JP7827774B2 - Composition for treating dysmenorrhea - Google Patents

Description

The present invention relates to a pharmaceutical composition for treating dysmenorrhea.

Dysmenorrhea refers to pathological symptoms that occur during menstruation and accompany menstruation, and the most common symptoms are lower abdominal pain, lower back pain, abdominal distension, nausea, headache, fatigue/weakness, loss of appetite, irritability, diarrhea, and depression, in that order (Non-Patent Document 1).
Dysmenorrhea is classified into organic dysmenorrhea, which occurs when there is an organic lesion such as endometriosis or adenomyosis, and functional dysmenorrhea, which occurs when there is no organic lesion in the pelvis that would cause pain.
According to a survey of dysmenorrhea conducted as part of a health science research project in fiscal year 2000, 33% of women aged 20 to 49 were found to have dysmenorrhea, and among these, functional dysmenorrhea was the most common diagnosis when they visited a medical institution, accounting for approximately half at 47.0%. It has been reported that endometriosis was the most common organic abnormality at 26.7%, followed by uterine fibroids at 17.3% (Non-Patent Document 2).

Functional dysmenorrhea without organic disease is characterized by heavy bleeding on the first and second days of menstruation, and the pain is spasmodic and cyclical. It is believed to be caused by cervical stenosis or excessive uterine contraction due to endogenous physiologically active substances such as prostaglandins (PGs).
On the other hand, organic dysmenorrhea is often characterized by persistent dull pain that lasts from 4-5 days before menstruation until after menstruation. However, the mechanism behind menstrual pain is the same for both functional and organic dysmenorrhea, which is thought to be caused by excessive contraction of the uterine smooth muscle in order to expel menstrual blood that has accumulated in the uterine cavity (Non-Patent Document 3).

The first-line treatment for functional dysmenorrhea is analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit PG production, or drug therapy using low-dose estrogen-progestin combination drugs (hereinafter referred to as "LEP preparations" in this specification) (Non-Patent Document 1).

LEP preparations contain estrogen and progestin, but the main hormone effective for dysmenorrhea is said to be progestin, and estrogen is necessary for the expression and maintenance of progesterone receptors, and it is explained that it plays a supporting role in allowing even low doses of progestin to exert sufficient progesterone action. Progestin is said to suppress endometrial proliferation and thin the endometrium through its progesterone activity, and further suppress PG production during menstruation by suppressing the expression of cyclooxygenase (COX) (Non-Patent Document 2).
LEP preparations can cause thrombosis as a serious side effect, and it is known that the risk of thrombosis is higher in smokers and obese patients.
Currently, in Japan, LEP preparations covered by health insurance for the treatment of dysmenorrhea include, for example, drospirenone-ethinylestradiol tablets (product name: Yaz (registered trademark) combination tablets) and norethisterone-ethinylestradiol tablets (product name: Lunabell (registered trademark) combination tablets LD and ULD) (Non-Patent Document 2).

The pharmacology section of the package insert for Yaz (registered trademark) combination tablets states that "this drug is thought to suppress uterine contractions by inhibiting the overproduction of PGs and other compounds through its ovulation suppression and endometrial proliferation suppression effects, thereby alleviating symptoms such as pain associated with dysmenorrhea" (Non-Patent Document 4). The package inserts for Lunabell (registered trademark) combination tablets LD and ULD contain similar information (Non-Patent Document 5).
The interview form for Yaz (registered trademark) combination tablets discloses serum estradiol concentrations at baseline and during the follicular phase of cycle 4 as an indicator of "ovulation suppression effect using serum estradiol concentration as an index." It has been shown that serum estradiol concentrations decreased during cycle 4, and only a few patients out of 32 patients with functional dysmenorrhea and 19 patients with organic dysmenorrhea had levels exceeding 30 pg/mL, which is considered the threshold for suppression of follicular maturation (Non-Patent Document 6).
On the other hand, it is known that an excessive decrease in serum estradiol concentration can cause side effects such as emotional instability, dizziness, and lipid metabolism disorders, as well as decreased bone mineral density.

The interview forms for Lunabell (registered trademark) Combination Tablets LD and ULD disclose the change in serum estradiol concentration as an "ovulation suppression effect." With LD, serum estradiol concentration decreases during the administration cycle and remains unchanged throughout the administration period, while with ULD, it remains slightly higher than with LD (Non-Patent Document 7).

The levonorgestrel-releasing intrauterine system (product name: Mirena (registered trademark) 52 mg), a type of progestin preparation, is effective for treating dysmenorrhea. This drug highly suppresses pregnancy while using this system because the levonorgestrel released over an extended period in the uterus causes the endometrium to atrophy. Furthermore, because endometrial atrophy reduces menstrual flow, it has been shown to be effective in easing menorrhagia and menstrual pain. Because its action is localized on the endometrium and has no systemic side effects, it does not suppress ovulation and therefore does not cause a hypoestrogen state, and its effects last for five years with a single insertion, it is considered useful in cases where LEP preparations are contraindicated or where oral compliance is poor (Non-Patent Document 8).

Furthermore, there are studies showing that dydrogesterone, which exhibits progesterone properties, was effective in treating functional dysmenorrhea without suppressing ovulation. In these two studies, dydrogesterone was administered from day 5 to day 25 of the menstrual cycle (Non-Patent Documents 9 and 10).

Dienogest is known to have a therapeutic effect on dysmenorrhea in patients with endometriosis, a typical causative disease of organic dysmenorrhea (Non-Patent Documents 8 and 11).
Regarding endometriosis, the application summary for Dienogest Tablets 1 mg discloses that in a late phase II trial for endometriosis, when dienogest was administered twice daily at doses of 1 mg/day, 2 mg/day, and 4 mg/day, the mean (median) serum estradiol concentrations from week 8 to the end of administration (24 weeks) were 84.5 pg/mL (72.5 pg/mL) in the 1 mg/day group, 2 mg/day group, and 4 mg/day group, respectively, and a dose-response relationship was observed (Non-Patent Document 12).
In Japan, dienogest is sold as "Dinagest (registered trademark) Tablets 1 mg" with the efficacy and effect of "endometriosis." The dosage and administration is "usually given orally to adults at 2 mg of dienogest per day in two divided doses from the second to fifth day of the menstrual cycle."
According to the package insert, the mechanism of action against endometriosis is that "this drug exhibits selective agonist action on progesterone receptors and is thought to be effective against endometriosis by suppressing ovarian function and inhibiting the proliferation of endometrial cells" (Non-Patent Document 13).

Regarding the ovulation suppression effect of dienogest, in order to determine the minimum dose of dienogest required for ovulation suppression, 33 healthy women without organic diseases such as endometriosis were administered dienogest at doses of 0.5 mg/day, 1 mg/day, 1.5 mg/day, and 2.0 mg/day once daily for 21 days. It was reported that dienogest at 0.5 mg/day suppressed ovulation in two-thirds of the subjects, while dienogest at 1 to 2 mg/day suppressed ovulation in all subjects. It was disclosed that in this study, there were four cases of dysmenorrhea during the control period (before administration), but the incidence of dysmenorrhea decreased to zero during the treatment period (Non-Patent Document 14).
In another study, to investigate the ovulation suppression effect of dienogest, 102 healthy women were administered dienogest (0.5 mg/day, 1 mg/day, 2 mg/day, and 3 mg/day) once daily for 72 days. During the administration period, ovulation occurred in 3 of 21 women in the 0.5 mg/day group, 1 of 23 women in the 1 mg/day group, 0 of 20 women in the 2 mg/day group, and 0 of 23 women in the 3 mg/day group. Furthermore, the maximum serum estradiol concentration was similar to the baseline value in the 0.5 mg/day and 1 mg/day groups, but decreased slightly in the 2 mg/day and 3 mg/day groups. Endometrial thickness decreased at all doses (Non-Patent Document 15). However, there was no mention of dysmenorrhea.

Regarding the application of dienogest to functional dysmenorrhea, the clinical trial information webpage of the Japan Pharmaceutical Information Center, a general incorporated foundation, discloses that a placebo-controlled, randomized, double-blind, parallel-group comparative study will be conducted between August 3, 2015 and November 30, 2016 to examine the efficacy and safety of dienogest at 2, 1, and 0.5 mg/day in patients with functional dysmenorrhea (Non-Patent Document 16), but the results are unknown.
It has also been disclosed that a combination of estradiol valerate and dienogest was effective against functional dysmenorrhea, similar to a combination of ethinylestradiol and levonorgestrel. The formulation used here consisted of 3 mg estradiol valerate for 2 days, a combination of 2 mg estradiol valerate and 2 mg dienogest for 5 days, a combination of 2 mg estradiol valerate and 3 mg dienogest for 17 days, 1 mg estradiol valerate for 2 days, and a placebo for 2 days, all of which were administered repeatedly over a 28-day cycle (Non-Patent Document 17).

A patent application related to the treatment of dysmenorrhea proposes that in a preparation for the treatment of dysmenorrhea and other conditions for continuous hormone treatment containing estrogen and/or progestin, the pharmaceutical dose in the first composition administered during the first 21 to 28 days is increased by the pharmaceutical dose in the second composition administered thereafter, but no specific data are disclosed (Patent Document 1).

As described above, while it has been known that dienogest alone is effective in treating dysmenorrhea in patients with endometriosis, no trials have been conducted targeting dysmenorrhea.

Special Publication No. 2007-512291

Obstetrics and Gynecology Clinical Practice Guidelines - Gynecology Outpatient Edition 2014 - Japan Society of Obstetrics and Gynecology, Japan Society of Obstetrics and Gynecology, pp. 113-114 Pharma Medica Vol.32 No.6 (2014), pp.45-48 Obstetrics and Gynecology, 2011, No. 11, pp. 1315-1319 Yaz (registered trademark) Combination Tablets Package Insert May 2016 (7th edition) Lunabell (registered trademark) Combination Tablets Package Insert October 2016 Revised (13th Edition) Yaz (registered trademark) Combination Tablets Interview Form, September 2016 (revised 9th edition), page 18 Lunabell (registered trademark) Combination Tablet Interview Form, June 2016 revision (14th edition), page 14 Obstetrics and Gynecology, 2013, No. 8, pp. 993-997 Bulletin de la Societe Royale Belge de Gynecologie et d'Obstetrique, (1967) Vol. 37, No. 4, pp. 273-276. JAMA, (1965 Jun 14) Vol. 192, pp. 1003-5. Pharma Medica Vol.32 No.6 (2014), pp.35-38 Summary of Dienogest Application Documents, Late Phase II Trial, Pages 792-860 Dinagest Tablets 1mg Package Insert May 2013 (5th Edition) Clin Drug Invest 1999 18(4) p.271-278 J Clin Pharmacol 2012; 52: p.1704-1713 Japan Pharmaceutical Information Center Clinical Trial Information JapicCTI-152977 International J Gynecol. Obs. 125(2014) p.270-274

In recent years, drug therapy using analgesics (NSAIDs, etc.) or low-dose estrogen-progestin combination drugs (LEP preparations) has been considered the first choice for treating functional dysmenorrhea. However, these drugs may not be effective in treating dysmenorrhea, including sufficient pain relief. In addition, there are concerns about side effects, such as gastrointestinal symptoms with analgesics and thrombosis with LEP preparations, and some patients may not be able to take these drugs.
The levonorgestrel-releasing intrauterine system, a type of progestin preparation, can also be used to treat dysmenorrhea, but it is a preparation that is continuously inserted into the uterus and must be removed by a doctor, and it has the disadvantage that it is not easy to discontinue or change the medication schedule.Dydrogesterone, which has progesterone effects, does not suppress ovulation, so it may be less effective against dysmenorrhea than preparations that suppress ovulation.
In severe cases of dysmenorrhea, patients often experience extremely strong abdominal pain, lower back pain, etc., which can last for two or three days or more, during which time they must continue to take painkillers. In particularly severe cases, or when painkillers cannot be administered, patients may be bedridden for more than a day. Such severe cases of dysmenorrhea pose a serious problem for patients, as they are unable to perform their work, studies, or even daily life.

The object of the present invention is to provide a therapeutic agent for dysmenorrhea that is more effective than LEP preparations, which are considered the standard hormone preparation for the treatment of dysmenorrhea, has a low risk of serious side effects such as thrombosis, is easy to administer, and can be administered daily. In particular, the object of the present invention is to provide a therapeutic agent that is highly effective in improving both patients with moderate or severe pain associated with dysmenorrhea and patients with functional dysmenorrhea who do not have organic diseases.
Another object of the present invention is to provide a highly effective therapeutic agent for dysmenorrhea that reduces physical burden without significantly affecting the serum estradiol concentration of a patient. That is, since a decrease in serum estradiol concentration can cause bone mass loss, menopausal symptoms such as hot flashes, insomnia, depression, and other symptoms, it is desirable not to decrease serum estradiol concentration more than necessary.
Another object of the present invention is to provide a therapeutic drug that can be the first choice for patients for whom it is desirable not to significantly decrease serum estradiol levels during the administration period.

The inventors investigated the potential of dienogest as a treatment for dysmenorrhea and conducted a clinical trial involving patients with functional dysmenorrhea. The results showed that dienogest exhibited superior efficacy compared to an LEP preparation (product name: Yaz®), which is also effective against dysmenorrhea. Specifically, when the change in dysmenorrhea score after 8 weeks of administration was evaluated, it was found that 8 weeks of daily administration of dienogest at 0.5 mg/day, 1 mg/day, or 2 mg/day reduced dysmenorrhea scores with a statistically significant difference compared to placebo administration. When the change in dysmenorrhea score after 12 weeks of administration was evaluated, it was found that 12 weeks of daily administration of dienogest at 1 mg/day or 2 mg/day reduced dysmenorrhea scores with a statistically significant difference compared to Yaz® administration.

In the evaluation of the rate of complete disappearance of dysmenorrhea scores at 12 weeks of administration, no clear difference was observed in the rate of complete disappearance with Yaz (registered trademark) administration compared to placebo, but the complete disappearance rates with dienogest administration of 1 mg/day or 2 mg/day were both higher than with Yaz (registered trademark) administration, and a statistically significant difference was observed.
It was also suggested that administering 1 mg of dienogest per day in two divided doses would provide excellent therapeutic effects for functional dysmenorrhea comparable to those achieved by administering 2 mg of dienogest per day, without significantly affecting the patient's serum estradiol levels.
Furthermore, even in a survey of patients with functional dysmenorrhea whose serum estradiol concentrations during the luteal phase were relatively low (e.g., 150 pg/mL or less) before administration of the composition of the present invention, the mean and median average serum estradiol concentrations during the period of administration of 1 mg/day of dienogest were almost the same as those obtained with placebo, suggesting that dysmenorrhea can be effectively treated without significantly reducing serum estradiol concentrations.

That is, the present invention includes the following inventions.
[1] A composition for treating dysmenorrhea for patients suffering from dysmenorrhea, comprising dienogest as an active ingredient.
[2] The composition according to [1] above, which contains dienogest as the only active ingredient.
[3] The composition according to [1] or [2] above, which is administered daily for a period of 8 consecutive weeks or more.
[4] The composition according to any one of [1] to [3] above, wherein dienogest is orally administered at a dose of 1 mg per day in two divided doses.
[5] The composition according to any one of [1] to [4], wherein a constant dose of dienogest is administered without periodic fluctuation of the dose during the administration period.
[6] The composition according to any one of [1] to [5] above, which does not significantly decrease the serum estradiol concentration during the administration period compared to the concentration before administration.
[7] The composition according to any one of [1] to [6] above, wherein the patient is a patient for whom it is desirable that the serum estradiol concentration not be significantly reduced during the administration period.
[8] The composition according to any one of [1] to [7] above, wherein the patient is a patient not suffering from endometriosis, uterine fibroids, or adenomyosis.
[9] The composition according to any one of [1] to [8] above, wherein the patient has a serum estradiol concentration of 150 pg/mL or less during the luteal phase before administration of the composition.
[10] The composition according to any one of [1] to [9] above, wherein the patient is a patient who, before administration of the composition, has moderate or severe pain (lower abdominal pain/lower back pain) thought to be caused by dysmenorrhea.
[11] The composition according to any one of [1] to [10] above, wherein the patient is a patient who, before administration of the composition, has moderate or severe pain (lower abdominal pain/lower back pain) that is thought to be caused by dysmenorrhea, and who requires the use of an analgesic when experiencing the pain.
[12] The composition according to any one of [1] to [11] above, wherein the patient has a dysmenorrhea score of 3 or more before administration of the composition.
[13] The composition according to [12] above, wherein the patient has a dysmenorrhea score of 5 or 6 before administration of the composition.
[14] The composition according to any one of [1] to [13] above, wherein the dysmenorrhea is functional dysmenorrhea.

According to the present invention, it is possible to provide a treatment option for functional dysmenorrhea, for which sufficient pain relief cannot be achieved with analgesics or LEP preparations. Dienogest can be administered orally and easily, and has a lower risk of serious side effects such as thrombosis compared to LEP preparations.
LEP preparations generally have a drug-free period (or placebo administration period), during which dysmenorrhea symptoms may occur, but dienogest is administered daily without a drug-free period, so there is no need to worry about this. Also, while excessive use of painkillers can lead to gastrointestinal symptoms, edema, systemic blood flow disorders, and kidney damage, dienogest carries a relatively low risk of these problems.
Furthermore, the present invention may be highly effective in treating patients with moderate or severe pain associated with dysmenorrhea, and in those who require the use of analgesics during pain. The composition is also effective in patients with a dysmenorrhea score of 3 or more, particularly 5 or 6, before administration of the composition.
Furthermore, when dienogest is administered at 1 mg per day in two divided doses, it does not affect the patient's serum estradiol concentration and reduces the burden on the body, and has the advantage of being less likely to cause side effects such as decreased bone mass, menopausal symptoms such as hot flashes, insomnia, depressed mood, and depression-like symptoms.

Complete disappearance rate of dysmenorrhea score at the end of administration (12 weeks after administration) Complete disappearance rate of dysmenorrhea score in patients with severe functional dysmenorrhea Median mean serum estradiol concentrations in each group

1. Dienogest The present invention relates to a composition for treating dysmenorrhea, which contains dienogest as an active ingredient.
Dienogest (17-hydroxy-3-oxo-19-nor-17α-pregna-4,9-diene-21-nitrile), the active ingredient of the present invention, is a compound having the structure shown in the following formula (1).

Dienogest, the active ingredient of the composition of the present invention, is sold in Japan under the product names "Dinagest Tablets (registered trademark) 1 mg" and "Dinagest (registered trademark) OD Tablets 1 mg" for the efficacy and effect of treating endometriosis.
The disease to be treated in the present invention is dysmenorrhea, particularly functional dysmenorrhea.
In this specification, the composition for treating dysmenorrhea according to the present invention, which contains dienogest as an active ingredient, may be referred to as the "composition of the present invention."

2. Dysmenorrhea and Functional Dysmenorrhea Dysmenorrhea refers to pathological symptoms that occur during menstruation. The most common symptoms are lower abdominal pain, lower back pain, abdominal distension, nausea, headache, fatigue/weakness, loss of appetite, irritability, diarrhea, and depression, in that order. In severe cases, the pain from lower abdominal pain and lower back pain can last for two or even three days or more, causing bedriddenness and interfering not only with work or school but also with daily life.
Dysmenorrhea is classified into functional dysmenorrhea and organic dysmenorrhea.
Functional dysmenorrhea (also known as primary dysmenorrhea) is dysmenorrhea without any organic lesions that could cause pain in the pelvis. It begins two to three years after menarche and is common among women in their late teens to early twenties who have not given birth. It is most severe when bleeding is heavy around the first and second days of menstruation, and the pain is crampy and cyclical. The primary cause is thought to be hypercontraction of uterine smooth muscle caused by endometrial-derived prostaglandins due to a decrease in blood progesterone levels during the late luteal phase, resulting in ischemia, hypoxia, and peripheral nerve stimulation.
On the other hand, organic dysmenorrhea (also called secondary dysmenorrhea) is dysmenorrhea caused by organic lesions such as endometriosis, uterine fibroids, adenomyosis, cervical stenosis, or occlusion of the menstrual outflow tract due to Mullerian duct abnormalities. It is often characterized by persistent dull pain that lasts from 4-5 days before menstruation until after menstruation.

3. Target Patients The disease targeted by the present invention is dysmenorrhea, and the patients targeted for treatment are those suffering from dysmenorrhea.
In one embodiment of the present invention, the disease targeted by the present invention is functional dysmenorrhea, and the target patient is a patient with functional dysmenorrhea.

In another embodiment of the present invention, the patient targeted by the present invention is preferably a patient in whom it is desirable that the serum estradiol concentration not be significantly reduced during the administration period, i.e., a patient in whom it is desirable that the serum estradiol concentration not be significantly reduced during the administration period of the therapeutic drug compared to the serum estradiol concentration before the start of administration.
In the examples of this specification, the mean and median values of the mean serum estradiol concentration during the administration period of the dienogest 1 mg/day administration group were almost the same as those of the placebo administration group, so it is predicted that the administration of dienogest 1 mg/day will not significantly reduce the subject's serum estradiol concentration before administration. Therefore, for such "patients for whom it is desirable not to significantly reduce serum estradiol concentration during the administration period," it is desirable to set the daily dose of dienogest to 1 mg or less. More preferably, it is desirable to administer a daily dose of dienogest of 1 mg twice a day.

Here, one example of a "patient in whom it is desirable not to significantly decrease serum estradiol levels during the administration period" is a patient who does not suffer from endometriosis, uterine fibroids, or adenomyosis. These diseases are known to be affected by estrogen, and for example, in the case of endometriosis, there is a theory (the therapeutic window hypothesis) that suggests that maintaining blood estrogen levels at 30-50 pg/mL is therapeutically desirable.

Another embodiment of "patients for whom it is desirable not to significantly decrease serum estradiol concentrations during the administration period" is a patient with a relatively low serum estradiol concentration, specifically a patient whose serum estradiol concentration (preferably the mean or median of multiple measurements) during the luteal phase before administration of the composition of the present invention is 150 pg/mL or less. More preferably, the patient has a serum estradiol concentration during the luteal phase before administration of the composition of 120 pg/mL or less, and even more preferably, 100 pg/mL or less. In the present invention, "luteal phase" refers to the period from after ovulation until menstruation. More preferably, it refers to the period from 10 to 5 days before the expected onset of menstruation, and even more preferably, it refers to the period from 8 to 6 days before the expected onset of menstruation.

Estradiol is a type of estrogen, a follicle hormone. Estrogens play various roles, including proliferation of the endometrium, hypertrophy and proliferation of uterine muscle, mammary gland development, and bone development. Estradiol in particular is highly physiologically active and plays the most important role among estrogens.
Serum estradiol concentrations usually fluctuate with the cycle, including the follicular phase, ovulation phase, and luteal phase. There are various opinions on the standard value for serum estradiol concentrations in women during the luteal phase, but it is generally said to be 45 to 300 pg/ml. If serum estradiol concentrations before administration are relatively low, further lowering the estradiol concentration by administering a drug increases the risk of side effects associated with low serum estradiol levels, so it is desirable to avoid excessive lowering of serum estradiol concentrations.
When serum estradiol levels decrease, some people may experience side effects such as menopausal symptoms such as hot flashes, sweating, and fatigue, as well as decreased ovarian function and decreased bone mass. Therefore, unless necessary in relation to disease treatment, it is preferable to maintain the serum estradiol level prior to administration.

Serum estradiol levels tend to be low due to conditions such as hypoovarian function, and even in the absence of any particular illness, serum estradiol levels can be low due to hormone imbalance caused by excessive stress, malnutrition, menopause, and aging. In such cases, it is desirable to avoid further lowering serum estradiol levels through treatment for dysmenorrhea. The same applies to patients with low bone density, such as those suffering from osteoporosis.

Such patients are particularly resistant to LEP preparations, which tend to lower serum estradiol levels.
On the other hand, the composition for treating dysmenorrhea of the present invention, which contains dienogest as an active ingredient, has been suggested to not significantly reduce serum estradiol levels during the administration period, and is therefore a pharmaceutical composition that can be administered as a first choice to such "patients for whom it is desirable not to significantly reduce serum estradiol levels during the administration period."

In the present invention, another embodiment of "patients for whom it is desirable not to significantly decrease serum estradiol levels during the administration period" includes patients with low serum estradiol levels due to hormone imbalance caused by stress or aging, or patients suffering from ovarian failure, or patients with low bone density, such as patients suffering from osteoporosis.

In another preferred embodiment of the present invention, the patient targeted by the present invention is a patient with dyslipidemia. It is known that estrogen (including estradiol) affects lipid metabolism in women, and that a deficiency of estrogen causes changes in lipid metabolism. Therefore, it is desirable for patients with dyslipidemia (e.g., hypertriglyceridemia) to avoid an excessive decrease in serum estradiol levels. In the clinical trial described in the examples herein, it was not found that dienogest administration had any effect on blood triglycerides compared to placebo administration, so it is expected that the composition of the present invention will not exacerbate dyslipidemia.

In another preferred embodiment of the present invention, the target patient of the present invention is a dysmenorrhea patient with a dysmenorrhea score (described below in 4.) of 3 or more points before administration of the composition. In the examples of this specification, in a test involving patients with functional dysmenorrhea who had a dysmenorrhea score of 3 or more points before administration of the composition, the dienogest 1 mg/day group and 2 mg/day group were shown to exhibit statistically significant therapeutic effects compared to the reference drug group in evaluation of the change in dysmenorrhea score and the rate of complete disappearance of dysmenorrhea score. Thus, dienogest was shown to exhibit a high therapeutic effect in patients with functional dysmenorrhea who had a dysmenorrhea score of 3 or more points before administration of the composition, suggesting that it exhibits excellent therapeutic effects for dysmenorrhea patients with a dysmenorrhea score of 3 or more points before administration of the composition.

In another preferred embodiment of the present invention, the target patient is a patient with dysmenorrhea who had a dysmenorrhea score of 5 or 6 before administration of the composition. In an example of the present invention, in patients with severe functional dysmenorrhea who had a dysmenorrhea score of 5 or 6 before administration of the composition, the rates of complete disappearance of dysmenorrhea score at 12 weeks of administration when dienogest was administered daily at 1 mg/day or 2 mg/day were 60.0% and 59.1%, respectively, which were significantly higher than the 19.0% achieved with Yaz (registered trademark) administration. This demonstrates that dienogest has a high therapeutic effect even in patients with severe functional dysmenorrhea who had a dysmenorrhea score of 5 or 6 before administration of the composition, suggesting that dienogest also has an excellent therapeutic effect on severe dysmenorrhea who had a dysmenorrhea score of 5 or 6 before administration of the composition.

In another preferred embodiment of the present invention, the target patient of the present invention is a patient who, before administration of the composition, has moderate or severe pain (lower abdominal pain/lower back pain) that is thought to be caused by dysmenorrhea, or a patient who has moderate or severe pain associated with dysmenorrhea and requires the use of an analgesic during the pain.
For the "pain" and "pain level" in these aspects, the description of the dysmenorrhea score shown in Example 1 (Table 1) can be referred to. That is, "moderate" pain level means that the pain interferes with work (schoolwork/housework) to the extent that the patient wants to lie down and rest, and "severe" pain means that the patient is bedridden for one day or more and is unable to work (schoolwork/housework). Furthermore, "analgesic" here refers to a drug taken for the purpose of pain relief, and includes, but is not limited to, NSAIDs such as aspirin, acetaminophen, ibuprofen, diclofenac sodium, and loxoprofen sodium.
In the examples of the present specification, the composition of the present invention exhibited excellent therapeutic effects on patients with a dysmenorrhea score of 5 or 6 before administration of the composition, and these patients were at least patients with moderate or severe pain. This suggests that the composition of the present invention exhibits a high therapeutic effect on patients with moderate or severe pain associated with dysmenorrhea. It also suggests that the composition of the present invention exhibits a high therapeutic effect on patients with moderate or severe pain associated with dysmenorrhea who require the use of analgesics during pain.

In another preferred embodiment of the present invention, the target patient is a patient with dysmenorrhea who has not responded to treatment with an LEP preparation (a low-dose estrogen/progestin combination drug). As described above, dienogest has a greater therapeutic effect on functional dysmenorrhea than the LEP preparation Yaz (registered trademark). Therefore, it is expected that dienogest will also be effective in patients who have not achieved sufficient therapeutic effects with an LEP preparation. In the present invention, "LEP preparation" refers to a pharmaceutical containing low doses of an estrogen-like substance and a progestin-like substance, and includes, but is not limited to, drospirenone/ethinylestradiol tablets (product name: Yaz (registered trademark) combination tablets) or norethisterone/ethinylestradiol tablets (product name: Lunabell (registered trademark) combination tablets LD and ULD).

In another preferred embodiment of the present invention, the patient targeted by the present invention is a patient at risk of thrombosis. Examples of patients at risk of thrombosis include patients suffering from or with a history of thrombotic diseases such as thrombophlebitis, pulmonary embolism, cerebrovascular disease, and coronary artery disease, smokers aged 35 or older, diabetic patients with vascular lesions, patients with a thrombophilia, patients with hypertension, and patients with abnormalities in blood coagulation test parameters. Examples of blood coagulation test parameters include, but are not limited to, prothrombin time (PT), activated partial thromboplastin time (APTT), protein S activity, D-dimer, antithrombin III, and tissue plasminogen activator (tPA). In the clinical trial described in the Examples herein, the dienogest-administered group showed only minor abnormalities in blood coagulation test parameters, suggesting that the composition of the present invention will not further exacerbate the patient's risk of thrombosis.

4. Evaluation method used in the present invention <Dysmenorrhea score>
The "dysmenorrhea score" is known as one of the indices for evaluating dysmenorrhea ( Obstetrics and Gynecology, Vol. 9, 2008, pp. 1165-1181). The "dysmenorrhea score" is a numerical representation of the severity of dysmenorrhea. More specifically, the degree of pain (lower abdominal pain and lower back pain) thought to be caused by dysmenorrhea and the use of analgesics during that pain are scored on a four-point scale from 0 to 3, and the total score is obtained. The higher the score, the more severe the dysmenorrhea, with 6 being the most severe. Specific evaluation criteria are, for example, as shown in Table 1 of Example 1 of the present specification. Herein, a numerical range indicated using "to" indicates a range that includes the numerical values before and after "to" as the minimum and maximum values, respectively.

<Change in dysmenorrhea score>
In the present invention, the "change in dysmenorrhea score" is a numerical value obtained by subtracting the dysmenorrhea score before administration from the dysmenorrhea score after a certain period of administration. When the change in dysmenorrhea score is a positive numerical value, it indicates that the dysmenorrhea symptoms have worsened during the certain period of administration, and when it is a negative numerical value, it indicates that the dysmenorrhea score has decreased during the certain period of administration, and that the dysmenorrhea symptoms have been alleviated or disappeared.

In the examples herein, it was found that administration of dienogest at 1 mg/day or 2 mg/day for 12 weeks reduced the dysmenorrhea scores of patients with functional dysmenorrhea with a statistically significant difference compared to the placebo group and the reference drug (Yaz (registered trademark)) group, demonstrating excellent therapeutic effects for functional dysmenorrhea. When the composition of the present invention is administered daily for 12 weeks, the change in dysmenorrhea score between before administration and 12 weeks after administration is preferably -2 or less, and more preferably -3 or less.

<Complete disappearance rate of dysmenorrhea score>
In addition, in the present invention, "complete disappearance of dysmenorrhea score" means that the dysmenorrhea score becomes 0 at the end of administration. "Complete disappearance rate of dysmenorrhea score" means the proportion of subjects whose dysmenorrhea score becomes 0 in a specific subject group.

<Measurement and comparison of serum estradiol concentrations>
Serum estradiol can be measured using various commercially available measurement reagents and measurement kits.
In the present invention, when comparing the serum estradiol concentrations of a subject before and during the administration period, it is desirable to use the average or median of multiple measurements. In the examples of the present invention, the median is used to display and evaluate the results in order to avoid the influence of outliers.

5. Composition of the Present Invention The composition of the present invention contains dienogest as an active ingredient, but may also contain other pharmaceutically acceptable additives, etc., as long as they do not impair the effects of the present invention.
Examples of additives include, but are not limited to, bases, carriers, solvents, diluents, solubilizers, dispersants, emulsifiers, buffers, isotonicity agents, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, moisturizers, colorants, fragrances, and chelating agents.
When the composition of the present invention contains an additive, the composition of the present invention can be produced using the additive according to a conventional method suitable for the dosage form.

The composition of the present invention can be safely administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously, intradermally, intravaginally, etc., and directly to a lesion, etc.). In this case, oral administration is preferable because it is convenient.
The composition of the present invention may be in any dosage form, such as, but not limited to, a tablet, an orally disintegrating tablet, a capsule, a film, a pill, a powder, a powder, a granule, a liquid, an injection, a suspension, an emulsion, etc. Preferably, the composition is in the form of a tablet or an orally disintegrating tablet.

In addition, dienogest, the active ingredient of the present invention, may be incorporated into the formulation as an adduct with other compounds, such as a solvate, or as a prodrug, depending on the formulation needs.

When the composition of the present invention is orally administered, the daily dose of dienogest for adult women is preferably 0.5 mg to 2 mg/day, more preferably 1 mg/day. When orally administered, the preferred daily dose is once or twice a day, more preferably twice a day. When the daily dose is divided into two doses, it is preferable to divide the daily dose into two equal doses. For example, when 1 mg/day of dienogest is administered twice a day, it is preferable to administer a dose of 0.5 mg twice a day. It is also preferable that dienogest is administered at a fixed time every day.
The administration of the medication is preferably started from the second to fifth day of the onset of menstruation.

The administration period of the composition of the present invention is not particularly limited, but is preferably at least 8 weeks, more preferably at least 12 weeks, and it is desirable that a constant dose of dienogest is administered without periodic dose fluctuations. From the tests described in the examples of this specification, it was found that the composition of the present invention exerts a sufficient therapeutic effect on functional dysmenorrhea by administration for about 8 weeks.
Furthermore, there is no limit to the administration period of the composition of the present invention, and it may be administered for several years. There is no limit to the administration period for "Dinagest (registered trademark) Tablets 1 mg" for the efficacy of endometriosis, and there are cases where it has been administered for several years, so it is relatively safe.

The composition of the present invention is preferably administered daily throughout the administration period. Daily administration of a fixed dose of dienogest for at least 8 weeks, more preferably 12 weeks, is preferred. LEP preparations generally have a drug-free period during which withdrawal bleeding occurs from the uterus, which can lead to the pain of dysmenorrhea. However, since the composition of the present invention is administered daily, this is not a concern.

The compositions of the present invention can be used in combination with other drugs, as long as the effects of the present invention are not inhibited. Examples of other drugs that can be used in combination include, but are not limited to, GnRH analogs (goserelin acetate, buserelin acetate, leuprorelin acetate, nafarelin acetate, etc.), testosterone derivatives (danazol, etc.), hormones containing progesterone- or estrogen-like substances as their main components (estradiol, conjugated estrogens, oral contraceptives, etc.), estrogen antagonists, aromatase inhibitors, analgesics (NSAIDs such as aspirin, acetaminophen, ibuprofen, diclofenac sodium, and loxoprofenac sodium), anemia treatments (iron preparations, etc.), hemostatic agents (tranexamic acid, carbazochrome sodium sulfonate hydrate, etc.), and herbal medicines (Kyukikyogaito, etc.).

In the present invention, "combination with other drugs" includes administering a composition containing dienogest as an active ingredient and the other drug simultaneously, as well as administering them separately. When administered simultaneously, they can be administered as a combined drug or as two drugs. When administered separately, the composition containing dienogest as an active ingredient can be administered before or after the other drug.

In another preferred embodiment of the present invention, the composition containing dienogest is not administered in combination with a drug selected from the group consisting of a GnRH analogue, a testosterone derivative, a hormone drug whose main component is a progesterone-like substance and/or an estrogen-like substance, an estrogen antagonist, and an aromatase inhibitor.
In addition, an embodiment in which the composition of the present invention does not contain an estrogen-like substance is also preferred. In the present invention, an estrogen-like substance refers to a substance that has an action similar to that of an estrogen (estrogen), and examples thereof include estrogen, estradiol, ethinylestradiol, and estradiol valerate.
In another preferred embodiment, the composition of the present invention contains dienogest as the only active ingredient for dysmenorrhea.

The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples.
Other terms and concepts in the present invention are based on the meanings of terms commonly used in the relevant field, and various techniques used to carry out the present invention, except for those whose sources are particularly specified, can be easily and reliably carried out by a person skilled in the art based on known literature, etc. Furthermore, various analyses were carried out mutatis mutandis according to the methods described in the instruction manuals, catalogs, etc. of the analytical instruments, reagents, and kits used.
The contents of the technical documents, patent publications and patent application specifications cited in this specification are to be referred to as the contents of the present invention.

(Example 1) Clinical trial to examine the efficacy and safety of dienogest in patients with functional dysmenorrhea (1-1) Study design A clinical trial (multicenter, randomized, placebo-controlled, double-blind, parallel-group comparative study) was conducted to examine the efficacy and safety of dienogest in patients with functional dysmenorrhea.
The target number of subjects was 225, and subjects were randomly assigned to five groups (46-49 subjects in Group 1). The doses in each group were as follows. Group V was an open-label group administered with the reference drug.

Group I: placebo
Group II: dienogest 0.5 mg/day (also referred to as DNG 0.5 mg/day)
Group III: dienogest 1 mg/day (also referred to as DNG 1 mg/day)
Group IV: dienogest 2 mg/day (also referred to as DNG 2 mg/day)
Group V: drospirenone 3 mg/day, ethinylestradiol 0.020 mg/day, and placebo (reference drug)

Groups I to IV were orally administered twice daily for 12 weeks. The single dose of dienogest for groups I to IV was 0 mg for group I, 0.25 mg for group II, 0.5 mg for group III, and 1 mg for group IV, and these single doses were administered twice daily. Administration began on days 2 to 5 of the menstrual cycle.
Group V used 28 tablets of Yaz® combination tablets, consisting of 24 pale red tablets containing 3 mg of drospirenone and 0.020 mg of ethinylestradiol (as ethinylestradiol betadex) per tablet, and 4 placebo (white tablets). Group V was administered orally once daily for 12 weeks at a fixed time each day. Treatment began on the first day of the menstrual cycle, with the pale red tablets being used.

The inclusion criteria for subjects were: (1) patients who provided written consent to participate in this clinical trial; (2) patients who were 20 years of age or older on the day consent was obtained; (3) patients who were diagnosed with functional dysmenorrhea by transvaginal ultrasound and pelvic examination from the day consent was obtained until approximately one week before the start of study drug administration; (4) patients whose menstrual cycle was 38 days or less; and (5) patients who, during the menstrual cycle from the day consent was obtained until approximately one week before the start of study drug administration, experienced pain (lower abdominal pain or lower back pain) thought to be caused by functional dysmenorrhea, and whose total score for pain severity and analgesic use on the Dysmenorrhea Score (see below) was 3 or more.
The exclusion criteria for subjects were as follows: (1) patients with a history of endometriosis, uterine fibroids, adenomyosis, or organic dysmenorrhea; (2) patients with complications that cause lower abdominal pain or lower back pain other than during menstruation; (3) patients with severe or moderate anemia (hemoglobin level less than 10.0 g/dL) on the day of consent; (4) patients with undiagnosed abnormal genital bleeding, endometrial polyps, uterine malformations, or endometrial hyperplasia; (5) patients with thrombosis, embolism, cerebrovascular disease, or coronary artery disease, or a history thereof, or patients with a predisposition to thrombosis; and patients who were deemed unsuitable for participation in the study by a physician were excluded.

As one of the evaluation indices, the dysmenorrhea score was used. As shown in Table 1, the severity of the most severe pain (lower abdominal pain and lower back pain) thought to be caused by functional dysmenorrhea and the use of analgesics during that pain were each scored on a four-point scale, and the total scores were used to determine the dysmenorrhea score.
The standard evaluation time points were: 1) approximately 7 days before the expected start of menstruation at the time of initiation of administration (before administration), 2) the 29th day from the start of administration (4 weeks), with the start of administration considered as day 1, 3) the 57th day from the start of administration (8 weeks), with the start of administration considered as day 1, and 4) the 85th day from the start of administration (12 weeks), or when administration was discontinued, with the start of administration considered as day 1.
The survey period for the dysmenorrhea score was approximately 28 days up to the day before each evaluation point in 1) to 3). 4) The survey period at 12 weeks of administration was the period from the previous evaluation point to the end of administration or discontinuation of administration.

(1-2) Changes in dysmenorrhea score Changes in dysmenorrhea score (mean ± standard deviation) were evaluated in each of groups I to V at 1) before administration, 2) 4 weeks, 3) 8 weeks, and 4) 12 weeks (or when administration was discontinued).
As a result, the average dysmenorrhea score for each group before administration was between 4.3 and 4.6, and all groups showed similar values.
The mean dysmenorrhea scores for each group at 8 weeks of administration were 3.3 for Group I (placebo), 1.9 for Group II (DNG 0.5 mg/day), 1.5 for Group III (DNG 1 mg/day), 1.0 for Group IV (DNG 2 mg/day), and 2.3 for Group V (reference drug), which were almost the same as the mean dysmenorrhea scores for each group at 12 weeks of administration (or when administration was discontinued).

(1-3) Evaluation of change in dysmenorrhea score The change in dysmenorrhea score from the dysmenorrhea score obtained before administration to 12 weeks after administration of the investigational drug (or at the time of discontinuation of administration) was evaluated as the "change in dysmenorrhea score at 12 weeks after administration."
The mean change in dysmenorrhea score at 12 weeks after administration for each group is shown in Table 2.

As shown in Table 2, the mean change in dysmenorrhea score at 12 weeks of administration was −2 or less in groups II to V, and −3 or less in groups III (DNG 1 mg/day) and IV (DNG 2 mg/day).
Statistical analysis using the adjusted mean differences and two-sided 95% confidence intervals for Groups I to V revealed statistically significant differences in the change in dysmenorrhea scores between Groups II (DNG 0.5 mg/day), III (DNG 1 mg/day), and IV (DNG 2 mg/day) and Group I (placebo). This indicates that Groups II (DNG 0.5 mg/day), III (DNG 1 mg/day), and IV (DNG 2 mg/day) had a greater reduction in dysmenorrhea scores than Group I (placebo). Furthermore, similar analysis revealed statistically significant differences in the change in dysmenorrhea scores between Groups III (DNG 1 mg/day) and IV (DNG 2 mg/day) and Group V (reference drug). That is, it was shown that Group III (DNG 1 mg/day) and Group IV (DNG 2 mg/day) reduced the dysmenorrhea score more than Group V (reference drug).

Similarly, when the change in dysmenorrhea score at 8 weeks of administration was evaluated, the mean change in dysmenorrhea score for each group was -1.3 for Group I (placebo), -2.5 for Group II (DNG 0.5 mg/day), -3.0 for Group III (DNG 1 mg/day), -3.3 for Group IV (DNG 2 mg/day), and -2.3 for Group V (reference drug). Statistical differences in the change in dysmenorrhea score were observed between Group II (DNG 0.5 mg/day), Group III (DNG 1 mg/day), and Group IV (DNG 2 mg/day) and Group I (placebo).

(1-4) Evaluation of the rate of complete disappearance of dysmenorrhea score Subjects whose dysmenorrhea score became 0 at 12 weeks after administration (or at the time of discontinuation of administration) were defined as "cases with complete disappearance of dysmenorrhea score," and the rate was evaluated.
The results are shown in Figure 1. The complete eradication rate at 12 weeks of administration was 4.3% (2/46 cases) in Group I (placebo), 26.1% (12/46 cases) in Group II (DNG 0.5 mg/day), 55.3% (26/47 cases) in Group III (DNG 1 mg/day), 59.2% (29/49 cases) in Group IV (DNG 2 mg/day), and 21.3% (10/47 cases) in Group V (reference drug). Statistical analysis using two-sided 95% confidence intervals revealed no clear difference in the complete eradication rate of Group V (reference drug) compared to Group I (placebo). Furthermore, the complete eradication rates of Group III (DNG 1 mg/day) and Group IV (DNG 2 mg/day) were both higher than those of Group V (reference drug), demonstrating a statistically significant difference. Administration of 1 mg/day to 2 mg/day of dienogest has been shown to have superior efficacy for functional dysmenorrhea compared to Yaz®, a reference drug indicated for dysmenorrhea.

(1-5) Evaluation of the rate of complete disappearance of dysmenorrhea score in severe cases According to the selection criteria for subjects in this study, the dysmenorrhea score of the subjects who participated in the study before administration of the investigational drug was 3 to 6 points. Subjects with a dysmenorrhea score of 5 or 6 points before administration were considered to have severe cases of functional dysmenorrhea, and the rate of complete disappearance of dysmenorrhea score at 12 weeks after administration (or at the time of discontinuation of administration) in severe cases in each of groups I to V was evaluated.
The results are shown in Table 3 and FIG.

In severe cases with a dysmenorrhea score of 5 or 6 before administration, the complete disappearance rate of dysmenorrhea score at 12 weeks of administration was 60.0% in Group III (DNG 1 mg/day) and 59.1% in Group IV (DNG 2 mg/day), which were significantly higher than the 19.0% in Group V (reference drug) (chi-square test). Thus, it was found that administration of dienogest 1 mg/day or 2 mg/day has excellent effects even on severe cases of functional dysmenorrhea.
Considering that patients with a dysmenorrhea score of 5 or 6 before administration were patients with at least moderate or higher pain levels, it was suggested that the administration of dienogest would have a high therapeutic effect on patients with moderate or severe pain associated with dysmenorrhea. It was also suggested that dienogest would have a high therapeutic effect on patients with moderate or severe pain associated with dysmenorrhea who require the use of analgesics during pain.

(1-6) Effect on serum estradiol concentration In each group, the mean estradiol concentration (pg/mL) of the subjects during the administration period was determined to evaluate the effect of the investigational drug on the serum estradiol concentration of the subjects.
The average values of the serum estradiol concentrations adopted as data at 4 weeks, 8 weeks, 12 weeks after administration and at the time of discontinuation of administration were calculated for each subject, and this was used as the mean serum estradiol concentration.
In each of groups I to V, the mean, standard deviation, and median of the subjects' mean serum estradiol concentrations were determined.
The results are shown in Figure 3.

The mean serum estradiol concentrations (mean ± standard deviation (median)) (pg/mL) during the study drug administration period were 77.0 ± 35.5 (71.8) in Group I (placebo), 121.2 ± 112.1 (87.7) in Group II (DNG 0.5 mg/day), 87.5 ± 70.2 (69.3) in Group III (DNG 1 mg/day), 63.3 ± 86.3 (31.0) in Group IV (DNG 2 mg/day), and 42.8 ± 47.7 (29.7) in Group V (reference drug). The median mean serum estradiol concentrations in Groups II (DNG 0.5 mg/day) and III (DNG 1 mg/day) were similar to those in Group I (placebo), but were lower in Groups IV (DNG 2 mg/day) and V (reference drug).
In addition, the mean serum estradiol concentration in Group V (reference drug) during the administration period of the investigational drug was lower than that in Group I (placebo), and the difference was confirmed by statistical analysis using a two-sided 95% confidence interval.

Measurement of patients' serum estradiol levels before administration of the investigational drug was typically performed approximately seven days before the expected start of menstruation at the time of administration initiation (luteal phase). There are various opinions on the standard value of serum estradiol levels during the luteal phase, but it is generally said to be around 45 to 300 pg/ml.
Of the 47 subjects assigned to Group III (DNG 1 mg/day), 18 patients with pre-treatment serum estradiol levels of 100 pg/mL or less were evaluated for mean serum estradiol concentrations during the treatment period. The mean serum estradiol concentration (mean ± standard deviation (median)) (pg/mL) during the DNG 1 mg/day treatment period was 101.3 ± 85.2 (80.5). These values were considered comparable to the mean serum estradiol concentration in Group I (placebo) shown above. A similar trend was observed when the patient group was expanded to include patients with serum estradiol levels of 150 pg/mL or less (34 patients) (mean ± standard deviation (median)).

The results of (1-2) to (1-6) showed that when dienogest was administered at 1 mg/day twice daily, the subjects' serum estradiol concentrations remained at the same level compared to placebo administration, demonstrating excellent efficacy for treating functional dysmenorrhea. Furthermore, even in patients with relatively low serum estradiol levels before administration (for example, serum estradiol levels of 150 pg/mL or less approximately 7 days before the expected start of menstruation), serum estradiol concentrations were similar to those in the placebo-administered group, and serum estradiol concentrations were not excessively suppressed, demonstrating the efficacy of applying dienogest to these patient groups.

(1-7) Effect on Ovulation Suppression In order to examine the ovulation suppression effect of the composition of the present invention, the serum progesterone concentration of the subjects was measured 7 days before the expected start date of the next menstruation (luteal phase) after the start of administration, and the average value for each group was obtained.
As a result, the mean serum progesterone concentrations (ng/mL) in each group were 8.40 in group I (placebo), 2.72 in group II (DNG 0.5 mg/day), 0.91 in group III (DNG 1 mg/mL), 0.66 in group IV (DNG 2 mg/mL), and 0.87 in group V (reference drug).
When ovulation occurs, serum progesterone levels rise during the luteal phase, usually to around 8.5ng/mL to 21.9ng/mL. The mean serum progesterone levels in each dienogest administration group (Groups II to IV) and Group V (reference drug) were low, suggesting that ovulation was suppressed.

Claims (10)

A composition for treating dysmenorrhea in patients with functional dysmenorrhea with a dysmenorrhea score of 5 or more, containing dienogest as an active ingredient, characterized in that dienogest is orally administered at a dose of 1 mg per day in two divided doses, with a constant dose of dienogest administered during the administration period without periodic fluctuations in the dose. The composition of claim 1, containing dienogest as the only active ingredient. The composition described in claim 1 or 2, which is administered daily for a period of 8 consecutive weeks or more. The composition described in any one of claims 1 to 3, characterized in that it does not significantly reduce serum estradiol levels during administration compared to levels before administration. The composition described in any one of claims 1 to 4, wherein the patient is a patient for whom it is desirable to prevent a significant decrease in serum estradiol concentration during the administration period. A composition for treating dysmenorrhea for patients with functional dysmenorrhea who experience moderate or severe pain caused by the condition and require the use of analgesics during the pain, the composition containing dienogest as an active ingredient, wherein dienogest is administered orally at a dose of 1 mg per day in two divided doses, and wherein a constant dose of dienogest is administered during the administration period without any periodic fluctuations in the dose. The composition described in claim 6, containing dienogest as the only active ingredient. The composition described in claim 6 or 7, which is administered daily for a period of 8 consecutive weeks or more. The composition described in any one of claims 6 to 8, characterized in that it does not significantly reduce serum estradiol levels during administration compared to levels before administration. The composition described in any one of claims 6 to 9, wherein the patient is a patient for whom it is desirable to prevent a significant decrease in serum estradiol concentration during the administration period.