JP2018083806A - Dysmenorrhea therapeutic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a dysmenorrhea therapeutic agent that has high effect without significantly reducing serum estradiol concentration of a patient.SOLUTION: A dysmenorrhea therapeutic composition contains dienogest as an active ingredient. Preferably, the daily dose of the composition is 1 mg in total, which is orally administered twice a day.SELECTED DRAWING: None

Description

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

Dysmenorrhea is a morbidity that accompanies menstruation during menstrual periods, and is in the order of lower abdominal pain, lower back pain, abdominal bloating, nausea, headache, fatigue / weakness, loss of appetite, irritability, diarrhea and depression (Non-Patent Document 1).
Dysmenorrhea occurs when there is an organic lesion such as endometriosis or adenomyosis (organic dysmenorrhea) and when there is no organic lesion that causes pain in the pelvis (function) Dysmenorrhea).
According to the actual survey of dysmenorrhea conducted in the 2000 welfare science research, 33% of women aged 20 to 49 years had dysmenorrhea. Functional dysmenorrhea accounted for the largest number, accounting for about half of the total at 47.0%. As an organic abnormality, endometriosis was the most common at 26.7%, followed by 17.73% of those diagnosed as uterine fibroids (Non-patent Document 2).

Functional dysmenorrhea without organic disease is strong when there is a lot of bleeding on the first and second days of menstruation, and the nature of the pain is convulsive and periodic, narrowing of the cervix and prostaglandins (PG) It is said to be caused by excessive contraction of the uterus by endogenous physiologically active substances such as
On the other hand, organic dysmenorrhea is often sustained dull pain that lasts from 4 to 5 days before menstruation to after menstruation. However, the mechanism of menstrual pain generation is the same regardless of whether it is functional or organic, and it is said that the uterine smooth muscle undergoes excessive contraction in order to discharge menstrual blood accumulated in the uterine cavity (Non-patent Document 3). ).

  For the treatment of functional dysmenorrhea, analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit PG production and low-dose estrogen / progestin combination drugs (hereinafter also referred to as “LEP preparations” in this specification) ) Is the first choice (Non-Patent Document 1).

The LEP preparation contains estrogen and progestin, but the main hormone effective for dysmenorrhea is considered to be progestin, and estrogen is necessary for the expression and maintenance of the progesterone receptor. Even a low dose of progestin is sufficient It has been described to play an auxiliary role to exert progesterone action. Progestin suppresses endometrial proliferation by its progesterone activity, thins the intima, and further suppresses the expression of cyclooxygenase (COX), thereby suppressing PG production in the menstrual phase (Non-patent Document 2). .
LEP preparations have thrombosis as a serious side effect, and it is known that the risk of thrombosis is high in smoking cases and obesity cases.
In Japan, as LEP preparations currently covered by insurance for dysmenorrhea, for example, drospirenone / ethynylestradiol tablets (product name: Yaz (registered trademark) combination tablets) or norethisterone / ethynylestradiol tablets (product name: Lunabel ( (Registered trademark) combination tablets LD and ULD) are used (Non-patent Document 2).

The pharmacological pharmacology of the package insert of YARZ (registered trademark) includes: “This drug suppresses uterine contractile movement by suppressing overproduction of PGs, etc. by suppressing ovulation and inhibiting endometrial proliferation. It is thought to reduce symptoms such as pain of dysmenorrhea ”(Non-patent Document 4). The same contents are also described in the package inserts of Lunabel (registered trademark) combination tablets LD and ULD (Non-patent Document 5).
The interview form of YARZ (registered trademark) combination tablets discloses the serum estradiol concentration in the follicular phase of the baseline and the fourth cycle as “ovulation inhibitory effect using serum estradiol concentration as an index”. The serum estradiol concentration in the 4th cycle is decreased, and the number of patients exceeding 30 pg / mL, which is considered to be a threshold indicating suppression of follicular maturation, is 32 out of 32 patients with functional dysmenorrhea and 19 patients with organic dysmenorrhea It is shown that only an example was recognized (nonpatent literature 6).
On the other hand, it is known that excessive reduction in serum estradiol concentration may cause side effects such as emotional instability, dizziness, abnormal lipid metabolism, and bone density.

  In the interview form of Lunabel (registered trademark) combination tablets LD and ULD, the transition of serum estradiol concentration is disclosed as “ovulation-inhibiting action”. In LD, the concentration of serum estradiol in the administration cycle is decreased and there is no change during the administration period, but in ULD, it is slightly higher than in LD (Non-patent Document 7).

  Levonorgestrel-releasing intrauterine system (product name: Milena (registered trademark) 52 mg), which is a kind of progestin preparation, has the effect of dysmenorrhea. In this drug, levonorgestrel released in the uterus for a long time causes the endometrium to contract, so pregnancy during application of this system is highly suppressed. Furthermore, since the amount of menstruation is reduced due to atrophy of the intima, an effect of alleviating excessive menstruation and menstrual pain is recognized. The action is local to the endometrium and has no systemic side effects, does not inhibit ovulation, does not cause a low estrogen state, and remains effective for 5 years with a single insertion. It is useful for cases and cases with low internal compliance (Non-patent Document 8).

  In addition, there is a study that didrogesterone exhibiting luteinizing hormone action was effective against functional dysmenorrhea without suppressing ovulation. In these two studies, didrogesterone is administered from the 5th day to the 25th day of the menstrual cycle (Non-Patent Documents 9 and 10).

It is known that dienogest exerts a therapeutic effect on dysmenorrhea in patients with endometriosis which is typical as a causative disease of organic dysmenorrhea (Non-Patent Documents 8 and 11).
Concerning endometriosis, an overview of the application data for dienogest tablets 1 mg, in the late phase II study for endometriosis, each dose of dienogest (1 mg / day, 2 mg / day, 4 mg / day) The mean value (median) of serum estradiol concentration from the 8th week to the end of the administration (24 weeks) at the time of multiple administration was 84.5 pg in the 1 mg / day group, 2 mg / day group, and 4 mg / day group, respectively. / ML (72.5 pg / mL), 37.4 pg / mL (29.9 pg / mL), 26.2 pg / mL (21.1 pg / mL), and it was disclosed that a dose-response relationship was observed. (Non-patent Document 12).
Dienogest is marketed in Japan as “Dinagest (registered trademark) 1 mg” with the indication of “endometriosis”. The dosage and administration are “normally administered to adults as a dienogest, 2 mg per day in two divided doses and orally administered from the 2nd to 5th day of the menstrual cycle”.
According to the package insert, the mechanism of action against endometriosis is as follows: `` This drug exhibits a selective agonistic action on the progesterone receptor and is effective against endometriosis by suppressing ovarian function and growth of endometrial cells. It is thought that it shows the property "(non-patent document 13).

With regard to the ovulation-inhibiting effect of dienogest, for the purpose of determining the minimum dose of dienogest for ovulation suppression, 33 healthy women without organic diseases such as endometriosis were treated with dienogest (0.5 mg / day, 1 mg / day, 1.5 mg / day, 2.0 mg / day) was administered once a day for 21 days. Dienogest 0.5 mg / day suppressed ovulation in 2/3 of the subjects, and 1-2 mg / day. It is said that ovulation was suppressed in all subjects. In this test, there were 4 cases of dysmenorrhea during the control period (before administration), but it was disclosed that the occurrence of dysmenorrhea became zero during the treatment period (Non-Patent Document 14).
In another study, in order to examine the effect of dienogest on ovulation inhibition, each of 102 healthy women was given each dose of dienogest (0.5 mg / day, 1 mg / day, 2 mg / day, 3 mg / day) once a day for 72 days. When administered, women who had ovulated during the administration period were 3 cases in 21 cases in the 0.5 mg / day group, 1 case in 23 cases in the 1 mg / day group, 0 cases in 20 cases in the 2 mg / day group, In the 3 mg / day group, it was assumed that there were 0 cases out of 23 cases. In addition, the maximum serum estradiol concentration was similar to the value before administration in the 0.5 mg / day group and the 1 mg / day group, and decreased gently in the 2 mg / day group and the 3 mg / day group. Has been disclosed to decrease at all doses (Non-patent Document 15). However, there was no mention of dysmenorrhea.

About applying dienogest to functional dysmenorrhea, a randomized, double-blind study targeting patients with functional dysmenorrhea in the clinical trial information web page of the Japan Pharmaceutical Information Center A study to investigate the efficacy and safety of dienogest at 2, 1, and 0.5 mg / day in a comparison between groups between August 3, 2015 and November 30, 2016 Is disclosed (Non-Patent Document 16), but the result is unknown.
Moreover, it is disclosed that the combination drug of estradiol valerate and dienogest was effective against functional dysmenorrhea, similar to the combination drug of ethinyl estradiol and levonorgestrel. The preparations used here were estradiol valerate 3 mg for 2 days, estradiol valerate 2 mg and dienogest 2 mg for 5 days, estradiol valerate 2 mg and dienogest 3 mg for 17 days, estradiol valerate 1 mg 2 mg It is a preparation that is repeatedly taken with 28 days of 1 day, 2 days of placebo, and 1 cycle (Non-patent Document 17).

  Patent application relating to the treatment of dysmenorrhea with the first composition administered on the first 21-28 days in a therapeutic formulation such as dysmenorrhea for continuous hormone treatment including estrogen and / or progestin Although it has been proposed to increase the pharmaceutical dose of the second composition administered in a subsequent period rather than the pharmaceutical dose, no specific data is disclosed (Patent Document 1).

  As mentioned above, the therapeutic effect of dysmenorrhea in patients with endometriosis has been known for dienogest alone, but no trials targeting dysmenorrhea have ever been attempted. It was.

Special table 2007-512291

Obstetrics and Gynecology Practice Guidelines-Department of Gynecology Outpatient 2014-Japan Obstetrics and Gynecology Society, Japan Obstetrics and Gynecology Association, pages 113-114 Pharma Medica Vol.32 No.6 (2014), pp.45-48 Obstetrics and gynecology 2011 No.11 pages 1315-1319 YAZ® (registered trademark) combination tablet package insert Revised May 2016 (7th edition) Lunabell (registered trademark) combination tablet package insert Revised October 2016 (13th edition) YAZ® Combination Tablet Interview Form Revised September 2016 (Revised 9th Edition), page 18 Lunabell (registered trademark) Combination Tablet Interview Form Revised June 2016 (14th Edition), p. 14 Obstetrics and gynecology 2013 No. 8 pages 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 application for dienogest application Phase II study, 792-860 pages Dinagest Tablets 1mg package insert Revised 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, for functional dysmenorrhea, pharmacotherapy with analgesics (such as NSAIDs) and low-dose estrogen / progestin combination drugs (LEP preparation) has been the first choice. However, there are cases where these drugs do not provide the effect of treating dysmenorrhea including sufficient pain relief. In addition, there are concerns about side effects such as gastrointestinal symptoms for analgesics and thrombosis for LEP preparations, and some patients may not be able to administer these drugs.
Levonorgestrel-releasing intrauterine system, a type of progestin formulation, can also be used for dysmenorrhea, but it is a formulation that continues to be worn in the uterus and needs to be attached and detached by a doctor, so it cannot be easily interrupted or rescheduled There is a demerit. Didrogesterone, which exhibits luteinizing hormone action, does not suppress ovulation, and thus may have a weaker effect on dysmenorrhea than a preparation that suppresses ovulation.
In severe cases of dysmenorrhea, extremely intense lower abdominal pain, low back pain, etc. continue for 2 days or 3 days or more, and the analgesic is often continued during that period. In particular, when the pain is severe or when the analgesic cannot be administered, the patient may fall asleep for more than one day. Such a severe case of dysmenorrhea is a very serious problem for patients because it causes troubles in daily life as well as work and school.

The problem of the present invention is that it is highly effective compared with the LEP preparation which is a standard for the treatment of dysmenorrhea as a hormonal preparation, has a low risk of serious side effects such as thrombosis, is easy to administer, and is administered daily. It is to provide a drug for treating dysmenorrhea. In particular, by providing a therapeutic agent with a high improvement effect for patients with moderate or severe pain associated with dysmenorrhea and for patients with functional dysmenorrhea without organic diseases. is there.
Another object of the present invention is to provide a highly effective dysmenorrhea drug that does not significantly affect the serum estradiol concentration of a patient and reduces the burden on the body. That is, some patients may experience symptoms such as bone loss, climacteric symptoms such as hot flashes, insomnia, depressed mood, and depression as serum estradiol levels decrease. It is desirable not to lower it.
It is another object of the present invention to provide a therapeutic agent that is a first option for patients who do not want to significantly reduce serum estradiol concentration during the administration period.

  The present inventors examined the possibility of dienogest as a therapeutic agent for dysmenorrhea and conducted a clinical trial targeting functional dysmenorrhea patients. As a result, it was found that dienogest exhibits excellent efficacy even when compared with an LEP preparation (product name: YARZ (registered trademark)) having the effect of dysmenorrhea. That is, when the dysmenorrhea score change amount at the 8th week of administration was evaluated, the daily administration of dienogest 0.5 mg / day, 1 mg / day, or 2 mg / day for 8 weeks was more statistically compared to the placebo administration. The difference was found to have reduced the dysmenorrhea score. In the evaluation of the change in dysmenorrhea score at 12 weeks of administration, dienogest 1 mg / day or 2 mg / day, for 12 weeks, had a statistical difference even when compared with Yards® administration. It was found that the dysfunction score was lowered.

In the evaluation of the complete disappearance rate of dysmenorrhea score at 12 weeks after administration, there was no clear difference in the complete disappearance rate of Yards (registered trademark) administration compared to placebo, but dienogest 1 mg / day or 2 mg / day The complete disappearance rate of the administration was higher than that of Yards (registered trademark) administration, and a statistical difference was observed.
Moreover, if 1 mg of dienogest is administered in 2 divided doses, the therapeutic effect of functional dysmenorrhea comparable to that of 2 mg of dienogest administered per day without significantly affecting the serum estradiol concentration of the patient. It was suggested that
Moreover, even in the aggregation in functional dysmenorrhea patients whose serum estradiol concentration in the luteal phase before administration of the composition of the present invention is relatively low (for example, 150 pg / mL or less), the mean serum during the administration of dienogest 1 mg / day The mean and median estradiol concentrations were approximately the same as compared to placebo administration, 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 with dysmenorrhea containing dienogest as an active ingredient.
[2] The composition according to [1] above, containing dienogest as the only active ingredient.
[3] The composition according to [1] or [2] above, wherein the composition is administered every day continuously for a period of 8 weeks or more.
[4] The composition according to any one of [1] to [3] above, wherein the dienogest is orally administered in 1 mg twice daily.
[5] The composition according to any one of [1] to [4] above, wherein a constant dose of dienogest is administered during the administration period without cyclic fluctuation of the administration dose.
[6] The composition according to any one of [1] to [5] above, wherein the serum estradiol concentration during the administration period is not significantly reduced as compared to before administration.
[7] The composition according to any one of [1] to [6], wherein the patient is preferably a patient who does not significantly reduce serum estradiol concentration during the administration period.
[8] The composition according to any one of [1] to [7], wherein the patient is a patient who does not suffer from endometriosis, uterine fibroids, or uterine adenomyosis.
[9] The composition according to any one of [1] to [8], wherein the patient is a patient whose serum estradiol concentration in the luteal phase before administration of the composition is 150 pg / mL or less.
[10] The above-mentioned [1] to [9], wherein the patient has a moderate or severe degree of severe pain (lower abdominal pain / back pain) considered to be caused by dysmenorrhea before administration of the composition A composition according to any one of the above.
[11] The patient is a patient with moderate or severe severe pain (lower abdominal pain or low back pain) considered to be caused by dysmenorrhea before administration of the composition, and the use of an analgesic during the pain The composition according to any one of [1] to [10], wherein the composition is a patient in need.
[12] The composition according to any one of [1] to [11], 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], wherein the dysmenorrhea is functional dysmenorrhea.

ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the treatment option with respect to the functional dysmenorrhea in which sufficient pain relief cannot be obtained with an analgesic or a LEP formulation. Dienogest can be administered orally and can be conveniently administered, and has a lower risk of serious side effects such as thrombosis than LEP preparations.
LEP preparations generally have a drug holiday (or placebo administration period), and symptoms of dysmenorrhea may occur during the drug holiday, but dienogest is administered daily without a drug holiday, There is no such worry. In addition, there are concerns about gastrointestinal symptoms, edema, systemic blood flow disorder, renal disorder, etc., if painkillers are taken too much, but dienogest has a relatively low risk.
In addition, according to the present invention, there is a possibility of exerting a high therapeutic effect on patients with moderate or severe pain associated with dysmenorrhea and patients who require the use of analgesics during the pain. is there. Further, it is effective for patients having a dysmenorrhea score of 3 points or more before administration of the composition, particularly 5 or 6 points.
When dienogest is administered 1 mg in two divided doses, the burden on the body is reduced without affecting the patient's serum estradiol concentration, bone loss, climacteric symptoms such as hot flashes, insomnia It has the advantage that side effects such as depression, symptoms such as depression are less likely to occur.

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

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

Dienogest, which is an active ingredient of the composition of the present invention, has the effects and effects of endometriosis in Japan under the product names “Dinagest Tablets (registered trademark) 1 mg” and “Dinagest (registered trademark) OD Tablets 1 mg”. Sold.
The disease to be treated according to the present invention is dysmenorrhea, particularly functional dysmenorrhea.
In the present specification, the composition for treating dysmenorrhea according to the present invention containing dienogest as an active ingredient may be referred to as “the composition of the present invention”.

2. Dysmenorrhea, functional dysmenorrhea Dysmenorrhea refers to a pathological condition that accompanies menstruation during the menstrual period. Lower abdominal pain, lower back pain, abdominal bloating, nausea, headache, fatigue / weakness, loss of appetite, irritability, diarrhea and depression are common. When symptoms are severe, pain such as lower abdominal pain and back pain lasts for more than 2 days or even 3 days or more and sometimes falls asleep, which may interfere with daily life as well as work and school.
Dysmenorrhea is classified into functional dysmenorrhea and organic dysmenorrhea.
Functional dysmenorrhea (also called primary dysmenorrhea) is dysmenorrhea that does not have an organic lesion that causes pain in the pelvis. Most women who have not experienced childbirth in the late 10s and early 20s, starting in the second to third years after menarche. It is strong when there is a lot of bleeding on the first day and the second day of menstruation, and the nature of the pain is convulsive and periodic. The main cause is the excessive contraction of uterine smooth muscle caused by prostaglandins derived from endometrium due to the decrease in blood progesterone concentration in the late luteal phase, and the accompanying ischemia, hypoxia and peripheral nerve stimulation. It is considered.
On the other hand, organic dysmenorrhea (also called secondary dysmenorrhea) is caused by organic lesions such as endometriosis, uterine fibroids, uterine adenomyosis, narrowing of the cervix, or closure of the menstrual outflow tract due to abnormal Mueller Dysmenorrhea. It is often said that persistent dull pain that lasts from 4-5 days before menstruation to after menstruation.

3. Target Patient The disease targeted by the present invention is dysmenorrhea, and the patient to be treated is a patient with dysmenorrhea.
In one aspect of the present invention, the target disease of the present invention is functional dysmenorrhea, and the target patient is a patient with functional dysmenorrhea.

In another aspect of the present invention, the patient targeted by the present invention is preferably a patient for whom it is desirable not to significantly reduce the serum estradiol concentration during the administration period. That is, it is desirable for the serum estradiol concentration during the period of administration of the therapeutic agent to be not significantly lower than the serum estradiol concentration before the start of administration.
In the examples of the present specification, the mean and median serum estradiol concentrations during the administration period of the dienogest 1 mg / day administration group were almost the same as those of the placebo administration group. It is expected that the serum estradiol concentration before administration of the subject will not be significantly reduced. Therefore, it is desirable that the daily dose of dienogest be 1 mg or less for such “patients who do not want to significantly reduce the serum estradiol concentration during the administration period”. More preferably, it is desirable to administer a daily dose of 1 mg of dienogest in two divided doses per day.

  Here, as one of the aspects of “a patient in whom it is desirable not to significantly reduce the serum estradiol concentration during the administration period”, the patient suffers from endometriosis, uterine fibroid, or uterine adenomyosis. There are no patients. These diseases are known to be affected by estrogen. For example, in the case of endometriosis, it is considered that it is therapeutically desirable to maintain a blood estrogen concentration of 30 to 50 pg / mL (Cera (Putic window hypothesis) also exists.

  Another aspect of “a patient in whom it is desirable not to significantly reduce the serum estradiol concentration during the administration period” is a patient having a relatively low serum estradiol concentration, specifically, administration of the composition of the present invention. Patients with a serum estradiol concentration (preferably an average or median of multiple measurements) in the previous luteal phase of 150 pg / mL or less. More preferably, it is a patient whose serum estradiol concentration in the luteal phase before administration of the composition is 120 pg / mL or less, more preferably 100 pg / mL or less. In the present invention, the “luteal phase” refers to a period from the ovulation period to menstruation. More preferably, it is a period of 10 days to 5 days before the scheduled start date of menstruation, and more preferably a period of 8 days to 6 days before the scheduled start date of menstruation.

“Estradiol” is a type of estrogen that is a follicular hormone. Estrogens play various roles such as endometrial proliferation, hypertrophy of myometrium, mammary gland development, and bone growth. In particular, estradiol has a high physiological activity and plays the largest role among estrogens.
Serum estradiol concentration usually varies with cycles such as follicular phase, ovulation phase, luteal phase. Although there are various theories regarding the standard value of serum estradiol concentration in the luteal phase in women, it is generally said to be 45 to 300 pg / ml. If the serum estradiol concentration prior to administration is relatively low, further reduction of the estradiol concentration by drug administration increases the risk of side effects associated with low serum estradiol levels, so it is desirable to avoid excessive reduction of the serum estradiol concentration.
Lowering serum estradiol levels may cause side effects such as menopause-like symptoms such as hot flashes, sweating, and fatigue, ovarian dysfunction, and bone loss, which is necessary in relation to disease treatment. For example, it is preferable to maintain the serum estradiol concentration before administration.

  Serum estradiol concentration decreases due to ovarian hypofunction etc., and even if there is no special disease, if exposed to excessive stress and hormonal balance is disturbed, serum due to aging such as undernutrition, menopause Estradiol levels tend to be low, but in that case it is desirable to avoid further lowering serum estradiol levels by treating dysmenorrhea. The same applies to patients with low bone density, such as patients suffering from osteoporosis.

Such patients are particularly difficult to apply LEP formulations that tend to lower serum estradiol levels.
On the other hand, it has been suggested that the composition for treating dysmenorrhea containing the dienogest of the present invention as an active ingredient does not significantly reduce the serum estradiol concentration during the administration period. It is a pharmaceutical composition that can be administered as a first option for “patients who do not want to significantly reduce the concentration”.

  In the present invention, as one of the other aspects of “a patient in whom it is desirable not to significantly reduce the serum estradiol concentration during the administration period”, hormonal balance disturbance due to stress, aging, etc., or ovarian hypofunction etc. Patients with low serum density of estradiol, or patients with low bone density such as patients suffering from osteoporosis.

  In another preferred embodiment of the present invention, the subject patient of the present invention is a patient with lipid metabolism abnormality. Estrogens (including estradiol) affect lipid metabolism in women, and it is known that lipid metabolism fluctuates due to estrogen deficiency. Therefore, patients with dyslipidemia (eg, hypertriglyceridemia) should avoid excessive reductions in serum estradiol levels. In the clinical trials described in the examples of the present specification, compared to placebo administration, administration of dienogest did not affect blood triglycerides, so the composition of the present invention may not exacerbate abnormal lipid metabolism. I can expect.

  In another preferred embodiment of the present invention, the patient targeted by the present invention is a patient with dysmenorrhea having a dysmenorrhea score (described later in 4 below) of 3 or more before administration of the composition. In the examples of the present specification, in the test for functional dysmenorrhea patients having a dysmenorrhea score of 3 or more before administration of the composition, the dienogest 1 mg / day group and the 2 mg / day group are dysmenorrhea. In the evaluation of the amount of change in score and the complete disappearance rate of dysmenorrhea score, it was shown that a high therapeutic effect was exhibited with a statistical difference compared to the reference drug administration group. Thus, it was shown that dienogest exerts a high therapeutic effect on patients with functional dysmenorrhea having a dysmenorrhea score of 3 or more before administration of the composition. This suggests that it has an excellent therapeutic effect on dysmenorrhea with a symptom score of 3 or more.

  In another preferred embodiment of the present invention, the subject patient of the present invention is a patient with dysmenorrhea having a dysmenorrhea score of 5 or 6 before administration of the composition. In the examples of the present invention, administration of dienogest 1 mg / day or 2 mg / day administered daily in patients with functional dysmenorrhea with severe cases of dysmenorrhea score of 5 or 6 before administration of the composition The complete disappearance rates of dysmenorrhea score at 12 weeks were 60.0% and 59.1%, respectively, which were significantly higher than those of 19.0% administered Yars (registered trademark). Thus, it was shown that dienogest exerts a high therapeutic effect on patients with functional dysmenorrhea in severe cases having a dysmenorrhea score of 5 or 6 before administration of the composition. It was suggested that the dysmenorrhea score before administration of the substance exerts an excellent therapeutic effect on dysmenorrhea in severe cases with 5 or 6 points.

In another preferred embodiment of the present invention, the subject of the present invention has a moderate or severe degree of pain (lower abdominal pain / back pain) considered to be caused by dysmenorrhea before administration of the composition or Patients who are severe or who have moderate or severe pain associated with dysmenorrhea and who require the use of analgesics during the pain.
As for “pain” and “degree of pain” in these embodiments, the description in the dysmenorrhea score shown in Example 1 (Table 1) can be referred to. In other words, “moderate” pain means that the more you lie down and you want to take a break, the more difficult it is to work (study / housework).・ Does not do housework. Further, the “analgesic agent” here refers to a drug taken for the purpose of pain relief, and is not particularly limited, and examples thereof include NSAIDs such as aspirin, acetaminophen, ibuprofen, diclofenac sodium, and loxoprofen sodium.
In the examples of the present specification, the composition of the present invention exerted an excellent therapeutic effect on patients having a dysmenorrhea score of 5 or 6 before administration of the composition. The degree is moderate or higher. This suggests that the degree of pain associated with dysmenorrhea exhibits a high therapeutic effect for patients with moderate or severe pain. It was also suggested that the degree of pain associated with dysmenorrhea is moderate or severe, and that it exhibits a high therapeutic effect even for patients who require the use of analgesics during the pain.

  In another preferred embodiment of the present invention, the subject patient of the present invention is a patient with dysmenorrhea who has not been successfully treated with the LEP preparation (low dose estrogen / progestin combination drug). As described above, dienogest has a higher therapeutic effect on functional dysmenorrhea than YEP® (registered trademark) of LEP preparations, and therefore, patients who have not been able to obtain sufficient therapeutic effects with LEP preparations. Are also expected to exert therapeutic effects. In the present invention, “LEP preparation” means a medicine containing low doses of follicular hormone-like substance and lutein hormone-like substance, and is not particularly limited. For example, drospirenone ethinylestradiol tablets (product name: YARZ (registered trademark)) Combination tablets) or norethisterone / ethynylestradiol tablets (product name: Lunabell (registered trademark) combination tablets LD and ULD).

  In another preferred embodiment of the present invention, the subject patient of the present invention is a patient at risk for thrombosis. Patients at risk for thrombosis include, for example, patients suffering from thrombotic diseases such as thrombophlebitis, pulmonary embolism, cerebrovascular disorders, coronary artery disease, patients with a history of thrombosis, smoking over 35 years old And diabetic patients with vascular lesions, patients with a predisposition to thrombosis, patients with hypertension, patients with abnormal blood coagulation system test items, and the like. Test items of the blood coagulation system include, for example, prothrombin time (PT), activated partial thromboplastin time (APTT), protein S activity, D-dimer, antithrombin III, tissue plasminogen activator (tPA) and the like. However, it is not limited to these. In the clinical trials described in the examples of the present specification, in the dienogest administration group, the test value abnormality of the test item of the blood coagulation system was small, so the composition of the present invention does not further exacerbate the patient's risk of thrombosis. I can expect that.

4). Evaluation method used in the present invention <Dysmenorrhea score>
As one of the indices for evaluating dysmenorrhea, the “dysmenorrhea score” is known (Obstetrics and Gynecology No. 9, 2008, pages 1165-1181). The “dysmenorrhea score” is a numerical value of the severity of dysmenorrhea, and more specifically, the degree of pain (lower abdominal pain / back pain) that is considered to be caused by dysmenorrhea, and It is a numerical value obtained by scoring the usage status of the analgesic at the time of the pain in 4 stages of 0 to 3 points, respectively, and adding them up. Higher numbers indicate more severe dysmenorrhea, with 6 points being the most severe. Specific evaluation criteria are, for example, as shown in Table 1 of Example 1 of the present specification. Here, the numerical range indicated using “to” in this specification indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.

<Dysmenorrhea score change>
In the present invention, the “dysmenorrhea score change amount” is a numerical value obtained by subtracting the dysmenorrhea score before medication from the dysmenorrhea score after a certain medication period. If the dysmenorrhea score change is positive, it indicates that the symptoms of dysmenorrhea have worsened during a certain dosing period, and if it is negative, it causes dysmenorrhea during a certain dosing period. It means that the score decreased and the symptoms of dysmenorrhea were reduced or eliminated.

  In the examples of the present specification, administration of dienogest at 1 mg / day or 2 mg / day for 12 weeks can be performed by assigning a dysmenorrhea score of a functional dysmenorrhea patient to a placebo group or a reference drug (Yars®) group It was found that even if compared, it was reduced with a statistical difference and exhibited an excellent therapeutic effect on functional dysmenorrhea. When the composition of the present invention is administered every day for 12 weeks, the amount of change in the dysmenorrhea score before administration and at 12 weeks of administration is preferably −2 or less, and more preferably −3 or less.

<Disease rate of complete dysmenorrhea score>
Further, in the present invention, “complete disappearance of dysmenorrhea score” means that the dysmenorrhea score becomes 0 at the end of administration. The “complete dysmenorrhea score disappearance rate” refers to the proportion of subjects whose dysmenorrhea score is zero for a specific group of subjects.

<Measurement and comparison of serum estradiol concentration>
For measurement of serum estradiol, various commercially available measurement reagents and measurement kits can be used.
Further, in the present invention, when comparing the serum estradiol concentration of the subject before administration and during the administration period, it is desirable to use the average value or the median value of a plurality of measured values. In the embodiment of the present invention, the median value is used for display and evaluation in order to avoid the influence of the jump value.

5. Composition of the Invention The composition of the present invention contains dienogest as an active ingredient, but may contain other pharmaceutically acceptable additives as long as the effects of the present invention are not inhibited.
Examples of additives include bases, carriers, solvents, diluents, solubilizers, dispersants, emulsifiers, buffers, isotonic agents, stabilizers, excipients, binders, disintegrants, lubricants. , Thickeners, humectants, colorants, fragrances, chelating agents, and the like, but are not limited thereto.
When the composition of the present invention contains an additive, the composition of the present invention can be produced by using the additive in accordance with a conventional method according to the dosage form.

The composition of the present invention should be safely administered orally or parenterally (eg, intravenously, intramuscularly, subcutaneously, intradermally, intravaginally, directly to the lesion, etc.). Can do. In this case, oral administration is convenient and desirable.
The composition of the present invention can be used in any dosage form, such as tablets, orally disintegrating tablets, capsules, films, pills, powders, powders, granules, solutions, injections, suspensions, emulsions, and the like. There can be, but is not limited to. Preferably, it is a tablet or an orally disintegrating tablet.

  In addition, the dienogest which is the active ingredient of the present invention may be incorporated in the preparation as an adduct with other compounds such as a solvate, or may be added as a prodrug in the preparation as necessary in the preparation. You may mix | blend.

When the composition of the present invention is orally administered, the daily dosage of dienogest is preferably 0.5 mg to 2 mg / day, more preferably 1 mg / day, for an adult female. In the case of oral administration, the preferred number of administrations per day is once a day or twice a day, and more preferably twice a day. When the daily dose is divided into two doses, the daily dose is preferably equally divided into two. For example, when dienogest 1 mg / day is administered twice a day, it is preferable to administer a single dose of 0.5 mg twice a day. In addition, it is preferable that the dienogest is administered at a certain time every day.
The dosing start time is preferably started from the 2nd to 5th day from the start of menstruation.

The dosing period of the composition of the present invention is not particularly limited, but is preferably administered for at least 8 weeks, more preferably for at least 12 weeks, without changing the dosage periodically. Desirably, a fixed dose of dienogest is administered. From the tests described in the examples of the present specification, it was found that the composition of the present invention exerts a sufficient therapeutic effect on functional dysmenorrhea when administered for about 8 weeks.
Moreover, there is no restriction | limiting in the dosing period of the composition of this invention, You may dose over several years. “Dinavist (registered trademark) 1 mg” is relatively safe because there is no restriction on the period of administration for the efficacy of endometriosis and it has been administered for several years.

  It is desirable to administer the composition of the present invention daily during the dosing 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 holiday, and dysmenorrhea pain may occur due to withdrawal bleeding from the uterus during the drug holiday, but the composition of the present invention is administered every day. There is no concern.

  The composition of the present invention can be used in combination with other drugs as long as the effects of the present invention are not impaired. Other drugs that can be used in combination are not particularly limited. For example, GnRH analogues (goserelin acetate, buserelin acetate, leuprorelin acetate, nafarelin acetate, etc.), testosterone derivatives (danazol etc.), lutein hormone-like substances and follicular hormone-like substances Hormonal agents (estradiol, conjugated estrogens, oral contraceptives, etc.), follicular hormone antagonists, aromatase inhibitors, analgesics (aspirin, acetaminophen, ibuprofen, diclofenac sodium, loxoprofena sodium, etc.) Etc.), anemia treatment agents (iron agents, etc.), hemostatic agents (tranexamic acid, carbazochrome sulfonic acid sodium hydrate, etc.), Chinese medicines (Kyu Kikyoto, etc.) and the like.

  In the present invention, the term “combination with other drugs” includes a mode in which a composition containing dienogest as an active ingredient and another drug are administered simultaneously, and a mode in which the composition is administered separately. When administered simultaneously, it can be a compounding agent or two agents. When administered separately, the composition containing dienogest as an active ingredient can be administered before or after other drugs.

In another embodiment of the present invention, the composition containing dienogest is a GnRH analog, a testosterone derivative, a hormonal agent based on a lutein hormone-like substance and / or an follicular hormone-like substance, an ovarian hormone antagonist, an aromatase inhibitor. An embodiment that is not combined administration with a drug selected from the group is also preferred.
In addition, an embodiment in which the composition of the present invention does not contain an follicular hormone-like substance is also preferable. In the present invention, the follicular hormone-like substance refers to a substance having the same action as follicular hormone (estrogen), and examples thereof include estrogen, estradiol, ethinyl estradiol, and estradiol valerate.
Further, as another preferred embodiment, an embodiment in which the composition of the present invention contains dienogest as the only active ingredient for dysmenorrhea is also desirable.

EXAMPLES The present invention will be specifically described 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 conventionally used in the field, and various techniques used for carrying out the present invention include those that clearly indicate the source. Except for this, it can be easily and reliably carried out by those skilled in the art based on known documents and the like. In addition, various analyzes were performed by applying the methods described in the analytical instruments or reagents used, kit instruction manuals, catalogs, and the like.
In addition, the description content in the technical literature, the patent publication, and the patent application specification cited in this specification shall be referred to as the description content of the present invention.

(Example 1) Clinical study to examine the efficacy and safety of dienogest in patients with functional dysmenorrhea (1-1) Study design To examine the efficacy and safety of dienogest in patients with functional dysmenorrhea (A multicenter, randomized, placebo-controlled, double-blind, parallel group comparison study) was conducted.
The target number of subjects was 225, and subjects were randomly assigned to 5 groups (46 to 49 cases per group). The dose of each group is as follows. Group V was performed open-label as a reference drug administration group.

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 expressed as DNG 1 mg / day)
Group IV: Dienogest 2 mg / day (also referred to as DNG 2 mg / day)
Group V: drospirenone 3 mg, ethinyl estradiol 0.020 mg / day and placebo (reference drug)

As for the usage, the groups I to IV were orally administered every day for 12 weeks divided into twice a day. That is, the dose of dienogest in groups I to IV is 0 mg for group I, 0.25 mg for group II, 0.5 mg for group III, and 1 mg for group IV. Administered once. The administration start date was the menstrual cycle 2 to 5 days.
Group V is a Yazu (registered trademark) combination tablet of 28 preparations comprising 24 pale red tablets and 4 placebos (white tablets) each containing 3 mg drospirenone and 0.020 mg ethinylestradiol as an ethinylestradiol betadex. Was used. Group V was orally administered once a day for 12 weeks and was taken every day at a fixed time. The starting date of administration was, in principle, the first day of the menstrual cycle, starting with pale red tablets.

The selection criteria for the subjects were (1) patients who agreed to participate in the study in writing, (2) patients whose consent acquisition date was at least 20 years old, and (3) about the start of study drug administration from the date of consent acquisition. Patients who have been diagnosed with functional dysmenorrhea by transvaginal tomography and internal examination up to 1 week before, (4) Patients whose menstrual cycle days are within 38 days, (5) Administration of study drug from the date of consent Pain (lower abdominal pain or low back pain) that is considered to be caused by functional dysmenorrhea in the menstrual cycle up to about 1 week before the dysmenorrhea score (see below) Patients with a total score of 3 or more.
Exclusion criteria for subjects include (1) patients with a history of endometriosis, uterine fibroids, adenomyosis or organic dysmenorrhea, and (2) complications indicating lower abdominal pain or low back pain in addition to menstruation Patients, (3) patients with severe and moderate anemia (hemoglobin value less than 10.0 g / dL) on the date of consent, (4) abnormal genital bleeding, endometrial polyps, uterine malformations or intrauterine Patients with membrane hyperplasia, (5) Patients with thrombosis, embolism, cerebrovascular disorder or coronary artery disease or history, patients with predisposition to thrombosis, etc. Patients judged inappropriate were excluded.

The dysmenorrhea score was used as one of the evaluation indices. As shown in Table 1, the severity of the most severe pain (lower abdominal pain and low back pain) that is considered to be caused by functional dysmenorrhea and the use status of analgesics at the time of the pain were scored in four stages, and totaled. The dysfunction score was used.
The standard evaluation time point is 1) about 7 days before the scheduled start date of menstruation at the start of administration (before administration), 2) the first day of administration is the first day, and the 29th day (at 4 weeks) from the start date of administration, 3) The first day of administration is the first day, the 57th day from the first day of administration (8 weeks), 4) The first day of the administration is the first day, 85th day from the first day of administration (12 weeks), or the administration is discontinued It was time.
The survey period in the dysmenorrhea score was about 28 days from the above 1) to 3) until the day before each evaluation time point. 4) The investigation period at the 12th week of administration was the period from the previous evaluation point to the end of administration or until discontinuation of administration.

(1-2) Change in dysmenorrhea score 1) Before administration, 2) At 4 weeks, 3) At 8 weeks, and 4) At 12 weeks (or at discontinuation of administration) The transition of the disease score (mean value ± standard deviation) was evaluated.
As a result, the average value of the dysmenorrhea score of each group before administration was between 4.3 and 4.6, and each group showed a similar value.
The average dysmenorrhea score of each group at 8 weeks after administration was 3.3 in group I (placebo), 1.9 in group II (DNG 0.5 mg / day), and 1 in group III (DNG 1 mg / day). .5, 1.0 in the IV group (DNG 2 mg / day), 2.3 in the V group (reference drug), and the mean value of the dysmenorrhea score at 12 weeks (or at the time of discontinuation) in each group The value was almost the same.

(1-3) Evaluation of dysmenorrhea score change amount From the dysmenorrhea score obtained before administration, the change amount of the dysmenorrhea score at the 12th week (or at the time of discontinuation) administration of the study drug Dysmenorrhea score change amount of ".
Table 2 shows the average change in dysmenorrhea score at 12 weeks of administration in each group.

As shown in Table 2, the average value of dysmenorrhea score change at the 12th week of administration is -2 or less in groups II to V, and-in group III (DNG 1 mg / day) and group IV (DNG 2 mg / day). 3 or less was shown.
Statistical analysis using the adjusted mean difference and bilateral 95% confidence interval of groups I to V, group II (DNG 0.5 mg / day), group III (DNG 1 mg / day) and group IV (DNG 2 mg / day) showed a statistical difference in the amount of change in dysmenorrhea score between group I (placebo). That is, Group II (DNG 0.5 mg / day), Group III (DNG 1 mg / day) and Group IV (DNG 2 mg / day) had a lower dysmenorrhea score than Group I (placebo). Indicated. Similar analysis revealed that there was a statistical difference in the amount of change in dysmenorrhea score between group III (DNG 1 mg / day) and group IV (DNG 2 mg / day) with group V (reference drug). It was. That is, it was shown that group III (DNG 1 mg / day) and group IV (DNG 2 mg / day) further reduced the dysmenorrhea score compared to group V (reference drug).

  Similarly, when the dysmenorrhea score change amount at the 8th week of administration was evaluated, the average value of the dysmenorrhea score change amount in each group was −1.3 in group I (placebo) and II group (DNG 0.5 mg). -2.5 for Group III (DNG 1 mg / day), -3.3 for Group IV (DNG 2 mg / day), and -2.3 for Group V (reference drug). Group II (DNG 0.5 mg / day), Group III (DNG 1 mg / day), and Group IV (DNG 2 mg / day) were statistically different from Group I (placebo) in the amount of change in dysmenorrhea score, respectively. Was recognized.

(1-4) Evaluation of complete disappearance rate of dysmenorrhea score Subjects who had a dysmenorrhea score of 0 at the 12th week of administration (or at the time of discontinuation of administration) were defined as “complete disappearance of dysmenorrhea score”. evaluated.
The results are shown in FIG. The complete elimination rate at 12 weeks after administration was 4.3% (2/46 cases) in group I (placebo), 26.1% (12/46 cases) in group II (DNG 0.5 mg / day), and group III (DNG 1 mg / day) 55.3% (26/47 cases), Group IV (DNG 2 mg / day) 59.2% (29/49 cases), Group V (reference drug) 21.3% (10/47) It was an example. Statistical analysis using a two-sided 95% confidence interval revealed no clear difference in the complete disappearance rate of group V (reference drug) compared to group I (placebo). In addition, the complete disappearance rate of Group III (DNG 1 mg / day) and Group IV (DNG 2 mg / day) was higher than that of Group V (reference drug), and a statistical difference was observed. It has been shown that administration of dienogest at 1 mg / day to 2 mg / day exhibits superior effects on functional dysmenorrhea as compared to Yaz (registered trademark), which is a reference drug having the effect of dysmenorrhea. It was done.

(1-5) Evaluation of complete elimination rate of dysmenorrhea score in severe cases According to the selection criteria of subjects in this study, the dysmenorrhea score before study drug administration of subjects who participated in the study is 3 to 6 points . Dysmenorrhea score at 12 weeks of administration (or at the time of discontinuation) in severe cases in each of the I to V groups, assuming that subjects with dysmenorrhea score of 5 points or 6 points before administration as functional dysmenorrhea in severe cases The complete disappearance rate 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 elimination rate of dysmenorrhea score at 12 weeks of administration was 60.0% in group III (DNG 1 mg / day), and group IV (DNG 2 mg / day). (Day) was 59.1%, and each group showed a significantly higher value than the group V (reference drug) 19.0% (chi-square test). Thus, it was found that administration of dienogest 1 mg / day or 2 mg / day exerted an excellent effect on severe cases of functional dysmenorrhea.
Here, in view of the fact that patients with a dysmenorrhea score before administration of 5 or 6 are at least moderately painful, administration of dienogest has a degree of pain associated with dysmenorrhea. It was suggested that it exerts a high therapeutic effect on moderate or severe patients. In addition, it was suggested that the degree of pain associated with dysmenorrhea is moderate or severe, and that it exhibits a high therapeutic effect even for patients who require the use of analgesics during the pain.

(1-6) Influence on serum estradiol concentration In each group, the average estradiol concentration (pg / mL) during the administration period of the subjects was determined, and the influence of the study drug on the serum estradiol concentration of the subjects was evaluated.
The average value of serum estradiol concentration adopted as the data at 4 weeks, 8 weeks, 12 weeks and at the time of discontinuation of administration was calculated for each subject and used as the average serum estradiol concentration.
In each group I to V, the average value, standard deviation, and median value of the average serum estradiol concentration of the subjects were determined.
The results are shown in FIG.

Mean serum estradiol concentration (mean ± standard deviation (median)) (pg / mL) during study drug administration was 77.0 ± 35.5 (71.8) in group I (placebo), group II ( DNG 0.5 mg / day) 121.2 ± 112.1 (87.7), and group III (DNG 1 mg / day) 87.5 ± 70.2 (69.3), group IV (DNG 2 mg / day) They were 63.3 ± 86.3 (31.0) and 42.8 ± 47.7 (29.7) in group V (reference drug). The median mean serum estradiol concentration was similar in group II (DNG 0.5 mg / day) and group III (DNG 1 mg / day) to group I (placebo), but in group IV (DNG 2 mg / day) and The value was low in Group V (reference drug).
The mean serum estradiol concentration during the study drug administration period in Group V (reference drug) was lower than that in Group I (placebo), and statistical analysis using a 95% confidence interval on both sides The difference was recognized.

Measurement of serum estradiol concentration in patients prior to study drug administration was typically performed about 7 days before the scheduled start of menstruation at the start of administration (luteal phase). Although there are various theories regarding the standard value of serum estradiol concentration in the luteal phase, it is generally said to be about 45 to 300 pg / ml.
Of the 47 subjects assigned to group III (DNG 1 mg / day), the average serum estradiol concentration during the administration period was evaluated for 18 patients whose serum estradiol concentration before administration was 100 pg / mL or less. The mean serum estradiol concentration (mean ± standard deviation (median)) (pg / mL) during the daily administration period was 101.3 ± 85.2 (80.5). These values were considered to be comparable to the average serum estradiol concentration of group I (placebo) indicated above. The same tendency was observed in the mean value ± standard deviation (median value) when the patient group was expanded to patients (34 cases) of 150 pg / mL or less.

  As a result of (1-2) to (1-6), when dienogest 1 mg / day was divided and administered twice a day, the serum estradiol concentration of the test subject remained at the same level compared to placebo administration, and the functionality It has been shown to have excellent efficacy against dysmenorrhea. In addition, in a patient group with a relatively low serum estradiol level before administration (for example, serum estradiol concentration of about 150 pg / mL or less about 7 days before the scheduled start date of menstruation), the serum estradiol concentration is lower than that in the placebo-administered group. The effectiveness of applying to these patient groups became clear because the serum estradiol levels were not too low.

(1-7) Effect on ovulation suppression In order to examine the ovulation suppression action of the composition of the present invention, the serum progesterone concentration of the subject was measured 7 days before the next scheduled menstrual start date (luteal phase) after the start of administration, Average values for each group were obtained.
As a result, the average serum progesterone concentration (ng / mL) in each group was 8.40 in group I (placebo), 2.72 in group II (DNG 0.5 mg / day), and 0 in group III (DNG 1 mg / mL). It was 0.66 in the .91, IV group (DNG 2 mg / mL) and 0.87 in the V group (reference drug).
It is said that when ovulation occurs, the serum progesterone concentration in the luteal phase rises and usually rises to about 8.5 ng / mL to 21.9 ng / mL. The mean serum progesterone levels of each group of Group II to IV dienogest administered and Group V (reference drug) were low, suggesting that ovulation was suppressed.

Claims (14)

  A composition for treating dysmenorrhea for patients with dysmenorrhea containing dienogest as an active ingredient.   The composition of claim 1 containing dienogest as the only active ingredient.   The composition according to claim 1 or 2, wherein the composition is administered every day continuously for a period of 8 weeks or more.   The composition according to any one of claims 1 to 3, wherein the dienogest is orally administered in 1 mg daily in two divided doses.   5. Composition according to any one of the preceding claims, characterized in that a constant dose of dienogest is administered during the dosing period without periodic fluctuations in the administered dose.   The composition according to any one of claims 1 to 5, wherein the serum estradiol concentration during the administration period is not significantly reduced compared with that before administration.   The composition according to any one of claims 1 to 6, wherein the patient is a patient who desires not to significantly reduce the serum estradiol concentration during the administration period.   The composition according to any one of claims 1 to 7, wherein the patient is a patient who does not suffer from endometriosis, uterine fibroids or uterine adenomyosis.   The composition according to any one of claims 1 to 8, wherein the patient is a patient whose serum estradiol concentration in the luteal phase before administration of the composition is 150 pg / mL or less.   10. The patient according to any one of claims 1 to 9, wherein the patient is a patient having moderate or severe severe pain (lower abdominal pain / back pain) considered to be caused by dysmenorrhea before administration of the composition. Composition.   The patient is a patient with moderate or severe severe pain (lower abdominal pain or low back pain) that is thought to be caused by dysmenorrhea prior to administration of the composition, and the use of an analgesic is required during the pain The composition according to any one of claims 1 to 10, wherein the composition is a patient.   The composition according to any one of claims 1 to 11, wherein the patient has a dysmenorrhea score of 3 or more before administration of the composition.   13. The composition of claim 12, wherein the patient is a patient with a dysmenorrhea score of 5 or 6 before administration of the composition.   The composition according to any one of claims 1 to 13, wherein the dysmenorrhea is functional dysmenorrhea.