Oral doses without progestogens used for female contraception and treatment of endometriosis

Abstract

The present invention relates to an oral administration unit for use in a method of contraception for female mammals or a method of treating endometriosis in female mammals, wherein the oral administration unit comprises a GnRH antagonist and an estrogen, but does not contain a progestogen; and the method comprises orally administering the oral administration unit once daily to a female mammal for at least 28 days.

Description

Technical Field

[0001] The present invention relates to oral administration units that do not contain progestogens and are used for female contraception and the treatment of endometriosis. The oral administration units of the present invention contain a combination of a gonadotropin-releasing hormone (GnRH) antagonist and estrogen.

Background Art

[0002] Currently, there are two types of oral contraceptives: the combination of estrogen-progestogen and progestogen alone. The most commonly prescribed pill is the combined hormonal pill containing estrogen and progestogen, which is usually called the combined oral contraceptive (COC). Briefly, progestogen is a hormone that suppresses ovulation and prevents pregnancy, and the estrogen component controls menstrual bleeding and compensates for the decrease in endogenous ovarian estrogen estradiol (E2).

[0003] Depending on the withdrawal bleeding desired by the patient and clinical recommendations, the COC can be prescribed as cyclic administration (bleeding once a month), extended cyclic administration (bleeding every three months), or continuous administration (without bleeding). · Cyclic prescription design: The cyclic prescription design involves taking an active hormonal pill for 21 to 24 days and then taking a hormone-free pill for 7 to 4 days. · Extended cyclic prescription design: The extended cyclic prescription design involves taking an active hormonal pill every day for three months and then taking a placebo for one week. · Continuous use prescription design: It can be controlled by using only the active pills of the monthly prescription design for one year, and all physiological bleeding will functionally stop.

[0004] Endometriosis is conventionally treated with hormonal therapy. Many physicians prescribe a combination of adding estrogen to progestogen.

[0005] Progesterone from a normal menstrual cycle is strongly correlated with the cause of breast cancer, as shown in the Perspective Review Paper (Herjan CT. Coelingh Bennink et al, Progesterone from ovulatory menstrual cycles is an important cause of breast cancer, Breast Cancer Research (2023), 25:60). The authors of this paper reviewed the literature on the relationship between ovulatory menstrual cycles (MCs) and breast cancer (BC) risk. The authors hypothesize that progesterone is a key factor in a woman's lifetime risk of developing BC, and that breast tumors occurring during hormonal contraception or after menopause are the result of the extension of pre-existing neoplastic lesions ultimately stimulated by estrogen and certain progestins, regardless of whether or not menopausal hormone therapy is administered. According to the authors, analysis of clinical and molecular data suggests that progesterone, and not estradiol or testosterone, is a key cause of BC by stimulating the proliferation of normal breast epithelium during the luteal phase of MCs via paracrine factors WNT4 and RANKL. Progesterone also appears to upregulate the expression of the DNA mutation enzyme APOBEC3B at this stage of mammary gland development (MC). These progesterone effects are likely to increase the accumulation of mutations in long-lived mammary gland stem cells and progenitor cells. Estrogen, testosterone (a precursor of estradiol), and most environmental factors associated with BC risk may stimulate the proliferation of already present ER+ / PR+ BCs, but their proliferative effect on normal mammary epithelium is mild and unlikely to cause BC in light of the inventors' hypothesis. The authors propose developing medical strategies to minimize women's exposure to natural progesterone and progestins.

[0006] Gonadotropin-releasing hormone (GnRH) antagonists are a class of drugs that antagonize GnRH receptors by competing with the binding of natural GnRH to GnRH receptors, thereby reducing or inhibiting GnRH activity in the body. GnRH antagonists are used to treat prostate cancer, endometriosis, uterine fibroids, female infertility in assisted reproductive technology, and other indications. Currently approved GnRH antagonists include the peptide molecules abarelix, cetrorelix, degarelix, and ganirelix, as well as the small molecule compounds ellagolix and relugolix. GnRH antagonists are administered by subcutaneous injection (cetrorelix, degarelix, ganirelix), intramuscular injection (abarelix), or oral administration (ellagolix, relugolix). Another non-peptide orally active GnRH antagonist under development is linzagolix.

[0007] International Publication No. 87 / 05514 concerns a delivery system for preventing pregnancy in female mammals, including: • A first delivery system for administering an effective amount of LHRH composition and an effective amount of estrogen steroid to the mammal during the follicular phase of the menstrual cycle; and A second delivery system for administering an effective amount of LHRH composition, an effective amount of estrogen steroid, and an effective amount of progesterone steroid to the mammal during the luteal phase of the menstrual cycle.

[0008] Fraser (GnRH analogues for contraception, British Medical Bulletin (1993) Vol 49, No 1, pp 62-72) discusses the use of GnRH analogues for contraception. The abstract of the paper is as follows: The production of chemical analogues of GnRH allows for direct suppression of the pituitary-gonadal axis at the gonadotropin-secreting cell level. Continuous administration of GnRH agonists suppresses the sensitivity of gonadotropin-secreting cells, uniformly suppressing ovulation and providing a practical basis for their use in contraception. However, long-term treatment is constrained by its variable effects on estrogen secretion, which can lead to irregular bleeding patterns and a risk of hypoestrogenism. Their use as postpartum contraceptives is attractive because none of the analogues in milk should be biologically active to infants. GnRH antagonists have the advantage of immediate inhibitory action. GnRH antagonists may be applicable even when an agonist is being used, and in addition, they can interfere at any stage of the menstrual cycle. Clinical trials to utilize their potential contraceptive effect have not been conducted. The use of GnRH analogs for female contraception may require a combination of low-dose estrogen and progestin, but such developments have been proposed as potentially offering significant health benefits. Combined with testosterone, GnRH antagonists could form the basis of male contraceptives.

[0009] Ryeqo® is a medication used in women of childbearing age to treat moderate to severe symptoms of uterine fibroids and endometriosis. Ryeqo contains 40 mg of relugolix, 1 mg of estradiol (hemihydrate), and 0.5 mg of norethisterone acetate. After at least one month of use of Ryeqo, it suppresses ovulation in women taking the recommended dose and provides adequate contraception. [Overview of the Initiative] [Means for solving the problem]

[0010] The inventors have devised a progestogen-free oral administration unit that can be appropriately used as a continuous-use formulation to suppress ovulation and / or maintain amenorrhea for 28 days or more. Therefore, the oral administration unit can be appropriately used as an oral contraceptive for women and also for the treatment of endometriosis.

[0011] Accordingly, one aspect of the present invention relates to an oral administration unit used for contraception in female mammals or for the treatment of endometriosis in female mammals, wherein the oral administration unit comprises a GnRH antagonist and an estrogen, but does not contain a progestogen; the method comprises oral administration of the oral administration unit to a female mammal once daily for at least 28 days.

[0012] Compared to known oral contraceptives for women, the oral contraceptive for women of the present invention offers a combination of advantages. Firstly, since the oral units do not contain progestogens, the increased risk of breast cancer associated with progestogens is avoided. Secondly, since the contraceptive method of the present invention induces prolonged amenorrhea, menstrual frequency and associated menstrual cycle irregularities are dramatically reduced.

[0013] Compared to hormone therapy for endometriosis that uses a combination of progestogens and estrogen to maintain amenorrhea, this method of treating endometriosis offers the advantage of avoiding the increased risk of breast cancer associated with progestogens.

[0014] Another aspect of the present invention is: • An amount of GnRH antagonist equivalent to 100-400 mg of Elagolix; and • Contains an amount of estrogen equivalent to 2.5-25 μg of ethinylestradiol; and • Regarding dosage units that do not contain progestogens. [Modes for carrying out the invention]

[0015] As described above, a first aspect of the present invention relates to an oral administration unit used for contraception in female mammals or for the treatment of endometriosis in female mammals, wherein the oral administration unit comprises a GnRH antagonist and an estrogen, but does not contain a progestogen; and the method comprises oral administration of the oral administration unit to a female mammal once daily for at least 28 days.

[0016] As used herein, the term "GnRH antagonist" refers to a class of drugs that bind to GnRH receptors without activating them.

[0017] As used herein, the term “estrogen” refers to a class of naturally occurring or synthetic steroid hormones that bind to and activate estrogen receptors.

[0018] As used herein, the term "estradiol" refers to estra-1,3,5(10)-triene-3,17β-diol.

[0019] As used herein, the term "estriol" refers to estra-1,3,5(10)-triene-3,16α,17β-triol.

[0020] As used herein, the term "estetrol" refers to estra-1,3,5(10)-triene-3,15α,16α,17β-triol.

[0021] As used herein, the term "ethinylestradiol" refers to 17α-ethinylestra-1,3,5(10)-triene-3,17β-diol.

[0022] As used herein, the term “progestogen” refers to a class of naturally occurring or synthetic steroid hormones that bind to and activate progesterone receptors.

[0023] As used herein, the term "prodrug" refers to a substance that is metabolized into a pharmaceutically active drug after oral administration. Thus, for example, a prodrug of estradiol is a substance that is metabolized into estradiol after oral administration. Estradiol valerate is an example of a prodrug of estradiol.

[0024] The method of the present invention preferably includes administration of an oral dosage unit to a human female, more preferably a fertile human female.

[0025] According to a particularly preferred embodiment, once-daily oral administration of an oral dosage unit according to the method suppresses ovulation.

[0026] According to another particularly preferred embodiment, once-daily oral administration of an oral dosage unit according to the method maintains amenorrhea.

[0027] According to a particularly preferred embodiment, the method includes once-daily oral administration of an oral dosage unit for at least 56 days, more preferably at least 84 days.

[0028] The GnRH antagonist used according to the present invention is preferably selected from leuprolide, elagolix, and linzagolix, and combinations thereof. More preferably, the GnRH antagonist is selected from leuprolide, linzagolix, and combinations thereof. Most preferably, the GnRH antagonist is leuprolide.

[0029] Preferably, in the method, the GnRH antagonist is orally administered at a daily dosage corresponding to a once-daily oral administration of 20 - 200 mg of leuprolide, more preferably 30 - 120 mg of leuprolide. The following table lists some equivalent dosages of GnRH antagonists that can be used according to the present invention.

[0030]

Table 1

[0031] In embodiments of the present invention, the GnRH antagonist is relugolix. The oral dose unit preferably contains 20 to 200 mg of relugolix, more preferably 30 to 120 mg of relugolix, and most preferably 35 to 80 mg of relugolix.

[0032] In another embodiment, the GnRH antagonist is ellagolyx. The oral dose unit preferably contains 60 to 600 mg of ellagolyx, more preferably 100 to 400 mg of ellagolyx, and most preferably 150 to 300 mg of ellagolyx.

[0033] In yet another embodiment, the GnRH antagonist used is linzagolix. Preferably, the oral dose unit contains 50 to 400 mg of linzagolix, more preferably 75 to 300 mg of linzagolix, and most preferably 80 to 300 mg of linzagolix.

[0034] The estrogen used in accordance with the present invention is preferably selected from ethinylestradiol, estradiol, estradiol prodrugs, estriol, estriol prodrugs, estetrol, estetrol prodrugs, and combinations thereof. More preferably, the estrogen is selected from ethinylestradiol, estradiol, estradiol valerate, estetrol, and combinations thereof. Even more preferably, the estrogen is selected from ethinylestradiol, estradiol, estetrol, and combinations thereof. In one particularly preferred embodiment, the estrogen used in this method is ethinylestradiol. In another particularly preferred embodiment, the estrogen used is estetrol.

[0035] In a particularly preferred embodiment of this method, estrogen is administered in a very low dose, which is sufficient to prevent symptoms of hypoestrogenism without stimulating the endometrium and causing irregular bleeding.

[0036] Therefore, estrogen is administered orally in a daily dose equivalent to the daily oral dose of preferably 3 to 30 μg of ethinylestradiol, more preferably 5 to 15 μg of ethinylestradiol. The following table lists the equivalent doses of several estrogens that can be used according to the present invention.

[0037] [Table 2]

[0038] In an advantageous embodiment of this method, the oral dose unit comprises ethinylestradiol, more preferably 2.5 to 25 μg of ethinylestradiol, and most preferably 5 to 15 μg of ethinylestradiol.

[0039] In another advantageous embodiment, the oral dose unit comprises estradiol and / or a prodrug of estradiol. More preferably, the oral dose unit comprises 0.25 to 2.5 mg of estradiol and / or an amount of estradiol prodrug equivalent to 0.25 to 2.5 mg of estradiol. Most preferably, the oral dose unit comprises 0.5 to 1.5 mg of estradiol and / or an amount of estradiol prodrug equivalent to 0.5 to 1.5 mg of estradiol.

[0040] In yet another advantageous embodiment, the oral dose unit contains estriol. More preferably, the oral dose unit contains 10 to 100 mg of estriol. Most preferably, the oral dose unit contains 20 to 50 mg of estriol.

[0041] In a more advantageous embodiment, the oral dose unit contains estetrol. More preferably, the oral dose unit contains 7.5 to 75 mg of estetrol. Even more preferably, the oral dose unit contains 15 to 45 mg of estetrol. Most preferably, the oral dose unit contains 20 to 40 mg of estetrol.

[0042] Through the action of a GnRH antagonist, this method suppresses the secretion of luteinizing hormone / follicle-stimulating hormone, thereby also suppressing the endogenous production of estradiol and testosterone. To prevent adverse effects due to a decrease in testosterone levels, the oral dose used in this method preferably contains 15 to 150 mg, more preferably 25 to 75 mg, of dehydroepiandrosterone.

[0043] To minimize the risk of bleeding or irregular bleeding, the method of the present invention preferably includes co-administration of a progestogen in utero. Preferably, the progestogen used is levonorgestrel. According to a particularly preferred embodiment, levonorgestrel is co-administered using an intrautero device that releases 3 to 25 μg of levonorgestrel per day.

[0044] Another aspect of the present invention is: • A GnRH antagonist equivalent to 100-400 mg of Elagolyx; and • Contains an amount of estrogen equivalent to 2.5-25 μg of ethinylestradiol; and • Regarding oral dose units that do not contain progestogens.

[0045] Preferably, the GnRH antagonist in the oral dose unit is selected from relugolix, ellagolix, linzagolix, and combinations thereof. More preferably, the GnRH antagonist is selected from relugolix and linzagolix, and combinations thereof. Most preferably, the GnRH antagonist is relugolix.

[0046] The amount of GnRH antagonist in an oral dose unit is preferably equivalent to 20-200 mg of relugolix, and more preferably to 30-120 mg of relugolix. Equivalent doses of several GnRH antagonists that can be used in oral dose units are described above.

[0047] In embodiments of the oral administration unit of the present invention, the GnRH antagonist is relugolix. The oral administration unit preferably contains 20 to 200 mg of relugolix, more preferably 30 to 120 mg of relugolix, and most preferably 35 to 80 mg of relugolix.

[0048] In another embodiment, the GnRH antagonist is ellagolyx. The oral dose unit preferably contains 60 to 600 mg of ellagolyx, more preferably 100 to 400 mg of ellagolyx, and most preferably 150 to 300 mg of ellagolyx.

[0049] In yet another embodiment, the GnRH antagonist used is linzagolix. Preferably, the oral dose unit contains 45 to 450 mg of linzagolix, more preferably 50 to 400 mg of linzagolix, and most preferably 80 to 300 mg of linzagolix.

[0050] The estrogen in the oral dose unit is preferably selected from ethinylestradiol, estradiol, estradiol prodrugs, estriol, estriol prodrugs, estetrol, estetrol prodrugs, and combinations thereof. More preferably, the estrogen is selected from ethinylestradiol, estradiol, estradiol valerate, estetrol, and combinations thereof. Even more preferably, the estrogen is selected from ethinylestradiol, estradiol, estetrol, and combinations thereof. In one particularly preferred embodiment, the estrogen used in this method is ethinylestradiol. In another particularly preferred embodiment, the estrogen used is estetrol.

[0051] The amount of estrogen in an oral dose unit is preferably equivalent to 2.5 to 25 μg of ethinylestradiol, more preferably 5 to 15 μg of ethinylestradiol. Equivalent doses of several estrogens that can be used in oral dose units are described above.

[0052] In advantageous embodiments, the oral dose unit comprises ethinylestradiol, more preferably 2.5 to 25 μg of ethinylestradiol, and most preferably 5 to 15 μg of ethinylestradiol.

[0053] In another advantageous embodiment, the oral dose unit comprises estradiol and / or a prodrug of estradiol. More preferably, the oral dose unit comprises 0.25 to 2.5 mg of estradiol and / or an amount of estradiol prodrug equivalent to 0.25 to 2.5 mg of estradiol. Most preferably, the oral dose unit comprises 0.5 to 1.5 mg of estradiol and / or an amount of estradiol prodrug equivalent to 0.5 to 1.5 mg of estradiol.

[0054] In yet another advantageous embodiment, the oral dose unit contains estriol. More preferably, the oral dose unit contains 10 to 100 mg of estriol. Most preferably, the oral dose unit contains 20 to 50 mg of estriol.

[0055] In a more advantageous embodiment, the oral dose unit contains estetrol. More preferably, the oral dose unit contains 7.5 to 75 mg of estetrol. Even more preferably, the oral dose unit contains 15 to 45 mg of estetrol. Most preferably, the oral dose unit contains 20 to 40 mg of estetrol.

[0056] The oral administration unit of the present invention preferably contains 15 to 150 mg, more preferably 25 to 75 mg, of dehydroepiandrosterone.

[0057] According to a particularly preferred embodiment, the dosage unit of the present invention is: • 30-120 mg of relugolix; • 15-45 mg of estetrol; and • Contains 25-75 mg of dehydroepiandrosterone; and • Does not contain progestogens.

[0058] Another aspect of the present invention relates to a package comprising at least 28 oral dose units according to the present invention. More preferably, the package comprises at least 56 oral dose units, most preferably 84 to 168 dose units.

[0059] Preferably, the oral administration units are arranged in a specific order within the package, and the total number of administration units within the package is a multiple of 7.

[0060] Preferably, the oral administration units are housed separately within the package.

[0061] In a particularly preferred embodiment, the date is indicated adjacent to each oral dose unit.

[0062] According to a particularly preferred embodiment, the oral administration units are arranged in a blister pack.

[0063] The present invention is further illustrated by the following non-limiting embodiments. [Examples]

[0064] Example 1 A multicenter, randomized clinical trial evaluated the efficacy and safety of three different oral contraceptive (OC) regimens in preventing pregnancy in sexually active women aged 18 to 35 years. Participants were randomly assigned in a 1:1:1 ratio to one of the following regimens: • A combination of oral tablets containing relugolix (80 mg) and ethinylestradiol (10 μg) is administered once daily for 182 days. • A combination oral tablet containing relugolix (80 mg) and ethinylestradiol (5 μg) is administered once daily for 182 days. • A combination oral tablet containing linzagolix (150 mg) and ethinylestradiol (10 μg) is administered once daily for 182 days.

[0065] All participants, regardless of randomization, will begin the study oral contraceptive therapy on the first Sunday after the start of their menstrual period ("Sunday starters") and will remain Sunday starters throughout the study. All participants will keep an electronic diary and download the information they enter. Assessments will include adherence to the investigational drug, use of additional contraception, bleeding patterns, weight, assessment of the incidence and severity of menstrual-related symptoms, and medications taken to alleviate these symptoms. Information will be automatically recorded in the electronic diary through a pre-programmed set of questions.

[0066] The 200 participants in each treatment group aim to complete the study.

[0067] To participate in the study, participants must meet the following criteria: 1. A sexually active adult woman (18-35 years old) who is in a heterosexual relationship, at risk of pregnancy, capable of giving birth, is healthy, has a history of using oral contraceptives (OCs) for at least three consecutive cycles prior to registration, and experiences regular withdrawal bleeding (bleeding during periods when not taking pills or during the first three days of the next cycle) (continuing user). or No prior experience with overclocking (Fresh-Starts) or No history of overclocking in the 6 months prior to registration (previous user). 2. The urine pregnancy test was negative. 3. I signed the informed consent form. 4. I agree to use the oral contraceptive therapy studied as my primary method of contraception (BCM).

[0068] Participants will be excluded from the study if they meet any of the following conditions: 1. A history of hypersensitivity to the estrogen or progestin component of oral contraceptives (OCs). 2. History of alcohol or drug abuse. 3. Chronic use of any medication that may interfere with the effectiveness of oral contraceptives. 4. A history of being positive for HIV or hepatitis C. 5. A history of persistent non-compliance with long-term medications. 6. A history of receiving injectable hormone therapy within 10 months prior to registration, having a progestin-releasing intrauterine device (IUD) inserted within 3 months prior to registration, having a contraceptive implant removed within 1 month prior to registration, or having received other hormonal contraception within 3 months prior to registration. 7. In addition to condoms, I habitually use other methods of contraception (IUD, diaphragm, contraceptive sponge). 8. Subjects who have recently undergone surgery or a medical abortion, miscarriage, or vaginal delivery or cesarean section must have experienced at least two normal menstrual cycles prior to registration. 9. A history of abnormal bleeding (breakdown bleeding or withdrawal bleeding lasting 10 consecutive days or more, or excessive bleeding lasting 10 consecutive days or more) while using conventional oral contraceptives. 10. A history of thromboembolic disease, vascular disease, cerebrovascular disease, or coronary artery disease. 11. Uncontrolled or untreated hypertension (systolic blood pressure ≥ 140 mmHg and diastolic blood pressure ≥ 90 mmHg occurring three or more times). 12. Known or suspected breast cancer, endometrial cancer, or known or suspected estrogen-dependent tumor. 13. Undiagnosed abnormal genital bleeding. 14. A history of hepatocellular adenoma or carcinoma. 15. A history of cholestatic jaundice during pregnancy or jaundice prior to the use of oral contraceptives (OCs). 16. You are known to be pregnant, suspect you are pregnant, or are currently breastfeeding. 17. Hyperlipidemia requiring aggressive treatment with anti-hyperlipidemia agents. 18. A history of diabetes mellitus, glucose intolerance, or gestational diabetes. 19. History of abnormal test results during screening. 20. Any clinically significant abnormal findings or conditions or any laboratory findings that contraindicate the use of oral contraceptives, including medical history, screening, physical examination, pelvic examination, or any other laboratory findings. 21. The individual participated in any clinical examination within 30 days prior to registration. 22. I donated or lost more than 500cc of blood within 30 days prior to registration.

[0069] All subjects are instructed to take one tablet daily at approximately the same time each day.

[0070] Detailed examinations, including Pap smears, and gynecological examinations will be performed at screening and at the end of treatment or early withdrawal from the study. Subjects with abnormal Pap smear results will be ineligible to participate unless the principal investigator determines that the results are not clinically significant and will not hinder the conduct of the study. The principal investigator's decision will be documented. Subjects who have had a Pap smear within three months prior to enrollment in the study and whose results are reported to be within the normal range do not require re-examination. A copy of the results is available in the subject's medical record. Subjects whose cell counts are reported to be insufficient must undergo re-examination before enrollment and documented by the researcher as being within the normal range.

[0071] Clinical tests are performed at screening and at the end of treatment or early discontinuation. All clinical tests are performed in a single central laboratory. Tests include CBC, serological chemistry, lipid profiling, urinalysis, and urinalysis for pregnancy.

[0072] All participants will be followed up for pregnancy occurrence for three months after the end of the study. This follow-up may be conducted via telephone. For all pregnancies that occur during the study or within three months after the end of the study, the gestational age of the fetus will be determined using ultrasound.

[0073] Participants will be required to keep an electronic diary. This diary is programmed to ask specific questions about adherence to the study, bleeding patterns, and the occurrence of symptoms generally associated with hormonal fluctuations during the menstrual cycle. The questions concern adherence, bleeding patterns, and hormone-related symptoms.

[0074] No significant toxicity is expected from the investigational drug. However, if a subject exhibits any symptoms or abnormal test results attributable to the drug, and the subject and / or physician determine that the condition is too severe to be acceptable, the investigational drug will be discontinued.

[0075] Participants will be asked about their use of concomitant medications via monthly telephone calls. All concomitant medication use (including herbal medicines and nutritional supplements, both prescription and over-the-counter (OTC) medications) must be reported during the study and recorded in the participant's Case Record (CRF).

[0076] Participants requiring long-term treatment with medications known to interact with oral contraceptives (OCs) will be excluded from the study. Participants requiring intermittent treatment with medications known to interact with OCs (e.g., antibiotic therapy) will remain in the study and receive counseling about the need for additional contraception throughout the entire cycle. Participants will be provided with a list of medications known to interact with OCs and instructed to inform the study coordinator as soon as any medication is prescribed so that they can receive appropriate counseling. These cycles in which participants take medications known to interact with OC therapy will not be used in the calculation of pregnancy rates.

[0077] The study results show that the oral contraceptive regimens tested effectively prevent pregnancy in sexually active women without significant side effects.

[0078] Example 2 The oral administration method according to the present invention, which is particularly suitable for use in contraception, does not contain a progestogen: 50mg relugolix; • 25 mg of estetrol; and Contains 50 mg of dehydroepiandrosterone.

Claims

1. An oral administration unit for use in a method of contraception for female mammals or a method of treating endometriosis in female mammals, comprising a GnRH antagonist and estrogen, but not a progestogen; an oral administration unit wherein the method comprises orally administering the oral administration unit to the female mammal once daily for at least 28 days.

2. An oral administration unit for use in the method according to claim 1, wherein oral administration of the oral administration unit once daily induces amenorrhea.

3. An oral dose unit for use in the method according to claim 1 or 2, wherein the GnRH antagonist is selected from relugolix, linzagolix, ellagolix, and combinations thereof.

4. An oral administration unit for use in the method according to any one of claims 1 to 3, wherein the GnRH antagonist is administered orally in a daily dose equivalent to a daily oral dose of 20 to 200 mg of relugolix.

5. An oral administration unit for use in the method according to any one of claims 1 to 4, wherein the oral administration unit comprises 20 to 200 mg of relugolix.

6. An oral administration unit for use in the method according to any one of claims 1 to 4, wherein the oral administration unit comprises 50 to 400 mg of linzagolix.

7. An oral administration unit for use in the method according to any one of claims 1 to 4, wherein the oral administration unit comprises 100 to 400 mg of elagolyx.

8. An oral dose unit for use in the method according to any one of claims 1 to 7, wherein the estrogen is selected from ethinylestradiol, estradiol, a prodrug of estradiol, estriol, a prodrug of estriol, estolol, a prodrug of estol, and combinations thereof.

9. An oral administration unit for use in the method according to any one of claims 1 to 8, wherein the estrogen is administered orally in a daily dose equivalent to the daily oral dose of 2.5 to 25 μg ethinylestradiol.

10. An oral administration unit for use in the method according to any one of claims 1 to 9, wherein the oral administration unit comprises 2.5 to 25 μg of ethinylestradiol.

11. An oral administration unit for use in the method according to any one of claims 1 to 9, wherein the oral administration unit comprises 0.25 to 2.5 mg of estradiol.

12. An oral administration unit for use in the method according to any one of claims 1 to 9, wherein the oral administration unit comprises 7.5 to 75 mg of estolol.

13. An oral administration unit for use in the method according to any one of claims 1 to 12, wherein the oral administration unit comprises 15 to 150 mg of dehydroepiandrosterone.

14. The aforementioned oral dose unit is: 30-120 mg of relugolix; 15-45 mg of estetrol; and • Contains 25-75 mg of dehydroepiandrosterone; and An oral dose unit for use in the method according to any one of claims 1 to 13, which does not contain a progestogen.

15. An oral administration unit for use in the method according to any one of claims 1 to 14, wherein the method includes simultaneous intrauterine administration of a progestogen.

16. - A GnRH antagonist in an amount equivalent to 20-200 relgolics; and - Contains an amount of estrogen equivalent to 2.5 to 25 μg of ethinylestradiol; and • Oral dose units that do not contain progestogens.

17. The oral administration unit according to claim 16, wherein the GnRH antagonist is selected from relugolix, ellagolix, linzagolix, and combinations thereof.

18. An oral dose unit according to claim 16, comprising 20 to 200 mg of relugolix.

19. An oral dose unit according to claim 16, comprising 100 to 400 mg of ellagolyx.

20. An oral dose unit according to claim 16, comprising 50 to 400 mg of linzagolix.

21. The oral dose unit according to any one of claims 16 to 20, wherein the estrogen is selected from ethinylestradiol, estradiol, a prodrug of estradiol, estriol, and combinations thereof.

22. An oral dose unit according to claim 21, comprising 2.5 to 25 μg of ethinylestradiol.

23. An oral dose unit according to claim 21, comprising 0.25 to 2.5 mg of estradiol.

24. An oral dose unit according to claim 21, comprising 7.5 to 75 mg of estolol.

25. An oral dose unit according to any one of claims 16 to 24, comprising 15 to 150 mg of dehydroepiandrosterone.

26. The aforementioned oral dose unit is: 30-120 mg of relugolix; 15-45 mg of estetrol; and • Contains 25-75 mg of dehydroepiandrosterone; and - An oral dose unit according to any one of claims 16 to 25, which does not contain a progestogen.

27. A package comprising at least 28 oral administration units according to any one of claims 16 to 26, wherein the oral administration units are arranged in a certain order within the package, and the total number of administration units within the package is a multiple of 7.

28. The aforementioned package is a blister pack, as described in invoice 27.

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