18 years of age or older and 45 years of age or younger who have been surgically diagnosed with endometriosis and have endometriosis-associated pelvic pain (EAPP) of greater than or equal to 3 points on a numerical rating scale (NRS) over the past 3 months. This clinical trial consists of a screening period (up to 100 days), a treatment period consisting of 4 placebo-controlled, double-blind drug treatment cycles, and a follow-up period.

[0310] Participants were randomized to receive either LVDS 75mcg / day, LVDS 125mcg / day, or a placebo vaginal ring. The vaginal ring was to be inserted at the facility at visit 1b and replaced every 28 days (day 29). Thereafter, participants visited the facility at visit 2 on day 20 (+6) of the first drug treatment cycle. The final visit (visit 3) was to take place 1 to 3 days after the end of the fourth drug treatment cycle (i.e., a hypothetical day 29 (+2) of the fourth drug treatment cycle), or, in the case of early discontinuation, within 1 to 3 days after the last day the ring was used (early discontinuation consultation [EDV]).

[0311] Research purpose: Main purpose: This study aims to demonstrate the efficacy of two doses of levonorgestrel intravaginal delivery systems (LVDS), 75 mcg / day and 125 mcg / day, compared to placebo, for the management of endometriosis-related pelvic pain (EAPP) as assessed by a numerical rating scale (NRS).

[0312] Main grading items Population: Premenopausal women aged 18 to 45 years with a surgically confirmed diagnosis of endometriosis and an EAPP score of 3 or higher on the NRS for at least 3 months were randomized to receive either LVDS 0.075 mg / day, LVDS 0.125 mg / day, or placebo. The analysis included subjects who received at least one dose of each LVDS and at least one post-baseline assessment of the primary efficacy measure (modified ITT target population [mITT]).

[0313] Variable: Change from baseline in endometriosis-related pelvic pain (EAPP) score, as reported by subjects at week 16 (after 4 drug treatment cycles) based on NRS pain scores.

[0314] Intermediate events (ICE) and strategies: Changes in rescue medication during 16 weeks of treatment (4 drug treatment cycles) compared to baseline. Non-compliance with procedures (less than 80% or more than 120%) Discontinuation of treatment (due to lack of effectiveness, adverse events (AEs), or safety concerns).

[0315] Summary at the population level: The difference in mean EAPP score change at week 16 (after 4 drug treatment cycles) compared to baseline (or the individual's final cycle in the case of discontinuation) in the treatment groups (LVDS 0.075 mg / day, LVDS 0.125 mg / day, placebo).

[0316] Secondary purpose Percentage of patients who met the dysmenorrhea responder criteria and achieved a mean 50% reduction in the dysmenorrhea NRS score compared to baseline, 16 weeks after treatment with LVDS 75mcg and LVDS 125mcg compared to placebo. Percentage of patients who met the criteria for nonmenstrual pelvic pain (NMPP) responder and achieved a mean 50% reduction in the NRS score for nonmenstrual pelvic pain compared to baseline, 16 weeks after treatment with LVDS 75mcg and LVDS 125mcg compared to placebo. The above percentages are used to determine the functional benefits measured by the pain domain of the Endometriosis Health Profile 30. The above percentages are used to determine the benefits to function measured by the non-pain domain of the endometriosis-related quality of life health profile30. The benefit relative to the average EAPP NRS score is determined by the above percentage. The above percentages are used to determine the benefits of NRS scores for dysmenorrhea, non-menstrual pelvic pain, and dyspareunia. The above percentages are used to determine the benefits of the General Patient Assessment (PGA) for dysmenorrhea, NMPP, overall pain severity, and functional impairment. The patient's overall impression (PGIC) regarding changes in dysmenorrhea, NMPP, and dyspareunia is determined based on the above proportions. The above percentages are used to determine changes in the use of rescue medication.

[0317] Secondary evaluation criteria: Changes in pain domain scores from baseline to 16 weeks in the Endometriosis Health Profile 30 Changes in endometriosis-related quality of life from baseline to 16 weeks, as measured by the non-pain domain of EHP-30. Changes in mean NRS scores for dysmenorrhea, nonmenorrhea-related pelvic pain, and dyspareunia from baseline to weeks 4, 8, 12, and 16. Changes in average EAPP NRS score from baseline to weeks 4, 8, 12, and 16. Global Patient Assessment (PGA) at Week 16 regarding dysmenorrhea, NMPP, function, and current pain over the past four weeks. Patient's overall impression regarding changes in dysmenorrhea, NMPP, and dyspareunia at 16 weeks after the start of treatment (PGIC) Changes in rescue medication use (every 24 hours) at weeks 4 and 16 compared to baseline.

[0318] Dosage and route of administration: Test product Levonorgestrel vaginal delivery system (LVDS) 75mcg / day Levonorgestrel vaginal delivery system (LVDS) 125mcg / day

[0319] Reference product Placebo vaginal rings are manufactured to match the shape, size, and color of LVDS.

[0320] Each LVDS contains approximately 10 mg of LNG, which is designed to release 75 mcg / day and 125 mcg / day.

[0321] Duration of treatment Four treatment cycles with a duration of 28 days.

[0322] Participants will have a vaginal ring inserted on their first visit (1b) and will use it continuously for 28 days. After 28 days, participants will replace the vaginal ring (remove the current ring and insert the next one without any time gap).

[0323] The principal investigator instructs subjects not to remove the ring for more than three hours within a 24-hour period.

[0324] statistical methods The primary rating items will be analyzed using analysis of covariance (ANCOVA), and all secondary rating items will be analyzed using appropriate methods.

[0325] Unless otherwise specified in the statistical analysis protocol, efficacy analysis will be performed using the modified intention to treat (mITT) population, defined as all randomized patients who received at least one dose of the randomized investigational drug. The randomization ratio is for three treatment arms: LVDS 75mcg / day LVDS 125mcg / day placebo The ratio is 1:1:1 between them.

[0326] This study has the following primary assessment items: To demonstrate the efficacy of two doses of levonorgestrel intravaginal delivery system (LVDS), 75 mcg / day and 125 mcg / day, compared to placebo, in the management of endometriosis-related pelvic pain (EAPP) as assessed by a numerical rating scale (NRS).

[0327] EAPP includes dysmenorrhea, NMPP, and, if applicable, dyspareunia. The baseline mean EAPP is calculated using EAPP scores recorded in the electronic diary during the 28 days prior to visit 1b.

[0328] This study has secondary assessment items defined as follows: Percentage of patients who met the dysmenorrhea responder criteria after 12 weeks of treatment with 75 mcg / day and LVDS 125 mcg / day compared to placebo. Percentage of patients who met the criteria for nonmenstrual pelvic pain (NMPP) responder after 12 weeks of treatment with 75 mcg / day and LVDS 125 mcg / day compared to placebo.

[0329] Baseline pain ratings are based on the mean values ​​observed during the baseline cycle up to the day before the first dose of the investigational drug to which the patient was randomized.

[0330] A responder (defined separately for dysmenorrhea and NMPP) is defined as a patient who, compared to the baseline pain assessment period, shows no increase in rescue analgesic use during the 12-week / EOT pain assessment period (the last 35 days before the final dose of the investigational drug) and whose pain reduction exceeds the response threshold defined as follows: For dysmenorrhea, achieving a mean 50% reduction in NRS score compared to baseline. In cases of non-menstrual pelvic pain, a mean reduction of 50% in NRS score compared to baseline was achieved.

[0331] Patients who complete treatment for less than 5 weeks will be considered non-responders for both dysmenorrhea and non-menstrual pelvic pain. For patients who complete treatment for at least 5 weeks, responder status for dysmenorrhea and non-menstrual pelvic pain is defined as follows: For dysmenorrhea, responder status is defined using the following rules, which take into account the use of analgesics and require at least two days of dysmenorrhea NRS scores in an electronic diary, after which the average is calculated and used to assess dysmenorrhea responder status. Since a typical menstrual cycle has bleeding days ranging from 3 to 7 days, it is considered reasonable to require a minimum of two days of dysmenorrhea NRS scores. For nonmenstrual pelvic pain, responder status is defined using the following rules, which require a score for nonmenstrual pelvic pain for at least 14 days reported in an electronic diary, taking into account the use of analgesics, and then using the mean nonmenstrual pelvic pain score to assess nonmenstrual pelvic pain responder status. Requiring a minimum of 14 days of nonmenstrual pelvic pain scores is considered reasonable because this corresponds to at least half of the nonmenstrual days in a typical 28-day menstrual cycle.

[0332] The responder rate for the placebo arm is estimated to be between 30% and 35%.

[0333] Example 4 A single-center, open-label phase 2 clinical trial evaluating the ovulation inhibition of a levonorgestrel (LNG) vaginal delivery system (VDS) delivered in a continuous manner over 28 days in women with a BMI of 30 or higher was conducted, as further detailed below:

[0334] 1. Research Design 1.1. Research purpose: Main purpose: 30 kg / m 2 In the group of women with the above BMI, we will assess ovarian activity (determined by the Hoogland and Skouby scores) inhibition of ovulation in treatment cycles (TC) 1 and TC2 using a levonorgestrel (LNG) vaginal delivery system (VDS).

[0335] Secondary purpose: Luteal function after ovulation / luteinized unruptured follicle syndrome (LUF) is assessed according to Landgren et al.'s criteria. The effects of LNG VDS on cervical mucus, endometrial thickness, and follicular structure (FLS) diameter will be assessed. The effects of LNG VDS on blood levels of pituitary hormones (FSH, LH), ovarian hormones (E2, P), and sex hormone-binding globulin (SHBG) will be assessed. To evaluate the safety and tolerability of LNG VDS.

[0336] Exploratory purpose: The effects of body mass index (BMI) and SHBG levels on the pharmacokinetics (PK) of LNG and inhibition of ovulation will be assessed.

[0337] 1.2.Methodology 30 kg / m 2A single-center, open-label phase 2 clinical trial evaluating the inhibition of ovulation, as measured by ovarian activity (assessed by the Hoogland and Skouby scores), over a 28-day continuous period using a levonorgestrel (LNG) vaginal delivery system (VDS) in healthy female subjects aged 18-35 years with the above BMI.

[0338] 1.3. Test product, dosage, and administration method LNG VDS for vaginal administration was used. Each LNG VDS contained approximately 10 mg of LNG, which was designed to release 75 μg / day of LNG. One LNG VDS was intended to last for 28 consecutive days.

[0339] 1.4. Duration of treatment The treatment was performed in two consecutive treatment cycles of 28 days each, totaling 56 days.

[0340] 2. Results of effectiveness 2.1. Primary efficacy objectives The primary efficacy parameter, "inhibition of ovulation," was defined as HSS ≤ 4, while "no inhibition of ovulation" was defined as HSS ≥ 5.

[0341] This parameter analysis was performed not only over the entire treatment period for all 30 subjects included in the FAS, but also individually for each treatment cycle. To detect potential BMI-dependent differences, an additional "ovulation inhibition" analysis was performed for each BMI subgroup: BMI subgroup 1 (30 ≤ BMI < 35) with a total of 13 subjects, and BMI subgroup 2 (BMI ≥ 35) with 17 subjects.

[0342] [Table 10]

[0343] Ovulation inhibition was achieved in all subjects throughout the entire treatment phase. Therefore, no differences were observed between the two BMI subgroups or between treatment cycle 1 and treatment cycle 2.

[0344] All sensitivity analyses performed, namely cycle-by-cycle analyses and analyses across the entire treatment stage in the case of PPS, were consistent with the results of the primary analysis.

[0345] As a supportive analysis, the frequency of HSS was determined individually for all subjects and by BMI subgroup: HSS was 4 for most of the treatment cycle, with a higher frequency of HSS 4 in BMI subgroup 2, and a slight increasing trend in frequency throughout the course of treatment (BMI subgroup 1: 61.54% in cycle 1, 69.23% in cycle 2; BMI subgroup 2: 82.35% in cycle 1, 88.24% in cycle 2). Therefore, HSS values ​​of 3, 2, and 1 were present only in a single cycle and were too low in number to detect a dependency on BMI.

[0346] [Table 11]

[0347] The maximum HSS during the treatment cycle was assigned to one of three categories: "no ovarian activity / minimal ovarian activity" (score 1 / 2), "residual ovarian activity" (score 3 / 4), and "high ovarian activity including ovulation" (score 5 / 6). "Residual ovarian activity" was observed in 84.62% and 88.24% of subjects in BMI subgroup 1 and BMI subgroup 2, respectively.

[0348] In summary, there were no statistically significant differences between the two BMI subgroups, and ovulation inhibition was successfully achieved in all subjects throughout the treatment phase. The majority of subjects still showed residual ovarian activity under treatment, as indicated by an HSS score of 4. A trend of increasing frequency of HSS-4 scores was observed in cycle 2, with a slightly higher incidence in BMI subgroup 2.

[0349] 2.2 Secondary efficacy objectives 2.2.1 Effects on cervical mucus The effect of LVDS on cervical mucus was assessed by Insler score evaluation at each visit in which a follicle diameter greater than 13 mm was observed. The maximum Insler score was slightly lower during LNG treatment compared to the pre-treatment cycle, indicating a slight decrease in sperm penetration due to progestogen administration. The values ​​obtained for the two BMI subgroups (±SD) were comparable to the mean scores of 6.8 (±3.0) and 7.6 (±1.8) in BMI subgroup 1 and BMI subgroup 2, respectively.

[0350] 2.2.2 Effect of dominant follicle-like structure on diameter The effect of LVDS on the diameter of the dominant follicle-like structure was assessed by TVUS during various study visits. In the pre-treatment cycle, assessment was performed only until ovulation occurred.

[0351] In detail, during treatment cycle 1, the arithmetic mean (±SD) of MFD increased to 22.16±9.43 mm in BMI subgroup 1 and to 23.69±9.08 mm in BMI subgroup 2. During treatment cycle 2, the arithmetic mean (±SD) of MFD increased to 20.94±8.40 mm in BMI subgroup 1 and to 25.46±8.52 mm in BMI subgroup 2. These values ​​remained stable throughout the treatment period, and no ovulation was observed.

[0352] Throughout the trial, endometrial proliferation was monitored via endometrial thickness (ET) measurement using TVUS.

[0353] During treatment, summary assessments of both treatment cycles showed that ETmax values ​​decreased similarly in both BMI subgroups (BMI subgroup 1: 7.98 ± 1.15 mm, BMI subgroup 2: 8.66 ± 1.47 mm). When the treatment cycles were assessed individually, the arithmetic mean ETmax decreased further in treatment cycle 2, which was similar in both BMI subgroups.

[0354] In summary, endometrial proliferation was suppressed under LNG treatment, and the degree of suppression did not differ between the two BMI subgroups. Suppression of endometrial proliferation is a known effect of continuous progestin treatment, which may impair embryo implantation.

[0355] 2.2.3 Pituitary hormones and ovarian hormones Regarding pituitary and ovarian hormones, the following key results were obtained: [Table 12]

[0356] Maximum follicle-stimulating hormone (FSH) serum concentrations in each subject remained extremely stable throughout the treatment, with only similarly small fluctuations observed in both BMI subgroups.

[0357] [Table 13]

[0358] The maximum serum luteinizing hormone (LH) concentration for each subject was affected by ovulation inhibition, i.e., no LH peak occurred. The results were similar in both BMI subgroups; in BMI subgroup 1, the arithmetic mean (±SD) was 5.272±1.952 U / L in treatment cycle 1 and 5.432±2.182 U / L in treatment cycle 2, and in BMI subgroup 2, the arithmetic mean (±SD) 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.

[0359] In summary, treatment with LNG resulted in suppression of the LH peak, and therefore LH levels in both BMI subgroups remained well below 20 U / L.

[0360] [Table 14]

[0361] Individual maximal estradiol (E2) serum concentrations decreased from cycle 1 to cycle 2 during treatment. These were slightly higher in BMI subgroup 2 compared to BMI subgroup 1: in treatment cycle 1, the arithmetic mean (±SD) of individual maximal E2 concentrations was 170.538±130.587 pg / ml in BMI subgroup 1 and 208.353±150.904 pg / ml in BMI subgroup 2, and in treatment cycle 2, the maximal E2 concentrations were 87.538±77.954 pg / ml and 141.235±116.740 pg / ml, respectively. Individual maximal E2 levels showed considerable variability. The mean maximal E2 values ​​indicate that E2 concentrations were not consistently suppressed by LNG application, which is consistent with observed follicular activity.

[0362] [Table 15]

[0363] Maximum E2 concentration was assigned to a category. The majority of subjects' maximum E2 concentrations were classified as Category 4, with concentrations of 50 pg / ml or higher in both BMI subgroups and both treatment cycles. In BMI subgroup 1, the frequency of Category 4 was 76.92% in cycle 1 and 61.54% in cycle 2. In BMI subgroup 2, the frequency of Category 4 was even higher in both cycles, at 88.24% and 76.47%, respectively. In one treatment cycle in subgroup 1, there were no cases in Category 1 (<20 pg / ml), only one case in Category 2 (<30 pg / ml), and the remaining 13 cycles were classified as Category 3 (30 pg / ml or more and <50 pg / ml).

[0364] [Table 16]

[0365] The mean estradiol (E2) serum concentration for each subject also showed a decreasing trend throughout the course of treatment, with higher values ​​observed in BMI subgroup 2: In cycle 1, the arithmetic mean values ​​for BMI subgroup 1 and BMI subgroup 2 were approximately 81.27 ± 56.06 pg / ml and 86.54 ± 46.00 pg / ml, respectively. In cycle 2, the arithmetic mean values ​​for BMI subgroup 1 and BMI subgroup 2 were approximately 38.78 ± 16.92 pg / ml and 60.51 ± 31.71 pg / ml, respectively. The mean E2 for the entire treatment period was approximately 60.52 ± 33.17 pg / ml for BMI subgroup 1 and approximately 73.62 ± 35.16 pg / ml for BMI subgroup 2. In both BMI subgroups, the mean and median mean E2 concentrations were well above 30 pg / ml, which is the lower limit considered unlikely to lead to accelerated bone loss.

[0366] [Table 17]

[0367] The maximum progesterone (P) serum concentrations for each subject were similar throughout both treatment cycles and the entire treatment period, and the arithmetic mean (±SD) values ​​for both BMI subgroups were also similar: for BMI subgroup 1, 0.959±0.452 nmol / l in treatment cycle 1 and 0.758±0.445 nmol / l in treatment cycle 2; and for BMI subgroup 2, 0.849±0.333 nmol / l and 0.733±0.393 nmol / l, respectively. All individual values ​​were below 2.0 nmol / l. In summary, P serum concentrations remained low during treatment due to the absence of ovulation.

[0368] The effect of LVDS on blood levels of sex hormone-binding globulin (SHBG) was assessed compared to baseline levels obtained during the pretreatment cycle. Mean serum SHBG concentrations were similar in both BMI subgroups before the start of the study treatment (see Figure 10).

[0369] Under LNG therapy, SHBG levels were significantly reduced. Following the initiation of treatment in Cycle 1, the mean curves for both BMI subgroups showed a similarly steep decrease in SHBG levels for nearly the first half of the cycle. The decrease in SHBG concentration continued into the second half of the first cycle, but was more gradual thereafter. Throughout Treatment Cycle 2, the mean serum concentration-time curve showed a relatively stable course throughout the cycle.

[0370] Evaluation of changes from baseline confirms the impression derived from the serum concentration-time curve: Under LNG treatment, SHBG levels decreased to a clearly similar extent in both BMI subgroups: at visit D55, i.e., 55 ± 1 days after LNG treatment, SHBG levels in BMI subgroup 1 decreased to approximately 45% of the initial value (from 52.24 nmol / l to 23.54 nmol / l), and in BMI subgroup 2, they decreased to 48.74% (from 54.88 nmol / l to 26.75 nmol / l).

[0371] These results are in good agreement with literature data that explain a 50% reduction in SHBG levels during LNG treatment.

[0372] 2.2.4 Pharmacokinetic Results During this clinical trial, the pharmacokinetics of LNG were evaluated to assess the effect of BMI on LNG pharmacokinetics, as an exploratory study objective (see Figure 11).

[0373] The mean plasma concentration-time curve obtained after multiple doses of LVDS across all subjects showed a relatively stable course throughout the treatment phase, with a slight, continuous decrease from the start of treatment in treatment cycle 1 (466 pg / mL) to the lowest concentration at the final visit during treatment in treatment cycle 2 (382 pg / mL).

[0374] This trend is generally confirmed by mean curves separated by BMI subgroups, and these curves are similar in shape. However, BMI subgroup 1 showed higher LNG plasma concentrations throughout the treatment course compared to BMI subgroup 2. This observation is in good agreement with data from the literature reporting lower LNG plasma concentrations in subjects with higher BMI.

[0375] The mean pharmacokinetic parameters calculated for LNG support the impressions derived from the plasma concentration-time profile.

[0376] For LNG, the arithmetic mean (±SD) of the overall concentration over the entire 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 difference observed between the two subgroups (i.e., a difference of approximately 17.26% between BMI subgroup 1 and BMI subgroup 2).

[0377] The arithmetic mean values ​​for each treatment cycle (TC) ranged from 428 pg / mL (TC2) to 476 pg / mL (TC1) in BMI subgroup 1, and 374 pg / mL (TC1 and TC2) in BMI subgroup 2.

[0378] A similar trend was observed for the geometric mean of the area under the curve (AUC0-56, ss) calculated over the entire treatment period, which was 24,900 days·pg / mL and 20,900 days·pg / mL for BMI subgroup 1 and BMI subgroup 2, respectively (i.e., a difference of approximately 16.06% between BMI subgroup 1 and BMI subgroup 2). The geometric mean per treatment cycle ranged from 11,800 days·pg / mL (TC2) to 13,100 days·pg / mL (TC1) for BMI subgroup 1, and 10,100 days·pg / mL (TC1 and TC2) for BMI subgroup 2.

[0379] Linear regression of AUC0-56,ss and Cav,ss56 supports the impressions obtained from the analysis of variance: for both parameters, the regression lines show a decrease as BMI increases. These assessments clearly demonstrate that BMI influences total exposure over the observed medication intervals, and that maximal exposure tends to decrease as BMI increases.

[0380] 3. Conclusion Based on the results of this test, the following conclusions can be drawn: Treatment with 75 μg / day resulted in a weight of 30 kg / m². 2 Complete inhibition of ovulation was observed in the study population of subjects with the above BMI. In most subjects, ovarian activity was not completely suppressed, and most subjects in both BMI subgroups had an HSS score of 4. This profile is generally suitable for progestin monotherapy to avoid the side effects of low estrogen. Although ovarian activity was not completely suppressed, treatment with 75 μg / day of LNG sufficiently reduced the occurrence of LH surges, thereby completely inhibiting normal ovulation that could lead to pregnancy. Although mean E2 plasma levels were suppressed under treatment, they remained well above the generally acceptable threshold for clinically significant bone mineral density reduction; therefore, E2 suppression does not negate any safety concerns. Under LNG treatment, SHBG levels decreased to a similar and significant degree in both BMI subgroups. Pharmacokinetic assessments clearly demonstrate that BMI influences total exposure over observed drug-dosing intervals, and that maximal exposure tends to decrease with increasing BMI (i.e., when comparing BMI subgroup 2 to BMI subgroup 1, the arithmetic mean Cav was approximately 17.26% lower, and the geometric mean AUC0-56,ss was approximately 16.06% lower). A comparison of pharmacodynamic parameters (HSS, E2 concentration) within BMI subgroups revealed a slight tendency towards lower ovarian suppression in the higher BMI subgroups, but the variability was large, and the difference in HSS was not statistically significant. The treatment with LVDS was well-tolerated. The number of LNG VDS-related adverse events was similar between the two BMI subgroups.

[0381] References (1) Merck Sharp & Dohme Limited. CerazetR 75 μg (desogestrel). Ficha tecnica (SmPC Febrero 2019). Agencia Espanola 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 - Contraception, Editor(s): J. Larry Jameson, Leslie J De Groot, David M. de Kretser, Linda C. Giudice, Ashley B. Grossman, Shlomo Melmed, John T. Potts, Gordon C. Weir, Endocrinology: Adult and Pediatric (Seventh Edition), W.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, . B , Thomas , JW , Jain , RI and Chwalisz , K (2017). "Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist." N Engl J Med 377(1): 28-40. (16) Vercellini, P, Vigano, P, Somigliana, E and Fedele, L (2014). "Endometriosis: pathogenesis and treatment." Nature Reviews Endocrinology 10(5): 261-275. (17) Paolo Vercellini, MD, Laura Buggio, MD, Maria Pina Frattaruolo, MD, Alessandra Borghi, MD, Dhouha Dridi, MD, Edgardo Somigliana, MD. 51 , 68-9 (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 Womens 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) Bulun, 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 used in a method for providing contraception to a female subject, wherein the method comprises administering levonorgestrel to the subject continuously, the daily dose of levonorgestrel administered is approximately 60 μg / day to approximately 100 μg / day, and the route of administration is vaginal.

2. Levonorgestrel used in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP), and / or dysmenorrhea in female subjects, wherein the method comprises administering levonorgestrel to the subject continuously, the daily dose of levonorgestrel administered is approximately 60 μg / day to approximately 160 μg / day, and the route of administration is vaginal.

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

4. The use of levonorgestrel as a contraceptive involves continuously administering levonorgestrel to female subjects at a dose of approximately 60 μg / day to approximately 200 μg / day, with the route of administration being vaginal.

5. The use of levonorgestrel as used in the method according to any one of claims 1 to 3, or levonorgestrel as a contraceptive according to claim 4, wherein the female subject is not simultaneously administered any further contraceptive component, preferably estrogen.

6. The use of levonorgestrel according to any one of claims 1 to 3, or the use of levonorgestrel according to claim 4 or 5, wherein amenorrhea is also induced by the administration of levonorgestrel.

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

8. When the device was subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2, (i) Release approximately 150 μg or less of levonorgestrel during the initial 24-hour release period, and, (ii) The drug delivery device according to claim 7, having a drug release profile characterized by releasing about 60 μg to 90 μg of levonorgestrel per day for at least 27 days after the initial 24-hour release period.

9. When the device was subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2, (i) Release 250 μg or less of levonorgestrel during the first 24-hour release period, and, (ii) The drug delivery device according to claim 7, having a drug release profile characterized by releasing about 90 μg to 150 μg of levonorgestrel per day for at least 27 days after the initial 24-hour release period.

10. When the device was subjected to an in vitro release test in a 0.2 M sodium acetate buffer containing 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to a pH of 4.2, (i) Release approximately 300 μg or less of levonorgestrel during the initial 24-hour release period, and (ii) The drug delivery device according to claim 7, having a drug release profile characterized by releasing about 110 μg to 180 μg of levonorgestrel per day for at least 27 days after the initial 24-hour release period.

11. The drug delivery device according to any one of claims 7 to 10, wherein, after the delivery device is placed vaginally in the body of a female subject, the subject obtains an average Cmax value of less than 1 ng / ml for levonorgestrel after one 28-day treatment cycle and an average Cmax value of less than 0.7 ng / ml for levonorgestrel after two 28-day treatment cycles, and an average AUC(0.-t) value of less than 350 h·ng / ml after one 28-day treatment cycle and an average AUC(0.-t) value of less than 370 h·ng / ml after two 28-day treatment cycles.

12. The drug delivery device according to any one of claims 7 to 10, wherein after the delivery device is placed vaginally in the body of a female subject, the subject obtains an average Cmax value of less than 1.6 ng / ml for levonorgestrel after one 28-day treatment cycle and an average Cmax value of less than 1 ng / ml for levonorgestrel after two 28-day treatment cycles, and an average AUC(0-t) value of less than 580 h·ng / ml after one 28-day treatment cycle and an average AUC(0-t) value of less than 540 h·ng / ml after two 28-day treatment cycles.

13. The drug delivery device according to any one of claims 7 to 12, wherein the device contains no further contraceptive components, and preferably contains no estrogen.

14. (i) Levonorgestrel is present in the core at a concentration of about 0.20% to about 1.00% by weight relative to the total weight of the core, and / or (ii) The drug delivery device according to any one of claims 7 to 13, wherein the sheath has a thickness of about 5 μm to about 500 μm, preferably about 50 μm to about 200 μm.

15. The drug delivery device according to any one of claims 7 to 14, wherein the drug delivery device has a shape selected from a spiral shape or a ring shape, preferably the drug delivery device has a ring shape, and preferably the device is a vaginal ring.

Images