Treatment of hirsutism, polycystic ovary syndrome and other related conditions

Abstract

Treatment of hirsutism, polycystic ovary syndrome, and other related conditions. This invention relates to a novel treatment for hirsutism, wherein a combination of dinogest and ethinylestradiol is administered to the subject in need.

Description

Technical Field

[0001] This invention relates to the treatment of hirsutism and hyperandrogenemia, and particularly to the management of hirsutism associated with polycystic ovary syndrome using an orally controlled-release formulation containing 2 mg dienogest (DNG) and 0.02 mg ethinyl estradiol (EE) in a 24 / 4 regimen. Background Technology

[0002] Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder defined by excess androgens and ovarian dysfunction, provided other diagnoses have been ruled out. As perhaps the most common endocrine and metabolic disorder in women of reproductive age, the prevalence of PCOS is approximately 6% to 20% when using evolving diagnostic criteria. PCOS is caused by a complex interplay of genetic and environmental factors, resulting in a variety of clinical consequences affecting reproduction (infertility, hyperandrogenemia, hirsutism), metabolism (insulin resistance, impaired glucose tolerance, type 2 diabetes, adverse cardiovascular risk profile), and mental health (increased anxiety, depression, and deteriorating quality of life). Hirsutism is the predominant manifestation of hyperandrogenemia associated with PCOS, affecting 65% to 75% of women with PCOS.

[0003] To date, most medications used to manage PCOS have been used off-label. Current management strategies for PCOS include reducing excess androgens, for which combined oral contraceptives (COCs) remain the first-line treatment. In women with PCOS, the progestin component of COCs suppresses luteinizing hormone (LH) secretion, thereby reducing ovarian androgen production; protects the endometrium; regulates the menstrual cycle; and reduces hyperandrogenemia. The estrogen component of COCs increases circulating levels of sex-hormone-binding globulin (SHBG), which can lower serum free testosterone levels. In terms of effectiveness, low-dose COCs containing neutral or anti-androgenic progestins should be the first choice for PCOS treatment. Current evidence suggests that for most women with PCOS, the benefits of oral contraception outweigh the risks; however, concerns remain regarding the metabolic and cardiovascular safety of COCs for the long-term management of women with PCOS.

[0004] Therefore, there is a need to provide safe and modulated alternatives that are widely acceptable to those in need for the treatment of hirsutism, hyperandrogenemia and / or PCOS and / or their symptoms. Summary of the Invention

[0005] The present invention overcomes the limitations of the prior art by providing novel treatments using dinogest and ethinylestradiol, as well as compositions comprising dinogest and ethinylestradiol.

[0006] Therefore, in a first aspect, a controlled-release composition comprising a combination of DNG and EE is provided for treating hirsutism, hyperandrogenemia, and irregular menstrual cycles in subjects with such needs.

[0007] In a preferred aspect, the composition can be used to treat hirsutism associated with polycystic ovary syndrome (PCOS).

[0008] In another preferred aspect, the composition is intended for once-daily application.

[0009] In another preferred aspect, the composition may contain 2 mg DNG and 0.02 mg EE.

[0010] In another preferred aspect, the composition is intended for use in treating mild, moderate and / or severe hirsutism.

[0011] In another preferred aspect, the subject may be a person with a body mass index (BMI) <30 and / or a BMI >30; or, if necessary, a woman with hyperandrogenemia.

[0012] In another preferred aspect, the composition may be administered once daily for 24 days, followed by a placebo for 4 days.

[0013] In another preferred aspect, the composition may be applied over a period of at least 4 months, preferably over a period of at least 9 months.

[0014] In another aspect of the invention, a controlled-release composition comprising a combination of DNG and EE is provided for treating hirsutism, polycystic ovary syndrome, PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, irregular menstrual cycles, and / or PCOS-related irregular menstrual cycles in subjects with such need. Attached Figure Description

[0015] Figure 1The change of the least square (LS) mean relative to baseline in the adjusted modified Ferriman-Gallwey (mFG) total score (MMRM; full analysis set). The adjusted mFG score was determined by the investigator for terminal hair growth in the participants' chest, upper abdomen, lower abdomen, thighs, back, arms, and buttocks (lowest score 0; highest score 28).

[0016] Figure 2 Quality of life: PCOSQ domain scores at baseline and at the end of cycle 9 (or when the study was suspended) (full analysis set). The PCOSQ covers 26 items across five domains: mood (8 items), body hair (5 items), weight (5 items), infertility issues (4 items), and menstrual issues (4 items), using a 7-point Likert scale, where 7 represents best functioning and 1 represents worst functioning. Lower scores are associated with a greater negative impact on health-related quality of life. The total score is the sum of all domain scores. PCOSQ refers to the Polycystic Ovary Syndrome Questionnaire.

[0017] Figure 3 The proportion of participants experiencing scheduled bleeding / spotting during the reference period was calculated (full analysis set). Bleeding data from the six months prior to screening were collected at the screening visit (recalled data was defined as “scheduled” by the participant). Bleeding data during the trial period were collected via self-completion electronic diaries, with participants reminded to complete their entries. Scheduled bleeding during the trial period was defined as vaginal bleeding that began 2 to 4 days after taking the last active tablet. All reference periods P < 0.005. Detailed Implementation

[0018] definition

[0019] As used herein, the term "denorgestrel (DNG)" or "17α-cyanomethyl-17-β-hydroxyestra-4,9-dien-3-one" is defined for the purposes of this invention as comprising (i) unsalted denorgestrel (also known as denorgestrel base), pharmaceutically acceptable salts thereof, and mixtures thereof; and (ii) esters, solvates, complexes, polymorphs, hydrates, or prodrugs as used herein (i). Preferably, the denorgestrel in the composition is unsalted denorgestrel, pharmaceutically acceptable salts thereof, or mixtures thereof. The PubChem CID number for denorgestrel is 68861.

[0020] As used herein, the term "ethynylestradiol (EE)" or "17α-ethynylestradiol" is defined for the purposes of this invention as comprising: (i) unsalted ethynylestradiol (also known as ethynylestradiol base), pharmaceutically acceptable salts thereof, and mixtures thereof; and (ii) esters, solvates, complexes, polymorphs, hydrates, or prodrugs as used herein (i). Preferably, the ethynylestradiol in the composition is unsalted ethynylestradiol, pharmaceutically acceptable salts thereof, or mixtures thereof. Ethynylestradiol has a PubChem CID number of 5991.

[0021] Esters of DNG and / or EE can be prepared by functionalizing hydroxyl and / or carboxyl groups that may be present in the molecular structure of the compound (Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th ed. (New York: Wiley-Interscience, 1992). Pharmaceutically acceptable salts include those that form with free amino groups, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc.; and those that form with free carboxyl groups, such as those derived from sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, iron hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, or similar substances.

[0022] The mass of DNG and / or EE in any dosage form of the present invention used herein, or the mass of DNG and / or EE in a test, reference, control, or comparative dosage form containing DNG and / or EE, refers to the amount (mass) of unsalted DNG and / or EE, or pharmaceutically acceptable salts of DNG and / or EE, or mixtures thereof.

[0023] With respect to the dosage forms of this invention, the terms "oral," "oral dosage form," "oral pharmaceutical dosage form," "oral administration," "oral composition," "oral pharmaceutical composition," "oral contraceptive composition," "oral tablet," "oral capsule," "oral intake," "oral administration," "oral route," etc., as used herein, refer to any method of administration via the mouth. The oral dosage forms of this invention are generally ingested whole, but they may also be tampered with (e.g., crushed) and are usually administered with the aid of water or a beverage to facilitate passage through the mouth.

[0024] As used herein, the term "controlled-release" dosage form refers to a pharmaceutical preparation that releases the active ingredient from the dosage form or a portion thereof in a manner other than immediate release. Controlled-release pharmaceutical compositions are prepared by incorporating a controlled-release substance (e.g., a controlled-release excipient) into the dosage form. Controlled-release dosage forms are sometimes designed to achieve pharmaceutical, pharmacokinetic, pharmacodynamic, therapeutic, or convenience goals that conventional dosage forms, such as solutions or immediate-release dosage forms, cannot provide.

[0025] As used herein, the terms “controlled release” are interchangeable with “modified release,” “extended release,” “slow release,” “sustained release,” and “long-acting.” A controlled-release formulation releases the active ingredient from the formulation or a portion thereof over an extended period of time (preferably over a period of more than about 8 hours, and most preferably over a period of more than about 10, 12, 14, 16, 18, 20, 22, or 24 hours). A controlled-release formulation may be a delayed-onset formulation, i.e., “delayed onset, extended release” (e.g., a delay in release at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after ingestion, preferably at least 2 hours after ingestion) or “extended release” (i.e., no significant initial delay in release). In some embodiments, these controlled-release compositions are formulated for daily administration.

[0026] As used herein, “controlled release substance,” “controlled release means,” “rate control means,” “rate control excipient,” “rate control component,” “rate control substance,” “release rate control means,” “release rate control excipient,” “release rate control component,” “release rate control substance,” and “substance for providing controlled release” mean an in vitro or in vivo release rate control excipient or substance incorporated into a dosage form whose function or primary function is to adjust the release (e.g., release onset, release rate, release duration) of an active drug substance (e.g., DNG and / or EE) from the dosage form or a portion thereof (i.e., causing the dosage form to release in a manner other than immediate release). In some preferred embodiments of the invention, the function of controlling the release of the substance, compared to immediate release of DNG and / or EE, is to provide one or more of the following: (1) a change in the onset of release; (2) a change in the release rate; (3) a change in the duration of release; (4) a change in the time to peak plasma concentration; (5) a change in peak plasma concentration; (6) a change in the degree of absorption; (7) a change in the onset of therapeutic effect; (8) a change in the duration of therapeutic effect; and (9) a change in the gastrointestinal anatomical location of release.

[0027] As used herein, “treatment” and its variations mean: (i) preventing or delaying the onset of a disease, disorder, and / or condition in individuals who may be susceptible to it but have not yet been diagnosed with it; (ii) suppressing a disease, disorder, or condition, i.e., preventing or slowing its occurrence or progression; (iii) alleviating a disease, disorder, or condition, i.e., leading to its resolution; and / or (iv) preventing, suppressing, or alleviating the symptoms of a disease, disorder, and / or condition. In some embodiments, such terms refer to the improvement or eradication of a disease or disease-related symptoms.

[0028] As used herein, "therapeutic effective amount" refers to an effective amount at the dose and for the time period required to achieve a desired therapeutic outcome, for example, one or more of the following: significantly delaying the onset or progression of disease; or significantly reducing the severity of one or more symptoms. Therapeutic effective amount is also generally the amount in which any toxic or adverse effects of the active ingredient or pharmaceutical composition are exceeded by the therapeutically beneficial effects.

[0029] Hyperandrogenemia is a medical condition characterized by high levels of androgens (such as testosterone, which can be measured as free and / or total testosterone, dihydrotestosterone (DHT), androstenedione (A4), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS)) that are generally considered male sex hormones, although they are also present in women at lower levels. Other markers may be 17α-hydroxyprogesterone (17OHP) and / or sex hormone-binding globulin (SHBG). However, when the levels of these androgens are too high in women, symptoms may be observed, such as acne, seborrhea, hair loss on the scalp, increased body or facial hair, and irregular or absent menstruation. Hyperandrogenemia can be caused by external factors or can occur spontaneously. For example, it could be “PCOS-related hyperandrogenemia,” where PCOS is the cause of excessive androgen secretion.

[0030] Polycystic ovary syndrome (PCOS) is an endocrine disorder in women of reproductive age. The most important characteristics of PCOS are hyperandrogenemia, anovulation, insulin resistance, and neuroendocrine disturbances. Other observed side effects include irregular menstrual cycles, heavy periods, excessive hirsutism, acne, and infertility.

[0031] "Hypertrichosis" and "PCOS-associated hypertrichosis" are understood as excessive body hair in body parts (usually areas with little or no hair). Therefore, hypertrichosis in women may present as male-pattern hair growth. The amount and location of hair can be measured using the Ferriman-Gallwey (FG) score. The FG score uses up to 11 body areas to assess hair growth; however, the modified FG (mFG) considers only 9 body areas. The body areas used in the mFG score are the chest, back, upper abdomen, lower abdomen, arms, buttocks, upper lip, chin, and thigh. Hair growth is scored from "0" (no hair growth) to "4" (excessive hair growth). In this paper, the modified mFG score is used, which assesses the following 7 body areas: chest, back, upper abdomen, lower abdomen, arms, buttocks, and thigh. According to the modified mFG, a score of 7 or higher (≥7) is considered hypertrichosis. It can also be classified into mild (adjusted mFG=7 to 13), moderate (adjusted mFG=14 to 19) and severe (adjusted mFG>19) hypertrichosis.

[0032] "Irregular menstrual cycles" and "PCOS-related irregular menstrual cycles" refer to any irregularity in a woman's menstrual cycle where bleeding is unpredictable. This can include situations where a woman experiences no bleeding at all, as well as situations where menstruation is infrequent (amenorrhea) or menorrhagia (excessive menstrual bleeding).

[0033] "Acne associated with hyperandrogenemia" or "acne associated with PCOS" refers to acne in women that is caused by elevated levels of testosterone, dihydrotestosterone, and / or dehydroepiandrosterone, such as acne that may occur due to hyperandrogenemia and / or PCOS.

[0034] "Seborrhea" refers to skin problems and / or conditions caused by overactive sebaceous glands, such as oily skin.

[0035] Clinical trials and results

[0036] Details of the clinical trial will be described further below.

[0037] It has been shown that the combination of oral dinogest (DNG) 2 mg / ethinylestradiol (EE) 0.02 mg reduces androgen levels, increases SHBG levels, and significantly reduces total and free testosterone levels. Preferably, the combination of DNG 2 mg / EE 0.02 mg is in a controlled-release form to achieve the highest efficacy. Therefore, the DNG / EE combination has high anti-androgenic potential and can be used to treat conditions exhibiting abnormal values ​​of these androgens, such as hyperandrogenemia and hirsutism. In particular, the DNG / EE combination can be used to treat the following conditions: hirsutism, polycystic ovary syndrome, PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, irregular menstrual cycles, and / or PCOS-related irregular menstrual cycles, acne or seborrhea, and / or symptoms of these conditions.

[0038] Furthermore, conditions such as hirsutism, polycystic ovary syndrome (PCOS), PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, irregular menstrual cycles, and / or PCOS-related irregular menstrual cycles, acne or seborrhea, and / or their symptoms not only directly represent observable physiological conditions affecting women, but also significantly impact the quality of life, self-esteem, and body image of affected women. For example, a higher proportion of affected women report having a negative body image, experience increased anxiety and depression, and reduced health-related quality of life, and exhibit overall low self-esteem. Therefore, treating conditions such as hirsutism, polycystic ovary syndrome (PCOS), PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, irregular menstrual cycles, and / or PCOS-related irregular menstrual cycles, acne or seborrhea, and / or treating the symptoms of these conditions will help simultaneously improve and restore the self-esteem and quality of life of affected women.

[0039] In a preferred aspect, a controlled-release formulation of oral DNG 2 mg / EE 0.02 mg is used to treat PCOS-associated acne. PCOS-associated acne is caused by hormonal imbalances (especially androgen excess) resulting from PCOS. This type of PCOS-associated acne often flares up on the lower face, including the jawline, chin, and upper neck, corresponding to visible areas of the body. PCOS-associated acne also leads to deeper, larger, and slower-resolving lesions. Additionally, PCOS-associated acne tends to worsen around the menstrual cycle. All of these factors combined further exacerbate a patient's perception of PCOS, particularly in adult patients, and negatively impact their daily life and self-esteem.

[0040] This invention now provides treatments not only for PCOS and hirsutism, but also for PCOS-related conditions (such as acne) that are otherwise untreatable and only available through off-label use, and which so far only present complex combinations of different treatments.

[0041] In particular, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg has shown excellent efficacy in women for the clinical management of the following conditions in a 24 / 4 day regimen lasting up to nine consecutive 28-day cycles: hirsutism, polycystic ovary syndrome, PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, irregular menstrual cycles, and / or PCOS-related irregular menstrual cycles, acne or seborrhea, and / or symptoms of these conditions.

[0042] In particular, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg unexpectedly allowed for the control of androgens and biomarkers, reducing them to normal, physiological levels. These normal, physiological levels, expressed as upper / lower normal reference ranges, are for adult women: Free testosterone: 33.01 / 2.98 mmol / L; Testosterone: 1.66 / 0.28 nmol / L; Androstenedione: 4.58 / 1.71 nmol / L; 17-OH progesterone: 12.51 / 1.06 nmol / L; Dehydroepiandrosterone sulfate: 11 / 4 μmol / L (20 to 24 years), 9.2 / 2.7 μmol / L (25 to 35 years), 9.1 / 1.7 μmol / L (35 to 41 years); Sex hormone-binding globulin: 128 / 32.4 nmol / L; Free androgen index: 0.18 / 7.07%; Insulin resistance: < 2.0 (unlikely insulin resistance), 2.0 to 2.5 (possibly insulin resistance), 2.5 to 5.0 (most likely insulin resistance), > 5.0 (mean for type 2 diabetes).

[0043] Specifically, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg provided a rapid reduction in free testosterone after only a few cycles. After 3 cycles, free testosterone decreased by approximately 72% relative to pre-treatment baseline and was within the range of normal healthy women. After 6 cycles, this level was maintained, with a further decrease of 74% relative to baseline observed. However, no change was observed with placebo, meaning the control group still had abnormally high testosterone levels. The reduction in testosterone was associated with all treatments for all conditions or symptoms mentioned in this invention. All of these also had an effect on PCOS-related conditions, such as PCOS-related acne, and for the first time demonstrated effective treatment for them.

[0044] Simultaneously, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg provided an increase in SHBG levels, from approximately 30 to 40 nmol / L before treatment to over 140 nmol / L after 9 cycles. In the placebo setting, SHBG levels remained low and unchanged.

[0045] The controlled-release formulation of oral DNG 2 mg / EE 0.02 mg also provided favorable results for the treatment of hirsutism and / or PCOS-related hirsutism. Following treatment, approximately 46% of women showed no hirsutism, and their adjusted mFG scores were below 7. It was also observed that the more severe the hirsutism, the greater the effect of the DNG / EE combination of this invention.

[0046] After 9 cycles or after early discontinuation, the adjusted mFG score decreased by approximately 35% in the treatment group, compared to only approximately 17% in the control group. Alternatively, after 9 cycles or after early discontinuation, the adjusted mFG score decreased by 3.77 in the treatment group (change to -3.77), compared to only 1.54 in the control group (change to -1.54).

[0047] Changes were observed in all subgroups of hirsutism severity. Hirsutism severity was categorized as mild, moderate, or severe based on the mFG score: no hirsutism (score <7); mild hirsutism (score 7–13); moderate hirsutism (score 14–19); and severe hirsutism (score 20–28). Therefore, significant changes in hirsutism severity scores were observed in all severity groups after 9 cycles or after early discontinuation, but very few changes were observed when treated with the formulation of this invention, compared to placebo. In the DNG 2 mg / EE 0.02 mg treatment group, nearly 50% of patients achieved an mFG score less than 7.

[0048] The controlled-release formulation of oral DNG 2 mg / EE 0.02 mg also affected irregular menstrual cycles and restored regular bleeding. A decrease in women experiencing "no bleeding" was also observed after treatment with the DNG / EE of this invention. This was not the case in the placebo control group. In the control group, approximately 35% to 40% of women showed no bleeding during cycles 3 to 6; however, with the DNG / EE combination treatment of this invention, only approximately 15% to 20% of women experienced no bleeding. Simultaneously, treatment with the DNG / EE combination of this invention allowed women to generally experience regular, planned bleeding. Approximately 6 months prior to DNG / EE treatment, less than 20% experienced such regular, planned bleeding; during cycles 3 to 6, more than 75% observed regular, planned bleeding. This was not observed in the placebo control group. No improvement was detected in this case.

[0049] "Planned bleeding" during the trial was defined as vaginal bleeding that began 2 to 4 days after taking the last active tablet.

[0050] Specifically, in the six months prior to the trial, approximately 15% of women in the treatment group (the DNG / EE combination of this invention) experienced planned bleeding, compared to approximately 17% in the placebo control group. During cycles 2 to 4, planned bleeding increased to approximately 90% in the treatment group, compared to approximately 42% in the placebo group. During cycles 5 to 7, approximately 82% of women in the treatment group still experienced planned bleeding, compared to only approximately 33% in the control group. When considered collectively for cycles 2 to 9, approximately 90% of women in the treatment group experienced planned bleeding, compared to only approximately 54% in the placebo group. This is... Figure 3 As shown in the image.

[0051] Treatment using the DNG / EE combination of this invention also showed improvements in quality of life in treated women, which were not observed with placebo. Quality of life was determined using the PCOS Questionnaire (PCOSQ). The PCOSQ has been described, for example, in Cronin L, Guyatt G, Griffith L, et al. Development of a health-related quality-of-life questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 1998; 83(6): 1976-87. The PCOSQ covers 26 items across five domains: mood (8 items), body hair (5 items), weight (5 items), infertility problems (4 items), and menstrual problems (4 items), using a 7-point Likert scale (where 7 represents best functioning and 1 represents worst functioning). Lower scores were associated with a greater negative impact on health-related quality of life. The total score was the sum of scores across all domains.

[0052] The pre-trial total score was 19.23 in the treatment group and 17.20 in the control group. After 9 cycles or at the end of treatment following early discontinuation, the PCOSQ score in the treatment group increased to 24.61, a multiple of approximately 1.28, while the PCOSQ score in the control group only increased to 20.08, a multiple of approximately 1.16. Therefore, there was a significant improvement in the treatment group compared to the control group. This is shown in Table 1 below. Figure 2 As shown in the image.

[0053] Table 1: PCOSQ Scoring

[0054]

[0055] Treatment group = controlled-release formulation of oral DNG 2 mg / EE 0.02 mg; Control group = placebo; Baseline = before trial; End = after 9 cycles or after early termination.

[0056] Furthermore, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg did not show significant changes in coagulation and fibrinolysis parameters, indicating that the controlled-release formulation does not affect these factors. However, this is not the case with other similar COC products. These products carry an increased risk of thrombosis, such as venous thromboembolism (VTE). But the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg, with its reduced Cmax and controlled Tmax, did not affect hemostatic parameters and therefore significantly reduced EE exposure without impairing the bleeding profile. Therefore, since no effects on liver-dependent coagulation factors were observed, the potential changes in blood coagulation associated with the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg can be considered neutral.

[0057] Controlled-release formulations

[0058] International application WO 2022 / 034209 A1 describes an orally controlled-release formulation comprising 2 mg DNG / 0.02 mg suitable for use in this invention, and is incorporated herein by reference in its entirety.

[0059] In some preferred embodiments, the dosage form of the present invention is an oral dosage form, preferably a tablet, comprising: (i) 2 mg DNG and 0.02 mg EE, wherein at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, and more preferably all amounts of DNG and / or EE are intended for controlled release. In some embodiments, the dosage form is suitable for administration every 24 hours, i.e., the dosage form is a daily dosage form.

[0060] In some particularly preferred embodiments, the composition is adapted to provide a pharmacokinetic profile of DNG and / or EE characterized by a Tmax of 3 to 4 hours when administered orally once daily for 7 days on an empty stomach. Preferably, the pharmacokinetic profile of the composition when administered orally once daily for 7 days on an empty stomach is further characterized by a Cmax of less than 60 ng / mL to 65 ng / mL for DNG or EE.

[0061] In some embodiments, optionally in combination with any of the above, the composition is further characterized by its dissolution profile. In some specific embodiments, the composition is characterized by having a dissolution profile in which 30% to 60% of the initially present amount of DNG or EE in the composition dissolves within 2 hours. In some preferred embodiments, at least 70%, preferably at least 80%, of the initially present amount in the composition dissolves within 5 hours.

[0062] The in vitro dissolution rate (or dissolution profile) of EE and / or DNG in the composition is preferably evaluated using the USP1 method (basket method). In short, the tablet to be tested, consisting of a composition containing EE and DNG, is placed in 900 mL of water at 37°C (± 0.5°C). The dissolution test is performed using the USP Dissolution Test Apparatus 1 (basket method) with a stirring rate of 75 rpm. Alternatively, the tablet to be tested, consisting of a composition containing EE and DNG, is placed in 500 mL of water at 37°C (± 0.5°C). The dissolution test is performed using the USP Dissolution Test Apparatus 1 (basket method) with a stirring rate of 75 rpm. Therefore, the dissolution test using 900 mL of water is referred to herein as "Dissolution Method I"; however, the dissolution test using 500 mL of water is referred to herein as "Dissolution Method II".

[0063] Compositions having such in vitro dissolution profiles and / or in vivo pharmacokinetic profiles can be obtained by different methods.

[0064] The release of the EE (preferably EE and DNG) of the slow-release or controlled-release fraction can be controlled by a variety of controlled-release methods. For example, controlled release can be achieved by using controlled-release methods suitable for coating retardation, matrix retardation, particle retardation, osmotic retardation, or other forms of retardation. In coating retardation, the core of the pharmaceutical composition containing the active ingredient is provided with a coating composed of one or more hydrophilic and / or hydrophobic polymers that slows the release of the active ingredient. In matrix retardation, the active ingredient is contained in a matrix formed of one or more excipients that controls the release of the active ingredient.

[0065] In some embodiments, the oral dosage form comprising a controlled-release means (preferably in the form of an excipient whose release rate is controlled) is selected from: oral dosage forms comprising a slow-release or controlled-release coating, oral dosage forms comprising a pH-independent slow-release or controlled-release coating, oral dosage forms comprising a prolonged-release matrix, oral dosage forms comprising a permeation control system, or oral dosage forms comprising a mixture of particles or beads coated with a controlled-release substance. Preferably, the oral dosage form is an oral contraceptive composition.

[0066] Some examples of release rate-controlled excipients or controlled release methods are inert plastic matrices, hydrocolloids, ion exchangers, slow-release coatings, gastric-resistant coatings, particle mixtures, microplates and / or particle mixtures, microcapsules, permeation control systems, dissolution control systems, diffusion control systems, and combinations thereof, as well as fatty and waxy matrices.

[0067] In some embodiments, the oral dosage form comprises a plurality of pharmaceutically acceptable beads or granules coated with a drug and an outer coating of a controlled-release substance. These beads or granules may be compressed into tablets or filled into hard gel capsules. In other embodiments, the dosage form comprises capsules within capsules, each capsule containing a different drug or the same drug. In some specific embodiments, the outer capsule may be an enteric-coated capsule or a capsule containing an immediate-release formulation to provide rapid plasma concentrations or a rapid onset or loading dose, and the inner capsule contains a prolonged-release formulation. In one embodiment of the invention, the dosage form comprises one or more tablets within a capsule, wherein EE and / or DNG may be in one of the tablets and / or in one of the capsules. In one embodiment of the invention, the composition is taken orally as a tablet or capsule, preferably as a tablet.

[0068] In other embodiments, slow or controlled release is achieved via an osmosis-driven release system, wherein the oral dosage form may comprise (i) a drug layer; and (ii) a displacement layer comprising an osmopolymer; and (b) a semi-permeable wall surrounding a bilayer core having passageways configured therein for drug release. In some preferred embodiments, the oral dosage form comprises compressed tablets, compressed capsules, or uncompressed capsules. In some preferred embodiments, the oral dosage form comprises tablets.

[0069] One objective of certain embodiments of the present invention is to provide orally administered EE and DNG, wherein the EE is dispersed in a matrix, preferably wherein the EE and DNG are dispersed in the matrix. In some preferred embodiments, the orally administered dosage form of the present invention comprises a matrix containing a controlled-release substance and EE, preferably EE and DNG. In some preferred embodiments, the matrix is ​​compressed into tablets and optionally coated with a coating that, in addition to the controlled-release substance of the matrix, controls the release of EE from the formulation, preferably controlling the release of EE and DNG from the formulation, such that the blood level of the active ingredient is maintained within a therapeutic range over an extended period of time. In some embodiments, the coating is used for the immediate disintegration and release of the active ingredient. In some alternative embodiments, the matrix is ​​encapsulated. In some preferred embodiments, the extended-release orally administered dosage form of the present invention comprises a variety of pharmaceutically acceptable extended-release matrices containing EE, DNG, or EE and DNG, which, when administered to a patient, maintain the plasma level of the active ingredient within a therapeutic range over an extended period of time.

[0070] In some embodiments, the dosage form of the present invention comprises oral DNG and EE, formulated for releasing EE, preferably EE and DNG, from the dosage form, or for initiating the release of EE, preferably EE and DNG, after a specific amount of time following oral ingestion, or at a near-specific anatomical location in the gastrointestinal tract, or when the dosage form comes into contact with specific gastrointestinal conditions (e.g., pH range, osmolarity, electrolyte content, food content, pressure, time since first ingestion, osmolarity in the dosage form, osmolarity in the gastrointestinal tract, hydration, etc.), said dosage form being suitable for providing an orally effective therapeutic effect of short, medium, or prolonged duration, said dosage form providing a rapid or delayed onset of clinical effect. Preferably, the dosage form begins to release EE, preferably EE and DNG, immediately after ingestion.

[0071] In some embodiments of the invention, EE (preferably EE and DNG) is in a multi-particulate form. In some embodiments of the invention, EE (preferably EE and DNG) is dispersed in a matrix. In some embodiments of the invention, EE (preferably EE and DNG) is in a multi-particulate form that is dispersible in a matrix or contained in a capsule. In some embodiments of the invention, EE (preferably EE and DNG) is in a matrix in particulate form. In some embodiments of the invention, EE (preferably EE and DNG) is in coated beads. In other embodiments of the invention, EE (preferably EE and DNG) is in a multi-particulate form dispersed in a matrix and compressed into tablets.

[0072] In some particularly preferred embodiments, the dosage forms of the present invention comprise oral formulations (e.g., tablets or capsules) coated to prevent substantial direct contact between EE (preferably EE and DNG) and the oral cavity (e.g., tongue, oral mucosa), oropharyngeal mucosal surfaces, esophagus, or stomach. In some preferred embodiments, the dosage forms of the present invention comprise oral formulations coated with a film or polymer.

[0073] In some embodiments, optionally in combination with any of the above, the extended release form is a tablet and may be coated or uncoated. Preferably, the tablet is a film-coated tablet comprising a tablet core and a film coating, wherein the tablet core contains EE contents for slow or controlled release, preferably wherein the tablet core contains DNG and EE contents for slow or controlled release. Preferably, the coating film allows for immediate disintegration for rapid, active release. For example, the film may be a single-step film coating system (Opadry). TM Colorcon® | Opadry® II Complete Aqueous Film Coating System combines polymers, plasticizers, and pigments, allowing for immediate disintegration for rapid, active release.

[0074] In some embodiments, the extended-release EE (preferably EE and DNG) dosage forms of the present invention are solid dispersions. Bioavailability is substantially improved by reducing drug particle size and thus improving drug wettability. Additionally, surfactants may be included to stabilize the dosage form in order to improve solubility and reduce recrystallization (see Vasconcelos et al., DrugDiscovery Today, 2007; 12:1068-75, which is incorporated herein by reference in its entirety).

[0075] In some embodiments, the EE (preferably EE and DNG) may be dispersed in the extended-release matrix as described above. The term "extended-release matrix" refers to one or more hydrophilic polymers and / or one or more hydrophobic polymers and / or one or more other types of hydrophobic substances. In some embodiments, the extended-release matrix comprises one or more hydrophilic polymers and one or more hydrophobic polymers, for example in a hydrophobic / hydrophilic matrix system (PVAc / PVP). Suitable substances (also referred to herein as polymer matrix forming agents) for inclusion in the extended-release matrix are:

[0076] (a) The hydrophilic polymers include, but are not limited to, gums, cellulose ethers, hydrophilic acrylic polymers, ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polyvinyl alcohol, povidone (PVP), carbomer, potassium pectate, potassium pectinate, and protein-derived substances. Among these polymers, cellulose ethers, especially hydroxyalkyl cellulose and carboxyalkyl cellulose, are preferred. Oral formulations may contain 10% to 80% w / w, preferably 20% to 70%, more preferably 30% to 60% of at least one hydrophilic polymer.

[0077] (b) Hydrophobic polymers include, but are not limited to, ethyl cellulose, hydroxyethyl cellulose, hydrophobic acrylic polymers, and polyvinyl acetate (PVAc)-based polymers. Other suitable hydrophobic substances are digestible long-chain (C8-C50, especially C12-C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols such as cetearyl alcohol, stearyl alcohol; cetyl alcohol, myristyl alcohol, etc., fatty acids, mineral oils and vegetable oils, and waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite. Hydrocarbons with melting points of 25°C to 90°C are preferred. Among these long-chain hydrocarbons, fatty (aliphatic) alcohols are preferred. Oral formulations may contain up to 55% to 60% w / w of at least one digestible, long-chain hydrocarbon.

[0078] (c) Polyalkylene glycols. Oral formulations may contain up to 60% w / w of at least one polyalkylene glycol.

[0079] In some embodiments, the weight ratio of dinogest to matrix forming agent can be about 1:2.5, about 1:5, about 1:10, about 1:12.5, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, or about 1:50. In some preferred embodiments, it is 1:20 to 1:30, for example, about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26, about 1:27, about 1:28, about 1:29, or about 1:30.

[0080] At least one hydroxyalkyl cellulose is preferably a hydroxy (C1 to C6) alkyl cellulose, more preferably selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose, and more preferably the hydrophilic polymer is HMPC. Preferably, HPMC is a controlled-release (CR) grade. Typical HPMC products used as controlled-release matrices are METHOCEL (HPMC) K100 Premium LV, K4M Premium, K15M Premium, K100M Premium, E4M Premium, and E10M Premium CR. All of these products are available in controlled-release (CR) grade, which are specially produced ultrafine particle size materials. The main differences between these grades are viscosity and methoxy substitution type.

[0081] The viscosity of a matrix forming agent (e.g., HPMC) in a 2% by weight aqueous solution at 20°C can be from 2 to 150,000 mPa·s (determined using a Pharm. Eu. capillary viscometer). In one specific embodiment, the composition comprises HPMC with a viscosity of 80,000 to 120,000 cP, such as HPMC K100M, as a polymer matrix forming agent. In a preferred embodiment, the composition comprises HPMC with a viscosity of 80 to 120 mPa·s, such as HPMC K100 Premium LV, as a matrix forming agent. The viscosity ranges provided herein correspond to the apparent viscosity of 2% in water at 20°C (determined using a Pharm. Eu. capillary viscometer).

[0082] The amount of at least one hydroxyalkyl cellulose in this oral formulation will be determined, in particular, by the precise rate of release of the desired EE (and preferably EE and DNG).

[0083] In some preferred embodiments or in some of the preferred embodiments described herein, the hydrophilic polymer is preferably hydroxy (C1 to C6) alkyl cellulose with a concentration of 25% to 60% w / w, for example 30% to 50% w / w, including about 30%, about 40% and about 50%, or 45% to 55% w / w, more preferably about 50% w / w.

[0084] Acrylic polymers, such as polymethacrylate, are pharmacologically inactive and have good compatibility with skin and mucous membranes. Eudragit is a trade name for a copolymer derived from esters of acrylic acid and methacrylate. Different Eudragit grades have varying proportions of neutral, basic, or acidic groups, resulting in different physicochemical properties. In some preferred embodiments of the invention, a gastric-insoluble polymethacrylate grade (Eudragit RL / RS) is preferred. More preferably, the acrylic resin is Eudragit RS PO.

[0085] The amount of at least one acrylic polymer in this oral formulation will be determined, in particular, by the precise rate of release of the desired EE (and preferably EE and DNG). In some preferred embodiments, the acrylic resin is present at 10% w / w to 40% w / w, preferably at 20% w / w to 30% w / w.

[0086] In some embodiments, the matrix composition further comprises a flow aid. Various reagents can be used as flow aids (e.g., fumed silicon dioxide, aerosilicone). TM Aerosil TM COK84, Aerosil TM (e.g., 200, etc.) are incorporated. The gliding agent enhances the pharmaceutical formulation of the present invention by increasing solution viscosity and supplementing the effect of cellulose ethers (e.g., HPMC).

[0087] In addition to the above-mentioned components, the sustained-release matrix may also contain appropriate amounts of other excipients, such as diluents, lubricants, binders, granulating aids, colorants, flavoring agents, and flow aids commonly used in the pharmaceutical industry.

[0088] Suitable diluents (also known as fillers) include corn starch, microcrystalline cellulose, powdered cellulose, siliconized cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, sucrose, fructose, dextrose, and / or mixtures thereof. Preferably, lactose monohydrate and mannitol are used. The diluent may be present in amounts from about 20% to about 95% by weight of the total composition, preferably from 30% to 90% by weight, more preferably from 35% to 80% by weight, and even more preferably from 30% to 60% by weight, including about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, and about 60% by weight.

[0089] The dosage form according to the invention may also include a binder. The binder may be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and / or mixtures thereof. Preferably, polyvinylpyrrolidone (e.g., povidone K30) is used. The binder may be present in amounts of about 0.5% to about 20% by weight, preferably 1% to 10% by weight, and more preferably 2% to 7% by weight, and preferably about 5% by weight, based on the total weight of the composition.

[0090] The dosage form according to the invention may further comprise a disintegrant. The disintegrant may be selected from low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, and / or mixtures thereof. The disintegrant may be present in amounts of about 2% to about 50% by weight, preferably about 5% to about 45% by weight, and more preferably 10% to 40% by weight, based on the total weight of the composition.

[0091] The lubricant may be selected from talc, alkaline earth metal stearates (especially magnesium stearate and calcium stearate), stearic acid, glyceryl palmitate stearate, stearyl fumarate, and / or mixtures thereof. In some preferred embodiments, the lubricant is magnesium stearate. The lubricant may be present in the following amounts: from about 0% to 5% by weight, preferably from about 1% to about 3% by weight (e.g., about 2% by weight) based on the total weight of the composition.

[0092] Example

[0093] Example 1. Coagulation, hemostasis, and fibrinolysis parameters associated with administration of dinogest 2.00 mg / ethinylestradiol 0.02 mg controlled-release formulation.

[0094] The test product was a controlled-release tablet containing dinogest 2.0 mg / ethinylestradiol 0.02 mg, the composition of which is described in Table 2:

[0095] Table 2. Composition of Dinogestrol 2.0 mg / Ethynylestradiol 0.02 mg Controlled-Release Tablets

[0096]

[0097] The subanalysis of the randomized, double-blind trial involved 44 patients receiving dinogest 2.0 mg / ethinylestradiol 0.02 mg controlled-release tablets as the test product, with a regimen of 24 days followed by four placebo doses; and 47 patients receiving a COC (immediate-release formulation) with 0.02 mg EE / 3 mg DRSP as the comparator, using the same dosing regimen over nine complete 28-day cycles, with follow-up scheduled 7 to 10 days after the last dose of the study drug. These patients comprised a subgroup of the 716 patients receiving the extended-release formulation with 2 mg DNG / 0.02 mg EE and the 288 patients receiving 3 mg DRSP / 0.02 mg EE in the entire trial. Pre- and post-release data were obtained from 28 initial patients with 0.02 mg EE / 2 mg DNG and 30 initial patients in the control group.

[0098] This trial was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP), and relevant European Commission directives and laws in each country. Written informed consent was given to all participants prior to enrollment. The EudraCT trial registration number is 2019-001877-97.

[0099] It is generally accepted that estrogen in combined hormonal contraceptives is a cause of increased risk of thromboembolic events. The use of combined contraceptives leads to accelerated coagulation and fibrinolysis by increasing various markers of hemostasis and fibrin turnover.

[0100] This is induced by the significant effects of EE on liver and vascular function. Progestins with significant androgenic properties (such as LNG) can counteract estrogen-induced changes in hematologic factor synthesis in the liver, unlike other progestins with anti-androgenic properties (such as DNG) or those with neutral androgenic properties.

[0101] Hemostasis markers are not the only parameters influencing the occurrence of thrombotic events, but they represent key components affecting this clinical event. An increase of any 10 IU / dL in factor VIII increased the risk of single or recurrent venous thrombosis by 10% and 24%, respectively.

[0102] The following hemostatic parameters were evaluated before and after treatment: antithrombin III (AT III), activated protein C (APC) resistance ratio, D-dimer, and coagulation factors VII and VIII, as well as reactive protein C.

[0103] result

[0104] The only significant difference found between the start and end of treatment was in AT III. At baseline, the geometric mean for the controlled-release formulation of AT III was 0.88 and for the comparator 0.87 (SD, 95% confidence interval [CI], 0.83 to 0.94) and (SD, 95% CI, 0.81 to 0.92). At the end of the study, the following geometric means were observed: 1.06 for the DNG / EE formulation (SD, 95% CI, 0.98 to 1.15) and for the comparator 1.04 SD (95% CI, 0.96 to 1.12). The difference in AT III between the start and end of treatment was significant, with p-values ​​of 0.0006 and 0.0009, respectively. There were no inter-group differences in the geometric mean ratio before or after treatment.

[0105] When examining APC resistance rates, no significant changes were observed in either group from baseline to the end of treatment. The geometric mean in the DNG / EE formulation was 2.61 (SD, 95% CI, 2.33 to 2.93) before treatment and 2.50 (SD, 95% CI, 2.15 to 2.90) after nine months (p = 0.6212). Similar results were observed in the comparison group. The geometric mean was 2.82 (SD, 95% CI, 2.57 to 3.10) before treatment and 2.83 (SD, 95% CI, 2.50 to 3.21) after treatment (p = 0.9629).

[0106] D-dimer, frequently used as a surrogate marker for assessing VTE risk, showed no change in either group before or after treatment. In the DNG / EE group, the pre-treatment value was 276.62 (SD, 95% CI, 228.92 to 334.26) ng / mL, decreasing slightly to 243.98 (SD, 95% CI, 192.45 to 309.31) ng / mL after nine months. The comparative group showed a slight increase from 246.46 (95% CI, 205.44 to 295.66) ng / mL to 275.30 (SD, 95% CI, 219.21 to 345.75) ng / mL. This difference was only a non-significant trend (p = 0.4520).

[0107] For all other three factors analyzed, no significant differences were observed between the two groups before and after 9 months of treatment. Furthermore, the geometric means of the in-between comparisons were not significantly different. The only significant difference found between the start and end of treatment was ATIII. Table 3 shows all the analyzed values.

[0108] Table 3. Effects of the following formulations on coagulation and fibrinolysis parameters before and after coagulation: DNG / EE (a) or DRSP / EE (b)

[0109]

[0110] The p-values ​​for the differences in AT III between the two formulations before and after treatment were significant.

[0111] In summary, the COC with 2 mg DNG / 0.02 mg EE was not associated with any significant changes in the analyzed hemostatic parameters, suggesting that the extended-release formulation does not affect these factors.

[0112] Example 2. A double-blind, randomized clinical trial evaluating the efficacy and safety of dinogest 2.00 mg / ethinylestradiol 0.02 mg formulation relative to placebo over 9 cycles of treatment for polycystic ovary syndrome (PCOS).

[0113] The test product was a controlled-release tablet of dinogest 2.0 mg / ethinylestradiol 0.02 mg as disclosed in Example 1.

[0114] method

[0115] Experimental Design

[0116] This is a multicenter, multinational, double-blind, placebo-controlled trial for women who were 2 years postmenopausal, aged 14 to 40 years, diagnosed with PCOS, and whose adjusted modified Ferriman-Gallwey score (mFG) was ≥7 at screening, with a score of 28 considered the most severe. The trial is registered in EudraCT (2021-002178-17) and is part of the Pediatric Research Program (EMEA-002229-PIP02-21).

[0117] Ethics and Consent

[0118] The trial protocol, as well as written materials provided to participants and any recruitment advertisements, were approved by the relevant independent ethics committees of each trial center. The trials were conducted in accordance with Good Clinical Practice and the guidelines of the International Coordinating Committee, and in accordance with the national laws of all participating countries and the Declaration of Helsinki (2008). Written informed consent / permission was obtained from all participants and the parents of adolescents prior to enrollment in the trial.

[0119] Participants

[0120] All participants had a diagnosis of PCOS and hirsutism (adjusted mFG score ≥7), and were in good physical and mental health. At screening, their body mass index (BMI) was 18 to <35 kg / m² and their systolic / diastolic blood pressure was ≤140 / 90 mmHg. Pregnant women, women who wish to become pregnant, or women who are breastfeeding were not eligible to participate. Current smokers aged ≥36 years and / or with a BMI >30 kg / m² were also ineligible at screening. 2 Women are also ineligible to enroll. Patients with abnormal gynecological examination results, poorly controlled diabetes (hemoglobin A1C > 6.5%), anemia (hemoglobin < 10 g / dL), or those with venous or arterial thromboembolism or at risk of such thrombosis are also ineligible to enroll.

[0121] Randomization, investigational drugs, and blinding.

[0122] Participants were randomly assigned (4:1; stratified by age and center) to receive either the extended-release oral formulation of DNG 2 mg / EE 0.02 mg (active treatment) or placebo. Each participant was assigned a randomization number using a validated interactive network response system (GxPbrain GmbH, Berlin, Germany).

[0123] One treatment cycle consists of 24 white tablets (active or placebo) in the same blister pack, followed by 4 green placebo tablets (24 / 4 day regimen). Participants were instructed to take the investigational drug at approximately the same time each day for nine consecutive 28-day cycles. If a tablet was missed, participants were instructed to take it as soon as they remembered, even if that meant taking two tablets simultaneously if more than 24 hours had passed since the missed tablet. If more than two consecutive tablets were missed in a cycle, participants were instructed to continue taking the tablets and leave the missed tablets in the pack. All blister packs were returned for review of missed tablets. If vomiting occurred 3 to 4 hours after taking a white tablet, a replacement tablet should be taken as soon as possible.

[0124] Randomization codes are not displayed until all data has been collected, all protocol deviations have been recorded, and the trial database has been locked. In the event of a safety emergency, the trial safety manager (anyone not involved in the trial) is informed of the allocation of the investigational drug.

[0125] Experimental process

[0126] During the trial period, participants were not allowed to take any medications that might interfere with the effectiveness of hormonal contraceptives or with blood pressure regulation, serum lipid or carbohydrate metabolism.

[0127] Each participant may decide whether to shave their hair during the trial, but they are required to shave exactly 15 days before each adjusted mFG assessment, and the shaving protocol must be consistent throughout the trial. Any plucked hair was preserved by the researcher and photographed using a smartphone with a pre-installed app provided by the organizer, along with photographs of the body areas assessed using the adjusted mFG scoring system.

[0128] Laboratory evaluation

[0129] All laboratory evaluations were conducted centrally by the Laboratorium für Klinische Forschung GmbH, Hamburg, Germany.

[0130] ending

[0131] The two primary endpoints were the change in mean adjusted mFG score relative to baseline at the end of Cycle 9 or the early discontinuation visit (EDV), and the proportion of participants whose adjusted mFG score decreased by 50% from baseline to the end of Cycle 9 / EDV. The adjusted mFG score was assessed by each researcher based on seven body regions (chest, upper abdomen, lower abdomen, thigh, back, arm, and hip).

[0132] Secondary efficacy endpoints included changes in laboratory parameters of serum concentrations of free and total testosterone, androstenedione, 17α-hydroxyprogesterone (17OHP), dehydroepiandrosterone sulfate (DHEAS), and SHBG from baseline to the end of cycle 9 / EDV. Changes in insulin resistance from baseline to the end of cycle 9 / EDV were assessed using the Homeostasis Model of Insulin Resistance Assessment (HOMA2-IR) based on fasting serum glucose and insulin levels. Serum lipid profiles were assessed at baseline and at the end of the trial, targeting total cholesterol, high-density and low-density lipoprotein (HDL and LDL) cholesterol, and triglycerides. Adverse events were monitored throughout the trial. Other safety assessments included changes in vital signs, clinical laboratory parameters, electrocardiogram, gynecological examination (cervical cytology), and body weight from baseline to the end of the trial. Bleeding patterns (self-reported using an electronic diary) and quality of life based on the Polycystic Ovary Syndrome Questionnaire (PCOSQ; measuring 26 items across five domains: mood [8 items], body hair [5 items], weight [5 items], infertility issues [4 items], and menstrual issues [4 items]; using a 7-point Likert scale, where 7 represents best functioning and 1 represents worst functioning) were also assessed.

[0133] Statistical analysis

[0134] Sample size determination

[0135] The mFG scoring system quantifies and standardizes hirsutism based on nine body regions (chest, upper abdomen, lower abdomen, thigh, back, arm, buttocks, upper lip, and chin) to allow for data comparison, and is currently being used as a screening tool. When planning the trial, we used a dual primary endpoint to calculate the sample size. Our assumptions were that the relative reduction in mFG score (using the nine body regions) (primary endpoint) in the DNG / EE group and placebo group would be 50% and 30%, respectively, with a standard deviation of 25%. For the responder rate (secondary endpoint), we anticipated 60% and 20% of participants in the DNG / EE group and placebo group, respectively (defined as a 50% reduction in mFG score from baseline to the end of cycle 9 / EDV). Based on these assumptions, in addition to the anticipated 35% dropout rate, a sample size of 255 evaluable adult subjects (DNG / EE, n=204; placebo, n=51) was required to provide approximately 90% of the total power. Another 20 adolescents were randomly assigned to meet the regulatory requirements for drugs used in adolescent patients.

[0136] Main Analysis

[0137] Bonferroni correction was applied to test the two primary endpoints and the overall significance level was kept at 5%, resulting in a Type I error of 2.5% for each test.

[0138] For the first primary endpoint limited to changes in adjusted mFG scores, t-tests were assumed due to the lack of prior knowledge of the effects of baseline covariates. The primary analysis was based on mixed model repeated measures (MMRM) analyses, with visits and treatment as factors and baseline adjusted mFG scores as covariates. Each participant was included as a random effect. MMRM analyses were performed for the following repeated analyses: the BMI subgroup (≤30 or >30 kg / m²), and additional subgroups in post-analysis, including baseline adjusted total mFG scores (adjusted total mFG scores <14, 14 to 19, or >19), relative changes in adjusted total mFG scores relative to baseline (XX XX), and trial completion. At the end of period 9 / EDV, the overall population is shown as the least squares (LS) mean related to treatment, along with 97.5% confidence intervals (CI) and corresponding p-values. At the end of period 9 / EDV, treatment differences are expressed as a one-sided 98.75% CI and p-value. Missing primary endpoint values ​​are handled using the multiple imputation method, assuming the data are randomly missing. The statistical analysis plan (SAP) defines all additional analyses arising from different concurrency strategies and sensitivity analyses. For post-hoc analyses, the occurrence of any concurrency event is ignored.

[0139] A two-sided chi-square test was used for the second primary endpoint. Fisher's exact test was performed one-sided at a significance level of 1.25%. The primary analysis was repeated for the BMI subgroup and as a post-hoc analysis for a newly defined subgroup, which included: adjusted total mFG score at baseline and trial completers. Response rates and 97.5% CIs are shown for the treatment group. The difference in response rates was indicated with a 98.75% CI, and the p-value for Fisher's exact test was determined.

[0140] The primary analysis was performed using the full analysis set (FAS), and the supporting analysis was repeated in the per-protocol set (PPS).

[0141] Secondary efficacy endpoints were based on FAS and analyzed exploratoryly using appropriate statistical methods and according to BMI subgroups. Post-hoc analyses were performed on changes in serum testosterone levels (free and total testosterone) and serum SHBG levels from baseline to the end of cycle 9.

[0142] Further post-hoc analyses included the relationship between changes in the adjusted total mFG score from baseline to the end of period 9 / EDV and changes in PCOSQ scores (both in each domain and overall). This analysis was based on Pearson correlation coefficients (r values) and 95% confidence limits.

[0143] result

[0144] Patient distribution

[0145] Between November 2, 2021 and December 5, 2023, 500 patients were screened at 46 sites in the Czech Republic, Hungary, Lithuania, Poland, Serbia, Slovakia, Spain, and Ukraine. Of these, 305 provided informed consent and were randomized. Two hundred and two participants completed the trial (DNG / EE, n=168; placebo, n=34). A total of 291 participants were included in the safety set (DNG / EE, n=234; placebo, n=57), 256 in the full analysis set (FAS; DNG / EE, n=209; placebo, n=47), and 233 in the protocol-compliant set (DNG / EE, n=188; placebo, n=45). Demographic and baseline characteristics were similar between the two groups, but some group differences existed regarding the severity of hirsutism (Table 4). At baseline, the mean ± standard deviation (SD) of the adjusted mFG scores in the DNG / EE and placebo groups were 10.6 ± 3.15 and 11.7 ± 4.75, respectively. Most participants (207 / 256 [80.9%]) had an adjusted mFG score of <14 indicating mild hirsutism.

[0146] Table 4. Demographic and Baseline Characteristics (Security Set)

[0147]

[0148]

[0149] Data are expressed as mean ± standard deviation, or n (%); ATE = arterial thromboembolism; BMI = body mass index; DBP = diastolic blood pressure; mFG = modified Ferriman-Gallwey; PCOS = polycystic ovary syndrome; SBP = systolic blood pressure; VTE = venous thromboembolism.

[0150] Exposure

[0151] The mean treatment duration ± SD was 228.2 ± 59.22 days in the DNG / EE group and 215.2 ± 67.55 days in the placebo group (FAS). The mean exposure in the safety set was slightly shorter than the mean exposure in the FAS (211.6 ± 75.81 days vs. 193.8 ± 81.36 days, respectively).

[0152] Changes in the severity of hirsutism in response to treatment

[0153] For the primary endpoint, from baseline to the end of cycle 9 / EDV, the absolute changes in the mean ± SD of the adjusted mFG score in the DNG / EE and placebo groups were -3.8 ± 3.37 and -1.7 ± 2.28 (FAS), respectively, with mean scores of 6.8 ± 3.39 and 9.5 ± 5.22, respectively. At the end of cycle 9 / EDV, the mean LS difference between the treatment and placebo groups was -2.24 (98.75% CI: -∞, -1.14; p < 0.0001), supporting the DNG / EE group (MMRM analysis, FAS, Figure 1 Similar treatment group differences were observed in the mild and moderate hirsutism severity subgroups. In the LPRI-424 group, the more severe the category of the baseline-adjusted total mFG score (mild, moderate, or severe), the greater the change in the LS mean-adjusted total mFG score relative to baseline (-3.13, -6.11, and -12.15, respectively), as shown in Table 5.

[0154] Table 5. Changes in mFG score (FAS) adjusted for the end of cycle 9 / EVD in the baseline moderate severity subgroups.

[0155]

[0156] From baseline to the end of cycle 9 / EDV, the relative change in the mean ± SD of the adjusted mFG score in the DNG / EE group (-34.5 ± 29.09%) was also significantly greater than that in the placebo group (-16.6 ± 28.34%; p < 0.001).

[0157] For the second dual primary endpoint, participants whose adjusted mFG score decreased by 50% from baseline to the end of cycle 9 were defined as treatment responders; the responders in the DNG / EE group and the placebo group were 31.3% and 15.9%, respectively (treatment difference 15.5%; 98.75% CI -3.8, ∞; p=0.0271). Consistent protocol analysis suggests similar trends to those in the primary full analysis set.

[0158] Similar trends were observed in both BMI subgroups for both primary endpoints. In BMI ≤ 30 or > 30 kg / m² 2Among women, the mean LS difference in the treatment group was -3.8 and -3.7 in the DNG / EE group, and -1.9 and -0.6 in the placebo group, respectively; the mean LS difference in the treatment group was -1.92 (98.75% CI -∞, -0.66; p=0.0004) and -3.14 (98.75% CI -∞, -0.89; p=0.0011) (MMRM analysis, FAS).

[0159] Table 6: Analysis of changes in mFG scores relative to baseline at period 9 / EDV according to baseline hirsutism severity subgroups (full analysis set; post-hoc analysis)

[0160]

[0161] At the end of cycle 9, the number of patients with mFG score <7 (without hirsutism) in the DNG / EE group and the placebo group were 95 (45.5%) and 14 (28.9%), respectively.

[0162] Table 7: Changes in hirsutism severity based on the modified Ferriman-Gallwey scoring system (post-hoc analysis; full analysis set)

[0163]

[0164]

[0165] All data are n (%). DNG, dinogest; EE, ethinylestradiol; EDV, early termination of visit.

[0166] Changes in serum hormone levels, metabolism, and serum lipids

[0167] Secondary power analyses included changes in serum hormones and metabolic laboratory parameters from baseline to the end of cycle 9 / EDV. Beneficial changes in mean serum hormones of free testosterone, androstenedione, 17-OH-progesterone, dehydroepiandrosterone sulfate, and SHBG were observed in the DNG / EE group (Table 8). No similar changes were observed in the placebo group. Neither group showed a negative impact on insulin resistance, and all mean HOMO2-IR values ​​were below 2. At baseline and the end of cycle 9 / EDV, all mean serum lipid ranges were within the normal range in both groups, and the mean LDL:HDL and total cholesterol:HDL ratios remained unchanged.

[0168] Table 8. Summary of Exploratory Serum Laboratory Parameters (Full Analysis Set)

[0169]

[0170] Data are presented as mean ± standard deviation. Baseline values ​​were defined as the last non-missing values ​​collected prior to the first intake of the test drug. P-values ​​were calculated using t-tests. Insulin resistance was assessed using the Homeostasis Model for Insulin Resistance Assessment (HOMA2-IR) based on fasting serum glucose and insulin levels. Normal upper / lower reference ranges for adult women: Free testosterone: 33.01 / 2.98 mmol / L; Testosterone: 1.66 / 0.28 nmol / L; Androstenedione: 4.58 / 1.71 nmol / L; 17-OH progesterone: 12.51 / 1.06 nmol / L; Dehydroepiandrosterone sulfate: 11 / 4 μmol / L (20 to 24 years), 9.2 / 2.7 μmol / L (25 to 35 years), 9.1 / 1.7 μmol / L (35 to 41 years); Sex hormone-binding globulin: 128 / 32.4 nmol / L; Free androgen index: 0.18 / 7.07%; Insulin resistance: < 2.0 (unlikely insulin resistance), 2.0 to 2.5 (possibly insulin resistance), 2.5 to 5.0 (most likely insulin resistance), > 5.0 (mean for type 2 diabetes). The free androgen index is based on testosterone and sex hormone-binding globulin. EDV = Early termination of visit.

[0171] Quality of life

[0172] Participants' self-reported quality of life was assessed using the PCOSQ. At baseline, the mean overall PCOSQ scores for the DNG / EE and placebo groups were 19.23 and 17.30, respectively; lower scores indicated poorer functioning. From baseline to the end of cycle 9 / EDV, mean domain scores across all domains (mood, body hair, weight, infertility issues, and menstrual problems) improved in both groups; however, the DNG / EE group showed the greatest improvement (Table 1 and...). Figure 2 As a post-hoc analysis, we found a negative linear correlation between the adjusted mFG score in the DNG / EE group at the end of cycle 9 / EDV and the total PCOSQ score (r=-0.247; 95% CI -0.373, -0.0113; p=0.0004) and the PCOSQ body hair domain (r=-0.313; 95% CI -0.432, -0.183; p < 0.0001). Similar negative linear correlations were also found between the adjusted mFG score and the PCOSQ mood and menstrual problems domains. The correlation estimates between the placebo group's adjusted mFG score and the PCOSQ total score (r=-0.171; 95% CI -0.440, 0.125; p=0.2511) and the PCOSQ body hair domain (r=-0.199; 95% CI -0.463, 0.096; p=0.1802), as well as with any other PCOSQ domain, were not statistically significant.

[0173] Bleeding spectrum

[0174] Compared with the placebo group, the DNG / EE group reported a higher proportion of planned bleeding / drip bleeding during all reference periods (p<0.005 for each reference period). The overall proportion of participants without bleeding / drip bleeding in each cycle increased in the DNG / EE group from 10.0% (24 / 228) in cycle 1 to 23.3% (37 / 159) in cycle 9, but no clear pattern was observed in the placebo group, with the lowest proportion in cycle 4 (27.7%, 10 / 46) and the highest in cycle 2 (44.2%, 23 / 52). During cycles 2 through 9, the mean ± SD of the duration of bleeding / drip bleeding episodes was 4.1 ± 2.82 days in the DNG / EE group (234 participants, 1632 bleeding episodes) and 4.7 ± 3.24 days in the placebo group (57 participants, 253 bleeding episodes). Three women in the DNG / EE group prematurely discontinued their trial due to intermenstrual bleeding.

[0175] Safety profile

[0176] The proportion of women experiencing treatment-emergent adverse events (TEAEs) was similar in both treatment groups: 166 (70.9%) participants in the DNG / EE group and 42 (73.7%) participants in the placebo group. The most frequent TEAEs were headache (49 participants, 16.8%), intermenstrual bleeding (41 participants, 14.1%), nasopharyngitis (33 participants, 11.3%), and diarrhea (25 participants, 8.6%), with a similar proportion of women in both treatment groups. Most TEAEs were mild to moderate in intensity. No deaths occurred among participants during the trial. Six serious TEAEs were reported in participants (2.1%): five participants (2.1%) in the DNG / EE group (two cases of abdominal pain, limb pain, sensory impairment, and pulmonary embolism) and one participant (1.8%) in the placebo group (vestibular neuronitis). Researchers assessed that all serious TEAEs were unrelated to or unlikely to be related to the investigational drug, except for severe pulmonary embolism, which was considered to be associated with treatment using DNG / EE. Participants who developed pulmonary embolism approximately 3 months after starting DNG / EE had other pulmonary embolism risk factors, including previous COVID-19 infection, a BMI of approximately 30 kg / m2, and untreated type 2 diabetes diagnosed at the time of hospitalization. The investigational drug was withdrawn, antithrombotic therapy was started, and the patient discontinued the trial early. Poor diabetes control was an exclusion criterion for the trial because it is associated with a hypercoagulable state that may increase the risk of thromboembolism. One patient in the DNG / EE group developed insulin resistance, which researchers reported was potentially related to the investigational drug. No clinically relevant changes were found in vital signs, electrocardiogram, gynecological examination (cervical cytology), or weight.

[0177] discuss

[0178] This prospective, randomized controlled trial evaluated the treatment response of orally extended-release DNG 2 mg / EE 0.2 mg in a 24 / 4 dosing regimen relative to placebo over up to 9 cycles in women with PCOS managing hirsutism. The trial demonstrated that DNG / EE significantly improved hirsutism severity, assessed using an adjusted mFG score at the end of cycle 9 / EDV, compared to placebo. Favorable mean changes in serum hormones were observed in the DNG / EE group relative to placebo. Minor changes in glucose, insulin, or lipid metabolism were observed in the DNG / EE group, most of which were not clinically relevant. Participants in the DNG / EE group showed greater mean improvement in all domains of the PCOSQ compared to placebo. A significant negative correlation was found between total PCOSQ scores and adjusted mFG scores in the DNG / EE group, but not in the placebo group. Significantly more participants in the DNG / EE group had regular, planned bleeding compared to the placebo group. No new safety concerns emerged, and the safety profile of DNG / EE was similar to that of previous trials of the same extended-release formulation. One patient with multiple risk factors, including undiagnosed type 2 diabetes, experienced a pulmonary embolism. Insulin resistance plays a central role in the development of both PCOS and cardiovascular disease. Patients with PCOS also have altered clotting factors. As with all COCs, the decision to treat obese patients requires a balance between potential benefits and harms. The trial discontinuation rate (33.8%) was consistent with the expected discontinuation rate (35%).

[0179] The FG or mFG scoring system was used to evaluate clinical hirsutism. The original method used 11 body regions (upper lip, chin, chest, upper and lower back, upper and lower abdomen, upper arm, forearm, thigh, and leg) to assess hair growth. The modified method excluded the forearm and leg. The modified mFG scoring system was used here, which assesses hair growth on the chest, upper abdomen, lower abdomen, thigh, back, arm, and buttocks (lowest score 0; highest score 28). Facial regions as defined in the FG and mFG scoring systems were not included. Including facial regions as part of the mFG assessment could affect enrolment (no hair removal or shaving for at least 15 days prior to each assessment). Nevertheless, this is the first time this modified scoring system has been used to monitor treatment response in the management of PCOS-related hirsutism. The hypothesis used for sample size calculation was based on mFG, and since published information was lacking at the time, it was chosen as a "best guess." This helps explain why the responder rate based on adjusted mFG (as opposed to the responder rate based on mFG score) did not fully reach the predetermined significance level of p ≤ 0.025. Furthermore, most participants had mild hirsutism at baseline, which, compared to what was expected in groups with moderate or severe hirsutism, made detecting a significant reduction in adjusted mFG score more challenging.

[0180] While the FG and mFG scoring systems are widely used, they have limitations, including their subjective nature, failure to account for locally high scores that do not disproportionately contribute to the overall score, and lack of consideration for androgen-sensitive areas such as the lateral facial regions from the hairline to below the ears (temples) and the buttocks. Furthermore, hair growth on the upper lip and chin is androgen-sensitive and was not included in the adjusted mFG score. Since two of the four essential androgen-sensitive areas were not assessed in our trial, we may have seen a greater treatment response if the lip and chin facial regions had been included. Because mFG scores vary considerably with the severity of hirsutism, caution is needed when applying our results to other patient populations.

[0181] Other clinical trials have used reductions in FG or mFG scores to measure improvements in PCOS-related hirsutism; however, these trials used different score cutoffs, treatment durations, EE and progestin doses, and different trial populations. A recent Cochrane review found significant heterogeneity in mean study BMI and treatment response among 473 women from 10 trials comparing metformin with a contrastive contraceptive pill using FG scores to report hirsutism. Nevertheless, in women with PCOS, weight gain showed an additive effect on hair growth, and the highest mFG scores were observed in women with high BMI compared to those with low BMI. In our trial, a reduction in the mean adjusted mFG score was observed with DNG / EE regardless of BMI subgroup, but at the end of cycle 9 / EDV, we observed a greater reduction in BMI >30 compared to ≤30 kg / m 2 The subgroups showed greater treatment differences in adjusted mFG scores based on the LS mean (MMRM analysis) (adjusted mFG scores were -3.14 and -1.92, respectively). The placebo effect was lower in participants with a BMI > 30 kg / m², likely due to poorer efficacy of lifestyle modifications in this subgroup of women. Obesity demonstrated a significant impact on the PCOS phenotype, particularly on the metabolic associations and complications of the syndrome, including an increased risk of metabolic syndrome and a range of cardiovascular risk factors in these women.

[0182] DNG possesses potent anti-androgenic properties, as reviewed in a meta-analysis of 56 clinical studies (2266 treated women). The Hershberger test, evaluating the anti-androgenic effects of various progestins, showed that DNG has approximately 40% of the potency of cyproterone acetate (the most potent anti-androgenic progestin). With the use of the DNG / EE extended-release formulation, the peak exposure is reduced and delayed by several hours compared to the immediate-release formulation. This results in similar total systemic exposure, and a reduced peak intensity, and consequently, reduced variability in systemic blood levels of the active ingredient. Reduced hormonal variability leads to a more favorable bleeding profile, a desirable characteristic for women with PCOS. In our current trial, from baseline to the end of cycle 9 / EDV, favorable changes in the following circulating hormone levels were observed in participants in the DNG / EE group: free testosterone, testosterone, androstenedione, and the free androgen index (FAI), as well as an increase in mean serum SHBG levels, which were not observed in the placebo group. Furthermore, a significant beneficial reduction in 17-OHP and DHEAS was observed in the DNG / EE group compared to the placebo group. The DNG / EE combination has been shown to reduce androgen levels, increase SHBG levels, and significantly reduce total and free testosterone levels. Therefore, the DNG / EE combination possesses potent anti-androgenic potential and demonstrates efficacy in treating the following conditions in women: hirsutism, polycystic ovary syndrome, PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, irregular menstrual cycles, and / or PCOS-related irregular menstrual cycles, acne or seborrhea, and / or symptoms of these conditions.

[0183] COC has potentially harmful effects on metabolic markers such as lipids and carbohydrates; however, similar to other low-dose oral contraceptives, DNG / EE has mild effects on lipid and carbohydrate metabolism, adrenal hormones, and blood pressure parameters, and shows a balancing effect on the hemostatic system. In healthy women, DNG / EE can lead to insulin resistance and a slight increase in serum insulin levels. In our trial, although mean serum levels remained within the normal range, there was a small trend toward increased mean lipid concentrations (i.e., total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol) and fasting insulin in the DNG / EE group, although the LDL:HDL and total cholesterol:HDL ratios remained unchanged. These findings are consistent with the results shown in Example 1 for healthy women.

[0184] Available data suggest that the use of COC increases the risk of VTE in the general population. However, most studies on this topic do not evaluate all potential confounding factors and may be subject to bias. Whether COC creates an additional risk of VTE in women with PCOS (prethrombotic syndrome) remains controversial. Careful patient evaluation and exclusion of additional risk factors before initiating COC treatment is the best approach for VTE prevention in both the general population and women with PCOS.

[0185] In summary, the results of this trial demonstrate that oral DNG 2 mg / EE 0.2 is effective for treating hirsutism in women with PCOS in a 24 / 4 treatment regimen with up to 9 cycles, with no additional safety signals and generally well tolerated.

[0186] Those skilled in the art will recognize, or can determine, many equivalents of some specific embodiments of the invention described herein using only conventional experiments. Such equivalents are intended to be covered in this invention.

[0187] For the sake of completeness, several aspects of the invention are set forth in the following numbered clauses:

[0188] 1. A controlled-release composition comprising denrogesterone (DNG) and ethinylestradiol (EE) for the treatment of hirsutism, hyperandrogenemia and menstrual irregularities in subjects with such needs.

[0189] 2. The composition according to Clause 1, for the treatment of hirsutism associated with polycystic ovary syndrome (PCOS).

[0190] 3. The composition according to Clause 1 or Clause 2, which is to be applied once daily.

[0191] 4. The composition according to any one of clauses 1 to 3, comprising 2 mg DNG and 0.02 mg EE.

[0192] 5. The composition according to Clause 1 or 2, for the treatment of mild, moderate and / or severe hirsutism.

[0193] 6. The composition according to Clause 1, wherein the object is a person with a body mass index < 30 and / or a body mass index > 30.

[0194] 7. The composition according to Clause 1, wherein the person in need of this is a woman suffering from hyperandrogenemia.

[0195] 8. The composition according to Clause 1, wherein the composition is administered once daily for 24 days, followed by placebo administration for 4 days.

[0196] 9. The composition according to Clause 8, wherein the composition is applied over a period of at least 4 months, preferably over a period of at least 9 months.

[0197] 10. A controlled-release composition comprising a combination of DNG and EE, for use in treating hirsutism, polycystic ovary syndrome, PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, irregular menstrual cycles, and / or PCOS-related irregular menstrual cycles in subjects with such need.

[0198] 11. A combination of DNG and EE, used to treat hirsutism in individuals with this need.

[0199] 12. The combination described in Clause 11, wherein DNG and EE are applied together or one after the other.

[0200] 13. The combination described in Clause 11 is used to treat hirsutism associated with PCOS.

[0201] 14. A controlled-release composition comprising the combination of dinogest (DNG) and ethinylestradiol (EE) for the treatment of hirsutism, hyperandrogenemia, and irregular menstrual cycles in subjects with such needs.

[0202] 15. The composition according to Clause 14, for the treatment of hirsutism associated with polycystic ovary syndrome (PCOS).

[0203] 16. The composition according to Clause 14 or Clause 15, for treating hirsutism, hyperandrogenemia and irregular menstrual cycles in subjects with such need, wherein the composition is applied once daily.

[0204] 17. The composition according to any one of clauses 14 to 16, for treating hirsutism, hyperandrogenemia and irregular menstrual cycles in subjects in need, said composition comprising 2 mg DNG and 0.02 mg EE.

[0205] 18. The composition according to Clause 14 or 15, for the treatment of mild, moderate and / or severe hirsutism.

[0206] 19. The composition according to Clause 14, for treating hirsutism, hyperandrogenemia, and irregular menstrual cycles in subjects who require such treatment, wherein the subjects are individuals with a body mass index < 30 and / or a body mass index > 30.

[0207] 20. The composition according to Clause 14, for treating hirsutism, hyperandrogenemia, and irregular menstrual cycles in subjects in need of such treatment, wherein the subjects in need of such treatment are women suffering from hyperandrogenemia.

[0208] 21. The composition according to Clause 14, for treating hirsutism, hyperandrogenemia, and irregular menstrual cycles in subjects in need, wherein the composition is administered once daily for 24 days, followed by a placebo for 4 days.

[0209] 22. The composition according to Clause 21, for treating hirsutism, hyperandrogenemia and irregular menstrual cycles in subjects with such need, wherein the composition is administered for a period of at least 4 months, preferably for a period of at least 9 months.

[0210] 23. The composition according to Clause 14, for use in treating hirsutism, polycystic ovary syndrome, PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, irregular menstrual cycles, PCOS-related irregular menstrual cycles, hyperandrogenemia-related acne, and / or PCOS-related acne in subjects with such need.

[0211] 24. The composition used according to Clause 14 for improving quality of life in patients with hirsutism, PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, or polycystic ovary syndrome, wherein quality of life is determined by the Polycystic Ovary Syndrome Questionnaire (PCOSQ).

[0212] 25. The controlled-release composition comprising the combination of dinogest (DNG) and ethinylestradiol (EE) as described in Clause 14, for the treatment of hirsutism, hyperandrogenemia, and irregular menstrual cycles in subjects with mild, moderate, or severe hirsutism.

[0213] 26. A controlled-release composition comprising a combination of dinogest (DNG) and ethinylestradiol (EE) as described in Clause 14, for the treatment of hirsutism, hyperandrogenemia, and irregular menstrual cycles in subjects with a body mass index (BMI) > 30 kg / m². 2 .

[0214] 27. A controlled-release composition comprising dinogest (DNG) and ethinylestradiol (EE) for the treatment of hirsutism, hyperandrogenemia, and irregular menstrual cycles in subjects with a BMI <30 kg / m². 2 .

Claims

1. Use of the combination of dinogest (DNG) and ethinylestradiol (EE) in the preparation of a controlled-release composition for the treatment of hirsutism, hyperandrogenemia and irregular menstrual cycles in subjects with such needs.

2. The use according to claim 1, wherein the composition is formulated for the treatment of hirsutism associated with polycystic ovary syndrome (PCOS).

3. The use according to claim 1 or claim 2, wherein the composition is formulated for once-daily application.

4. The use according to any one of claims 1 to 3, wherein the composition comprises 2 mg DNG and 0.02 mg EE.

5. The use according to claim 1 or 2, wherein the composition is formulated for treating mild, moderate and / or severe hirsutism.

6. The use according to claim 1, wherein the object is a person with a body mass index < 30 and / or a body mass index > 30.

7. The use according to claim 1, wherein the person in need of this use is a woman suffering from hyperandrogenemia.

8. The use according to claim 1, wherein the composition is formulated for administration once daily for 24 days, followed by administration of a placebo for 4 days.

9. The use according to claim 8, wherein the composition is formulated for application over a period of at least 4 months, preferably over a period of at least 9 months.

10. The use according to claim 1, wherein the composition is formulated for treating hirsutism, polycystic ovary syndrome, PCOS-related hirsutism, hyperandrogenemia, PCOS-related hyperandrogenemia, irregular menstrual cycles, PCOS-related irregular menstrual cycles, hyperandrogenemia-related acne, and / or PCOS-related acne in subjects with such need.

11. Use of a combination of dinogest (DNG) and ethinylestradiol (EE) in the preparation of a controlled-release composition for improving quality of life in patients with hirsutism, PCOS-associated hirsutism, hyperandrogenemia, PCOS-associated hyperandrogenemia, or polycystic ovary syndrome, wherein quality of life is determined by the Polycystic Ovary Syndrome Questionnaire (PCOSQ).

12. Use of the combination of dinogest (DNG) and ethinylestradiol (EE) in the preparation of a controlled-release composition for the treatment of polycystic ovary syndrome.

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