WO2020261602A1

WO2020261602A1 - Pharmaceutical composition

Info

Publication number: WO2020261602A1
Application number: PCT/JP2019/048159
Authority: WO
Inventors: 市川　秀一
Original assignee: 医療法人北関東循環器病院
Priority date: 2019-06-28
Filing date: 2019-12-09
Publication date: 2020-12-30
Also published as: JPWO2020261602A1

Abstract

The present invention provides a pharmaceutical composition that is for treating or preventing unpleasant symptoms associated with an increase in progestogens and that contains, as an active ingredient, a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof. The present invention also provides a method that is for treating or preventing unpleasant symptoms associated with an increase in progestogens and that comprises administrating a pharmaceutical composition containing, as an active ingredient, a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof. The present invention is useful for treating or preventing unpleasant symptoms associated with an increase in progestogens, and is highly effective and has few side effects.

Description

Pharmaceutical composition

The present invention relates to a pharmaceutical composition for treating and preventing discomfort associated with an increase in progesterone, and a method for treating and preventing discomfort associated with an increase in progesterone.

Progesterone is a type of female hormone that has a steroid skeleton, and is a substance that causes implantation growth in the endometrium and has an action of maintaining pregnancy (progesterone action). Progesterone is produced and secreted by the ovaries, and together with another female hormone, estrogen, plays a role in developing and regulating female reproductive function.

Progesterone is present in the menstrual cycle of about 28 days (about 25 to 38 days) on average, during the period from ovulation to the start of the next menstruation (about 14 days after the start of the previous menstruation). Production and secretion increase during the luteal phase). Before menstruation, which is the luteal phase, it is said that about 70% to about 85% of women experience unpleasant symptoms such as irritability and headache. The degree of this symptom is so strong that it interferes with daily life (about 5.4%), in which case premenstrual syndrome (PMS) and premenstrual dyspholic disorder (premenstrual dyspholic disorder). (PMDD))) (Non-Patent Document 1).

On the other hand, the production and secretion of progesterone decreases with estrogen during the menopause. And, various symptoms appear due to the decrease of these female hormones, but among them, those that are not associated with other diseases are called menopausal symptoms, and these menopausal symptoms are serious and interfere with daily life. If so, it is diagnosed as menopause. Estrogen preparations are given to patients with this menopause to externally supplement the decreased female sex hormones, but for women whose uterus is preserved (not hysterectomy) , A progesterone preparation is used in combination for the purpose of preventing the growth of the endometrium due to the estrogen preparation (estrogen / progesterone combination therapy). However, with this estrogen / progesterone combination therapy, unpleasant symptoms such as irritability and headache may be experienced as the progesterone increases, and as a result, daily life may be hindered (Non-Patent Document 2).

Conventionally, pain and stiffness have been used to treat and prevent discomfort caused by premenstrual luteal phase, premenstrual syndrome or premenstrual discomfort mood disorder, menopausal disorder estrogen / luteinizing hormone combination therapy, etc. due to an increase in these luteinizing hormones. Anti-inflammatory analgesics for physical symptoms such as, tranquilizers and antidepressants (SSRI, etc.) for neuropsychiatric and autonomic symptoms, diuretics for swelling, etc. Symptomatic therapy according to the discomfort has been performed. However, the effectiveness of each of these drugs is not sufficient, and there are problems such as gastrointestinal disorders, decrease or increase in blood pressure, drowsiness, light-headedness, and frequent urination. In addition, oral contraceptives containing drospirenone, a progesterone-like substance derived from spironolactone, may be used as being empirically effective for the discomfort, but administration of the drug is conversely unpleasant. There are many problems such as unbearable use to reproduce the symptoms or discomfort to the body. Therefore, the actual situation is that the unpleasant symptom cannot be fundamentally treated or prevented (Non-Patent Document 1 and Non-Patent Document 2).

The present invention has been made to cope with such a situation, and is a pharmaceutical composition for treating and preventing discomfort associated with an increase in progesterone, which is highly effective and has few side effects, and a progesterone. An object of the present invention is to provide a method for treating and preventing discomfort associated with an increase in hormones.

In order to solve the above problems, the present inventor presents patients suffering from premenstrual syndrome and patients receiving estrogen / progesterone combination therapy due to menopause but experiencing discomfort associated therewith. As a subject, we examined methods for treating and preventing the discomfort. As a result, it was found that administration of a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof has no side effects and improves discomfort such as irritability and headache. ..

That is, the present invention
[Item 1]
A pharmaceutical composition for treating / preventing discomfort associated with an increase in progesterone, which comprises a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
Is.
Such a pharmaceutical composition is a pharmaceutical composition capable of treating and preventing unpleasant symptoms associated with an increase in progesterone, with high efficacy and few side effects.

Further, the present invention
[Item 2]
Item 2. The pharmaceutical composition according to Item 1, wherein the increase in progesterone is premenstrual luteal phase, premenstrual syndrome or premenstrual dysphoric disorder.
Is preferable.
Such a pharmaceutical composition is a pharmaceutical composition capable of treating and preventing premenstrual luteal phase, premenstrual syndrome, or discomfort associated with premenstrual dysphoric disorder with higher efficacy and fewer side effects. is there.

Furthermore, the present invention
[Item 3]
Item 2. The pharmaceutical composition according to Item 1, wherein the increase in progesterone is a menopausal disorder estrogen / progesterone combination therapy.
Is preferable.
Such a pharmaceutical composition is a pharmaceutical composition capable of treating and preventing the discomfort associated with the combined therapy of estrogen and progesterone for menopause with higher efficacy and less side effects.

Furthermore, the present invention
[Item 4]
The selective mineralocorticoid receptor antagonist is eplerenone (9,11α-epoxy-7α- (methoxycarbonyl) -3-oxo-17α-pregun-4-ene-21,17-carbolactone) or esakiselenone ((( 5P) -1- (2-hydroxyethyl) -N-[4- (methanesulfonyl) phenyl] -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxyamide) , The pharmaceutical composition according to any one of Items 1 to 3.
Is preferable.
Such a pharmaceutical composition is a pharmaceutical composition capable of treating and preventing discomfort associated with an increase in progesterone with higher efficacy and less side effects. In particular, such pharmaceutical compositions are more effective against premenstrual luteal phase, premenstrual syndrome or premenstrual dysphoric disorders and / or menopausal disorders estrogen / luteal hormone combination therapy. A pharmaceutical composition that is high, has fewer side effects, and can be treated and prevented.

In addition, the present invention
[Item 5]
The selective mineralocorticoid receptor antagonist is eplerenone for at least 1 day from 5 days after the start of the previous menstruation to the day before the start of the next menstruation, with eplerenone at least 2 mg / day, 400 Item 2. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is administered at mg / day or less.
Is preferable.
Such a pharmaceutical composition is a pharmaceutical composition capable of treating and preventing premenstrual luteal phase, premenstrual syndrome, or discomfort associated with premenstrual dysphoric disorder with higher efficacy and fewer side effects. is there.

In addition, the present invention
[Item 6]
The selective mineralocorticoid receptor antagonist is eplerenone, at least 1 day from 5 days before the start of administration of the progesterone preparation to 5 days after the end of administration, and eplerenone is 2 mg / day or more, 400. Item 3. The pharmaceutical composition according to Item 3, wherein the pharmaceutical composition is administered at mg / day or less.
Is preferable.
Such a pharmaceutical composition is a pharmaceutical composition capable of treating and preventing the discomfort associated with the combined therapy of estrogen and progesterone for menopause with higher efficacy and less side effects.

In addition, the present invention
[Item 7]
The selective mineralocorticoid receptor antagonist is esakiselenone for at least 1 day from 5 days after the start of the previous menstruation to the day before the start of the next menstruation, 0.1 mg / day or more for esakiselenone, 20 Item 2. The pharmaceutical composition according to Item 2, wherein the pharmaceutical composition is administered at mg / day or less.
Is preferable.
Such a pharmaceutical composition is a pharmaceutical composition capable of treating and preventing premenstrual luteal phase, premenstrual syndrome, or discomfort associated with premenstrual dysphoric disorder with higher efficacy and fewer side effects. is there.

In addition, the present invention
[Item 8]
The selective mineralocorticoid receptor antagonist is esakiselenone, and the period from 5 days before the start of administration of the progesterone preparation to 5 days after the end of administration is at least 1 day, and esakiselenone is 0.1 mg / day or more, 20 Item 3. The pharmaceutical composition according to Item 3, wherein the pharmaceutical composition is administered at mg / day or less.
Is preferable.
Such a pharmaceutical composition is a pharmaceutical composition capable of treating and preventing the discomfort associated with the combined therapy of estrogen and progesterone for menopause with higher efficacy and less side effects.

The present invention
[Item 9]
A method for treating / preventing discomfort associated with an increase in progesterone by administering a pharmaceutical composition containing a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
Is.
Such a treatment / prevention method is a method capable of treating and preventing discomfort associated with an increase in progesterone, with high efficacy and few side effects.

Further, the present invention
[Item 10]
Item 9. The treatment / prevention method according to Item 9, wherein the increase in progesterone is premenstrual luteal phase, premenstrual syndrome or premenstrual dysphoric disorder.
Is preferable.
Such a treatment / prevention method is a method capable of treating and preventing discomfort associated with premenstrual luteal phase, premenstrual syndrome or premenstrual dysphoric disorder with higher efficacy and fewer side effects. ..

Furthermore, the present invention
[Item 11]
Item 9. The treatment / prevention method according to Item 9, wherein the increase in progesterone is menopausal disorder estrogen / progesterone combination therapy.
Is preferable.
Such a treatment / prevention method is a method capable of treating and preventing the discomfort associated with the combined therapy of estrogen and progesterone for menopause with higher efficacy and fewer side effects.

Furthermore, the present invention
[Item 12]
The therapeutic / preventive method according to any one of Items 9 to 11, wherein the selective mineralocorticoid receptor antagonist is eplerenone or esakiselenone.
Is preferable.
Such a treatment / prevention method is a method capable of treating and preventing discomfort associated with an increase in progesterone with higher efficacy and less side effects. In particular, such treatment / prevention methods are effective for premenstrual dysphoric syndrome, premenstrual syndrome or premenstrual dysphoric disorder and / or climacteric disorder estrogen / luteal hormone combination therapy. It is a method that is higher and has fewer side effects and can be treated and prevented.

In addition, the present invention
[Item 13]
The selective mineralocorticoid receptor antagonist is eplerenone for at least 1 day from 5 days after the start of the previous menstruation to the day before the start of the next menstruation, with eplerenone at least 2 mg / day, 400 Item 2. The treatment / prevention method according to Item 10, wherein the drug is administered at mg / day or less.
Is preferable.
Such a treatment / prevention method is a method capable of treating and preventing premenstrual luteal phase, premenstrual syndrome, or discomfort associated with premenstrual dysphoric disorder with higher efficacy and fewer side effects. ..

In addition, the present invention
[Item 14]
The selective mineralocorticoid receptor antagonist is eplerenone, at least 1 day from 5 days before the start of administration of the progesterone preparation to 5 days after the end of administration, and eplerenone is 2 mg / day or more, 400. Item 2. The treatment / prevention method according to Item 11, wherein the drug is administered at mg / day or less.
Is preferable.
Such a treatment / prevention method is a method capable of treating and preventing the discomfort associated with the combined therapy of estrogen and progesterone for menopause with higher efficacy and fewer side effects.

In addition, the present invention
[Item 15]
The selective mineralocorticoid receptor antagonist is esakiselenone for at least 1 day from 5 days after the start of the previous menstruation to the day before the start of the next menstruation, 0.1 mg / day or more for esakiselenone, 20 Item 2. The treatment / prevention method according to Item 10, wherein the drug is administered at mg / day or less.
Is preferable.
Such a treatment / prevention method is a method capable of treating and preventing premenstrual luteal phase, premenstrual syndrome, or discomfort associated with premenstrual dysphoric disorder with higher efficacy and fewer side effects. ..

In addition, the present invention
[Item 16]
The selective mineralocorticoid receptor antagonist is esakiselenone, and the period from 5 days before the start of administration of the progesterone preparation to 5 days after the end of administration is at least 1 day, and esakiselenone is 0.1 mg / day or more, 20 Item 2. The treatment / prevention method according to Item 11, wherein the drug is administered at mg / day or less.
Is preferable.
Such a treatment / prevention method is a method capable of treating and preventing the discomfort associated with the combined therapy of estrogen and progesterone for menopause with higher efficacy and fewer side effects.

According to the present invention, a pharmaceutical composition for treating and preventing discomfort associated with an increase in progesterone, which is highly effective and has few side effects, and a method for treating and preventing discomfort associated with an increase in progesterone. It will be possible to provide.

It is a figure which showed the flow of the test which verified the efficacy and side effect of administration of a test drug (eplerenone or esakiselenone) for various discomforts associated with premenstrual syndrome. It is a figure which showed the flow of the test which verified the efficacy and side effect of administration of a test drug (eplerenone or esaxelenone) for various discomforts associated with the combined therapy of estrogen and progesterone for menopause.

Hereinafter, embodiments of the present invention will be specifically described. These descriptions are intended to illustrate the contents of the present invention, and do not limit the scope of the present invention in any way.

When a range is described in this specification, both ends that specify the range are included in the range unless otherwise specified. For example, when the range is described as "A to B", A and B are included in the range unless otherwise specified.

The pharmaceutical compositions of the present invention contain selective mineralocorticoid receptor antagonists or derivatives thereof, or pharmaceutically acceptable salts thereof, which are used to treat and prevent discomfort associated with an increase in progesterone. It is characterized by being contained as an active ingredient.
Such a pharmaceutical composition is a pharmaceutical composition capable of treating and preventing unpleasant symptoms associated with an increase in progesterone, with high efficacy and few side effects.

In addition, the therapeutic / preventive method of the present invention is a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof, in order to treat and prevent discomfort associated with an increase in progesterone. It is characterized in that a pharmaceutical composition containing the above as an active ingredient is administered.
Such a treatment / prevention method is a method capable of treating and preventing discomfort associated with an increase in progesterone, with high efficacy and few side effects.

The "progesterone" in the present invention is a kind of female hormone having a steroid skeleton, and has an action of causing implantation growth in the endometrium and, if pregnant, maintaining the pregnancy (progesterone action). Refers to a substance. The "progesterone" includes not only the natural "progesterone" that is physiologically or pathologically produced in the body, but also the progesterone-like substance that is artificially synthesized and has the progesterone action in the body. "Progesterone" is also included. Examples of the "progesterone" in the present invention include, but are not limited to, progesterone, pregnanediol, pregnantriol, levonorgestrel, norethisterone acetate, medroxyprogesterone acetate, medroxyprogesterone acetate, dydrogesterone, hydroxyprogesterone caproate, Includes chlormaginone acetate, ethisterone, dimethisterone, norethisterone, norethisterone enanthate, etinodiol acetate, megestrol acetate, desogestrel, dienogest, allylestrenol and the like.

The "progesterone" in the present invention is preferably progesterone, levonorgestrel, norethisterone acetate, medroxyprogesterone acetate, and ydrogesterone. Progesterone is a natural "progesterone" that increases in the body during the premenopausal luteal phase, and levonorgestrel, norethisterone acetate, medroxyprogesterone acetate, and didrogesterone are similar to the progesterone used in menopausal estrogen / progesterone combination therapy. This is because it is a substance "progesterone". The "progesterone" in the present invention is more preferably progesterone or medroxyprogesterone acetate.

"Increase in progesterone" in the present invention means that the amount of progesterone produced, secreted or acted upon in the body by a physiological or pathological scheme and / or by administration of a drug. Examples of physiological or pathological schemes in which "increased progesterone" occurs include, but are not limited to, premenstrual luteal phase, premenstrual syndrome, premenstrual dysphoric disorder, and the like. .. Furthermore, examples of administration of agents that cause "increased progesterone" in the present invention include, but are not limited to, natural progesterone agents, progesterogen-like agents (eg, hormone replacement therapy (eg, hormone replacement therapy). For example, drugs for menopausal disorders estrogen / progesterone combination therapy), etc.), drugs that convert to progesterone by being metabolized in the body even if they are not progesterone, production of progesterogen in the body, Drugs that induce / promote secretion or action, drugs that suppress the decomposition / metabolism of progesterogen, drugs that induce / promote the production or action of progesterogen receptors, drugs that suppress the decomposition / metabolism of progesterogen receptors, progesterone This includes administration of drugs that induce, promote or enhance the interaction between hormones and progesterone receptors.

The "increased progesterone" in the present invention is preferably premenstrual luteal phase, premenstrual syndrome or premenstrual dysphoric disorder, and menopausal estrogen / progesterone combination therapy. Premenstrual luteal phase, premenstrual syndrome or premenstrual dysphoric disorder increases progesterone in the body, and menopausal estrogen / progesterone combination therapy produces progesterone-derived progesterone-derived substances that are administered externally. Because it will increase.

The "luteal phase before menstruation" in the present invention refers to the period from the time of ovulation to the start of the next menstruation when the "increase in progesterone" occurs. The start time and length of the "premenstrual luteal phase" vary depending on the individual or within the same individual, but it is approximately 14 days before the start of menstruation to the day of the start of menstruation. Corresponds to the period.

Here, the menstruation means that the functional layer (surface layer) of the endometrium is exfoliated and detached leaving the basal layer, and is discharged together with bleeding from the wound surface. Menstruation is regulated by the action of hormones, and the onset of menstruation can be indicated by a decrease in basal body temperature.

Here, the above-mentioned ovulation means that an egg is discharged from the ovary to the uterus. Ovulation is regulated by the action of hormones, and can be indicated by an increase in basal body temperature, changes in the properties of cervical mucus, an increase in luteinizing hormone levels, and the like.

The "premenstrual syndrome" in the present invention refers to neuropsychiatric symptoms, autonomic symptoms, and physical symptoms that continue during the luteal phase of 3 to 10 days before menstruation, and those that improve or disappear with the onset of menstruation. Here, the diagnostic criteria of the American College of Obstetricians and Gynecologists or equivalent diagnostic criteria are used for the diagnosis of the "premenstrual syndrome", but the "premenstrual syndrome" in the present invention is used. ”Includes PMS in a broad sense, which has symptoms during menstruation and during the ovulation period.

The "premenstrual dysphoric disorder" in the present invention refers to the above-mentioned "premenstrual syndrome" having particularly severe mental symptoms. Here, for the diagnosis of "pre-menstrual discomfort disorder" in the present invention, "Diagnostic and Statistical Manual of Mental Disorder", which is a diagnostic classification of the American Psychiatric Association (APA), 5th edition (Diagnostic and) The diagnostic criteria described in Statistical Manual of Mental Disorders 5th edition (DSM-5), 2013) or equivalent diagnostic criteria are used.

The "menopausal disorder" in the present invention refers to a symptom that does not accompany other illnesses among various symptoms that appear in the climacteric period, and refers to a state in which the climacteric symptom is severe and interferes with daily life. Here, the menopause generally refers to a total of 10 years, which is a combination of 5 years before menopause and 5 years after menopause. Here, the menopause refers to a state in which the activity of the ovaries gradually disappears and menstruation is finally stopped permanently. The "menopause" in the present invention includes not only menopause but also menopause in a broad sense in which the symptom continues even after 5 years have passed since the menopause.

The "menopausal disorder estrogen / luteinizing hormone combination therapy" in the present invention is a kind of treatment method (hormone replacement therapy) for administering an estrogen preparation to the patient with climacteric disorder, and does not use the luteinizing hormone preparation in combination. It refers to a treatment method (estrogen / luteinizing hormone combination therapy) in which an estrogen preparation and a luteinizing hormone preparation are administered in combination with the treatment method (estrogen monotherapy). Here, examples of the estrogen preparation include, but are not limited to, bound estrogen, 17β-estradiol, ethyl estradiol benzoate, estradiol valerate, estradiol propionate, estriol, and estriol propionate. , Estrone, Ekirin and Echilenin and the like. Here, examples of the progesterone preparation include, but are not limited to, progesterone, pregnanediol, pregnantriol, levonorgestrel, norethisterone acetate, medroxyprogesterone acetate, medroxyprogesterone acetate, dydroxyprogesterone, and hydroxyprogesterone caproate. , Chlormaginone acetate, etisterone, dimethisterone, norethisterone, norethisterone enanthate, etinodiol acetate, megestrol acetate, desogestrel, dienogest and allylestrenol and the like. In the menopausal disorder estrogen / progesterone combination therapy in the present invention, any one or more types of estrogen preparations and any one or more types of progesterone preparations may be used in any combination.

The "menopausal estrogen / progesterone combination therapy" in the present invention preferably contains bound estrogen, 17β-estradiol, and estriol as estrogen preparations, and levonolgestrel, norethisterone acetate, medroxyprogesterone acetate, and didrogesterone as progesterone preparations. It is a "menopausal estrogen / progesterone combination therapy" to be used, and more preferably a "menopausal estrogen / progesterone combination therapy" using 17β-estradiol and medroxyprogesterone acetate. These preparations are widely used in the above-mentioned "menopausal disorder estrogen / progesterone combination therapy", and the discomfort associated therewith becomes a problem, while the pharmaceutical preparation according to the present invention is more effective in causing these discomforts. Moreover, it has fewer side effects and can be treated and prevented.

Further, in the "menopausal disorder estrogen / progesterone combination therapy" in the present invention, the administration patterns of the estrogen preparation and the progesterone preparation are used.
(1) Continuous combination method: A method of continuously administering both an estrogen preparation and a progesterone preparation,
(2) Periodic combination method: A method in which the progesterone preparation is temporarily suspended on the scheduled start date of menstruation (bleeding) or the start of menstruation (bleeding), and the administration of the progesterone preparation is resumed before and after the start of the luteal phase. ,
There is. Furthermore, the periodic combination method includes
(2a) Intermittent method: A method in which the estrogen preparation is temporarily suspended around the period of menstruation (bleeding) and the administration of the estrogen preparation is resumed around the end of menstruation (bleeding).
(2b) Sustained method: A method of continuously administering an estrogen preparation regardless of the presence or absence of menstruation (bleeding).
There is.

The "menopausal disorder estrogen / progesterone combination therapy" in the present invention may be carried out in any of the above-mentioned administration patterns, but is preferably a periodic combination method, and more preferably a continuous method of the periodic combination method. Is. The periodic combination method is mainly performed for pre- and post-menopausal women, and there is a higher need for management of discomfort associated with an increase in progesterone, and the pharmaceutical composition and the therapeutic / preventive method in the present invention are more effective. Moreover, it has fewer side effects and can be treated and prevented.

The "discomfort" in the present invention refers to a neuropsychiatric symptom, an autonomic nervous symptom, and a physical symptom that a human perceives as unpleasant. Examples of the "discomfort" are, but not limited to,
(1) Psychoneurological symptoms: Frustration (emotional instability, impatience, anger, irritability, excitement, increased interpersonal friction, panic, threatening ideas, etc.), depression (anxiety, decreased concentration) , Sadness, despair, depression, self-deprecating feelings, loss of interest in daily activities, withdrawal, etc.), sleep disorders (sleeplessness, drowsiness, oversleeping, drowsiness, etc.), etc.
(2) Autonomic symptoms: Changes in eating habits (loss of appetite, overeating, etc.), dizziness, tiredness (malaise, etc.), nausea (feeling bad, nausea, vomiting, etc.), constipation, hot flashes (hot flashes, hot flashes, etc.) Sweating, night sweats, etc.), palpitation, shortness of breath, thirst (thirst, dry eyes, etc.), coldness, etc.
(3) Physical symptoms: Pain (headache, abdominal pain (lower abdominal pain, etc.), stomach pain, lower back pain, back pain, joint pain, sexual intercourse pain, etc.), stiffness (stiff shoulders, neck stiffness, etc.), numbness, water retention Swelling (swelling of the abdomen, swelling of the breast, swelling of the lower limbs, etc.), tension (tension of the abdomen, swelling of the breast, etc.), feeling of pressure (feeling of pressure on the chest, etc.)
Is included.

The "discomfort" in the present invention is preferably a symptom selected from the group consisting of irritability, depression, nausea, pain, oppression, tension, water retention and swelling, and more preferably irritability and mood. It is a symptom selected from the group consisting of depression, nausea, headache, lower abdominal pain, lower back pain, chest tightness, breast tension, and swelling of the lower limbs. While the treatment and prevention of these "discomforts" are insufficient with conventional symptomatic treatments, they are more effective and have fewer side effects depending on the pharmaceutical composition or the treatment / prevention method in the present invention. This is because it is possible.

The "treatment" in the present invention means to permanently or temporarily eliminate, alleviate, alleviate, or prevent the progression of at least one or more of the above-mentioned "discomforts". , Delaying progress, etc.

The term "prevention" in the present invention means that at least one or more of the "discomfort" appears before at least one of the "discomfort" appears, or that at least one of the "discomfort" appears. Eliminating, alleviating, alleviating, inhibiting and / or delaying the appearance of at least one or more of the other "discomforts" after the appearance of at least one of the above. This includes eliminating, alleviating, alleviating, and / or inhibiting the risk of at least one or more of the above-mentioned "discomfort symptoms" appearing. Further, the "prevention" is to eliminate the recurrence of at least one or more of the "discomfort" after having at least one or more of the "discomfort". It also includes mitigating, mitigating, inhibiting and / or delaying.

The "selective mineralocorticoid receptor antagonist" in the present invention refers to a mineralocorticoid receptor antagonist which is an epoxy-steroidal compound and a non-steroidal compound.

Here, the epoxy / steroid compound refers to a steroid compound substituted with an epoxy type moiety.

Further, here, the epoxy type portion means including all portions characterized by having an oxygen atom that crosslinks between two carbon atoms. Examples of said epoxy type moieties include, but are not limited to:

[Chemical 1]

Epoxy ethyl;

[Chemical 2]

1,3-Epoxypropyl;

[Chemical 3]

1,2-Epoxypropyl.

Further, here, the steroidal compound means a compound having a skeleton (steroid skeleton) provided by a cyclopentenophenanthrene moiety having so-called “A”, “B”, “C” and “D” rings. .. The non-steroidal compound refers to a compound that does not have this steroid skeleton.

Further, here, the above-mentioned mineralocorticoid receptor antagonist is an action of aldosterone itself at the receptor site so as to modify the activity of aldosterone, which is a kind of mineralocorticoid, via the mineralocorticoid receptor. As a substance that competitively inhibits the above, it means a substance capable of binding to the mineralocorticoid receptor.

The "selective mineralocorticoid receptor antagonist" in the present invention is exemplified by spironolactone, potassium canrenoate, canrenone, disilenone, drospyrenone, potassium mexlenate, potassium prolenoart, spiroxason and the like due to the above-mentioned chemical structural characteristics. It is characterized by being selective for the mineralocorticoid receptor as compared with the non-selective mineralocorticoid receptor antagonist of the non-epoxy steroid compound.

Here, "selective for the mineralocorticoid receptor" means that the binding to the mineralocorticoid receptor is a steroid hormone receptor other than the mineralocorticoid receptor (for example, androgen receptor, progesterone). It means that it is particularly strong, rather than its binding to receptors, etc.).

Further, here, the fact that the binding to the mineralocorticoid receptor is particularly strong is not limited, for example, but in the binding test to various receptors derived from rats or rabbits, the IC _{50 to the} mineralocorticoid receptor is used. [M] value is either less about 100 times more than the IC ₅₀ [M] value for the androgen receptor or the progesterone receptor, it is.

In the mineralocorticoid receptor antagonist, which is an epoxy-steroid compound in the present invention, the epoxy type moiety may be attached to the steroid skeleton at any connectable or replaceable position, that is, of the steroid skeleton. It may be condensed into one of the rings, or the same part may be substituted on the atoms that make up the ring of the cyclic structure. The epoxy-steroid compound in the present invention includes a compound having a steroid skeleton containing one or more epoxy type moieties bound to the steroid skeleton.

Examples of the mineralocorticoid receptor antagonist, which is an epoxy-steroid compound in the present invention, include, but are not limited to, a compound having one epoxy moiety condensed on the “C” ring of the steroid skeleton. .. The mineralocorticoid receptor antagonist, which is an epoxy-steroid compound in the present invention, is preferably a 20-spiroxane compound characterized in that the 9α and 11α positions are substituted with epoxy moieties, and more preferably. Eplerenone. This is because it is a selective mineralocorticoid receptor antagonist that is more effective and has fewer side effects for treating and preventing discomfort associated with an increase in progesterone.

Examples of the mineralocorticoid receptor antagonist, which is a non-steroidal compound in the present invention, are, but are not limited to, esakiselenone, finelenone (BAY94-8862), LY-2623091, PF-3882845, MT-3995, Includes BR-4628, SM-368229, KBP-5074, AZD9977, etc. The mineralocorticoid receptor antagonist, which is a non-steroidal compound in the present invention, is preferably esakiselenone or finelenone, and more preferably esakiselenone. This is because it is a selective mineralocorticoid receptor antagonist that is more effective and has fewer side effects for treating and preventing discomfort associated with an increase in progesterone.

The "derivative" in the present invention means a biological activity that is structurally related to or substantially equivalent to that of the parent compound, while modifying the parent compound such as introduction of a functional group, oxidation, reduction, and replacement of atoms. Refers to any compound having. Examples of the "derivative" include, but are not limited to, prodrugs.

Here, the prodrug is a pharmaceutically active substance that can be enzymatically activated or converted into a more active parent drug form even if its biological activity is lower than that of the parent compound. Means the precursor of. The prodrug may be designed to improve bioavailability or stability or reduce toxicity.

The "pharmaceutically acceptable salt" in the present invention refers to a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Examples of the "pharmaceutically acceptable salt" are not limited to (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. , (2) Acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-Hydroxybenzoyl) Acid addition salts formed with organic acids such as benzoic acid, silicic acid, mandelic acid, and methanesulfonic acid, (3) Acidic protons present in the parent compound are metal ions (eg, alkalis). Salts formed when substituted with metal ions, alkaline earth ions, zinc ions or aluminum ions, (4) Acidic protons present in the parent compound are ethanolamine, diethanolamine, triethanolamine, N- Includes salts formed when coordinated with organic bases such as methylglucamine and dicyclohexylamine.

The "selective mineralocorticoid receptor antagonist or derivative thereof, or a pharmaceutically acceptable salt thereof" in the present invention includes intramolecular salts and adducts thereof, solvates or hydrates thereof, and the like. Is included.

The pharmaceutical composition in the present invention contains only one type or two or more types of active ingredients which are selective mineralocorticoid receptor antagonists or derivatives thereof, or pharmaceutically acceptable salts thereof. There is.

In addition, the therapeutic / preventive method in the present invention contains only one pharmaceutical composition containing a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, or Two or more pharmaceutical compositions containing a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient in different compositions may be administered.

In the pharmaceutical composition or therapeutic / prophylactic method of the present invention, the dose of the active ingredient, which is a selective minerarocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof, is the purpose of administration; Degree: Age, body weight of the subject to be administered; Frequency and interval of administration; Timing of administration; Properties, preparation, type of pharmaceutical preparation; Type of active ingredient; It may be arbitrarily and appropriately selected according to the judgment of a doctor.

Lower limit of the dose of eplerenone when eplerenone is used orally as an active ingredient for the purpose of treating and preventing luteal phase, premenstrual syndrome or premenstrual dysphoric disorder, and discomfort associated with estrogen / progesterone combination therapy. Examples of, but not limited to, are 2 mg / day or more, preferably 5 mg / day or more, more preferably 10 mg / day or more, and even more preferably 12.5 mg / day. These are the active ingredient doses. This is because higher efficacy can be obtained at these doses and above. Further, examples of the upper limit of the dose of eplerenone are not limited, but are 400 mg / day or less, preferably 300 mg / day or less, more preferably 200 mg / day or less, and even more. The active ingredient dose is preferably 100 mg / day or less. Below these doses, the risk of side effects can be further reduced while gaining efficacy.

In addition, when esaxelenone is orally used as an active ingredient for the purpose of treating and preventing luteal phase, premenstrual syndrome or premenstrual dysphoric disorder, and discomfort associated with estrogen / luteal hormone combination therapy, the dose of esaxelenone is administered. Examples of the lower limit of the above are, but are not limited to, 0.1 mg / day or more, preferably 0.25 mg / day or more, more preferably 0.5 mg / day or more, and even more preferably 0.625 mg. The active ingredient dose is / day or more. This is because higher efficacy can be obtained at these doses and above. Further, as an example of the upper limit of the dose of the Esakiselenone, it is not limited, but is 20 mg / day or less, preferably 15 mg / day or less, and more preferably 10 mg / day or less. Even more preferably, the active ingredient dose is 5 mg / day or less. Below these doses, the risk of side effects can be further reduced while gaining efficacy.

In the pharmaceutical composition or the therapeutic / preventive method in the present invention, the administration frequency of the pharmaceutical composition is the purpose of administration; the degree of symptoms; the age and body weight of the subject to be administered; the dose; the timing of administration; the nature, preparation and type of the pharmaceutical preparation; Type of active ingredient: It may be selected arbitrarily and appropriately according to the judgment of the doctor. Examples of the administration frequency are not limited, but are limited to once a day or multiple times a day (for example, 2 times a day, 3 times a day), and 1 day a day. Times, 3 days 1 time, 4 days 1 time, 5 days 1 time, 6 days 1 time, 6 days 1 time, 2 times a week, 2 weeks 1 time, 1 month 1 time, February The frequency of administration may be 1 time. In the pharmaceutical composition or the therapeutic / preventive method in the invention, when used orally, the administration frequency of the pharmaceutical composition is preferably 1 time per day, 2 times per day, and 3 times per day, which is the most. Preferably, it is once a day. When used transdermally, it is preferably 1 time a day, 1 time a day, and 2 times a week. This is because medication / medication management and combined use with other treatment methods become easier.

In the pharmaceutical composition or the therapeutic / preventive method in the present invention, the administration timing of the pharmaceutical composition is the purpose of administration; the degree of symptoms; the age and body weight of the subject to be administered; the dose; the frequency of administration, the interval; the nature of the pharmaceutical preparation, the preparation, Type; Type of active ingredient; It may be selected arbitrarily and appropriately according to the judgment of the doctor. Examples of the administration time include, but are not limited to, at least 1 day or more from the appearance of the discomfort to the elimination or alleviation of the discomfort. Further, when the pharmaceutical composition or the therapeutic / preventive method in the present invention is used for the purpose of preventing the unpleasant symptom, the example of the administration time is not limited, but progesterone is increased. However, if the discomfort may occur, it may be at least 1 day before the increase in progesterone and the period when the discomfort has not yet appeared. Further, when used for the purpose of preventing recurrence of discomfort, the administration time may be at least 1 day or more after the discomfort is resolved or alleviated.

Examples of, but not limited to, the timing of oral administration of the pharmaceutical composition for the purpose of treating and preventing discomfort associated with premenstrual luteal phase, premenstrual syndrome or premenstrual discomfort disorder. Includes at least 1 day from 5 days after the start of menstruation to the day before the start of the next menstruation, preferably at least 1 day from the day of ovulation to the day before the start of the next menstruation. More preferably, it is at least 1 day or more from 14 days before the start of menstruation to the day before the start of menstruation. During this period, discomfort associated with an increase in progesterone often appears, and the pharmaceutical composition and the treatment / prevention method in the present invention are more effective and have fewer side effects to treat and prevent them. Because it can be done.

Menopausal disorders Examples of the timing of oral administration of the pharmaceutical composition for the purpose of treating and preventing discomfort associated with estrogen / progesterone combination therapy are not limited, but the start of administration of progesterone preparations 5 It includes at least 1 day or more of the period from 1 day before the end of administration to 5 days after the end of administration, and more preferably at least 1 day or more of the period from 3 days before the start of administration of the progesterone preparation to 3 days after the end of administration. Preferably, the period from the day before the start of administration of the progesterone preparation to the day after the end of administration is at least 1 day or more. During this period, discomfort associated with an increase in progesterone often appears, and the pharmaceutical composition and the treatment / prevention method in the present invention are more effective and have fewer side effects to treat and prevent them. Because it can be done.

In the pharmaceutical composition or treatment / prevention method of the present invention, the pharmaceutical composition may contain a pharmaceutically acceptable carrier that does not impair the effectiveness of treating and preventing the discomfort associated with the increase in progesterone. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as preparation materials are used, and excipients, lubricants, binders, disintegrants in solid preparations, solvents in liquid preparations, and dissolution aids. It may be blended as an agent, a suspending agent, an isotonic agent, a buffering agent, a soothing agent, a transdermal absorption promoter in a transdermal preparation, a skin irritation inhibitor, and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, and sweeteners may be used.

Preferable examples of the excipient include, for example, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include, for example, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, sodium carboxymethyl starch and the like. Preferable examples of the solvent include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate; for example, polyvinyl alcohol. , Polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydrophilic polymers such as hydroxypropylcellulose and the like are included. Preferable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include, for example, a buffer solution such as phosphate, acetate, carbonate, citrate and the like. Preferable examples of the pain-relieving agent include, for example, benzyl alcohol and the like. Examples of the transdermal absorption promoter include crotamiton, L-menthol, peppermint oil, pyrothiodecane, hexylene glycol and the like. Examples of the skin irritation inhibitor include fatty acid esters such as glycerin monooleate and glycerin monolaurate, and sorbitol fatty acid esters. Preferable examples of the preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include, for example, sulfites, ascorbic acid, butylhydroxytoluene and the like.

In the pharmaceutical composition or therapeutic / prophylactic method of the present invention, the pharmaceutical composition has advantageous properties (eg, but not limited to, progesterone) when administered with a selective minerarocorticoid receptor antagonist. It is known to have greater effectiveness in treating and preventing discomfort associated with increased hormones, fewer side effects, other diseases and symptoms that can be treated and prevented at the same time, etc.). , Or the indicated, at least one or more other active ingredients may be contained in addition to the selective minerarocorticoid receptor antagonist. Examples of such other active ingredients include, but are not limited to, anti-inflammatory analgesics (salicylic acid-based, anthranilic acid-based, arylacetic acid-based, propionic acid-based, oxycam-based, COX-2 selective inhibitors, Basic, pyrimidine-based, pyrin-based antipyretic analgesics, non-pyrin-based antipyretic analgesics, non-pharmaceutical analgesics (opioids), etc.) , Anti-depressants (tricyclic, tetracyclic, SSRI, SNRI, NaSSA, selective noradrenaline reuptake inhibitor, etc.), anti-anxiety drugs (benzodiazepine, non-benzodiazepine, etc.), anti-depressants, estrogen preparations (binding) Type estrogen, 17β-estradiol, ethyl estradiol benzoate, estradiol valerate, estradiol propionate, estriol, estriol propionate, estron, equilin, echillenin, etc.), luteinizing hormone preparations (progesterone, pregnanediol, pregnanthriol, levo) Norgestrel, norethisterone acetate, medroxyprogesterone acetate, medroxyprogesterone acetate, didrogesterone, hydroxyprogesterone caproate, chlormaginone acetate, etisterone, dimethisterone, noretisterone, norethisterone enanthate, ethinodiol acetate, megestrol acetate, desogestrel Nord, etc.), aldosterone synthesis inhibitors (trilostan, etc.), etc. are included.

In the pharmaceutical composition or the therapeutic / preventive method of the present invention, the pharmaceutical composition may be administered to humans by any route. Examples of the administration route of the pharmaceutical composition include, but are not limited to, oral administration, rectal administration, nasal administration, local administration (including oral administration and sublingual administration), lung administration, vaginal administration, or Parenteral administration (including transdermal administration, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, etc.) is included. The route of administration of the pharmaceutical composition is preferably oral administration, transdermal administration, and most preferably oral administration. This is because it is less invasive in administration, less burden on the patient, and easier to be used in combination with other treatment methods.

In the pharmaceutical composition or the therapeutic / preventive method of the present invention, the pharmaceutical composition may take any dosage form suitable for oral administration. Examples of the dosage form when the pharmaceutical composition is orally administered include, but are not limited to, tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolving tablets, etc.), capsules, and the like. Includes granules, powders (fine granules, etc.), oral solutions (elixyl, suspension, emulsion, limonade), syrups, oral jelly, and the like. When the pharmaceutical composition is orally administered, the dosage form is preferably a tablet or a capsule. This is because the pharmaceutical composition can be prepared in the form of a dose unit containing a specific amount of the active ingredient, which makes it easier to administer medication and medication.

In the pharmaceutical composition or the therapeutic / preventive method of the present invention, the pharmaceutical composition may take an arbitrary dosage form suitable for transdermal administration. Examples of the dosage form when the pharmaceutical composition is transdermally administered include, but are not limited to, external solid preparations, external liquid preparations (liniment preparations, lotions, etc.), spray preparations (external aerosol preparations, pumps, etc.). Includes sprays, etc.), ointments, creams, gels, patches (tapes, bops, etc.) and the like. The dosage form when the pharmaceutical composition is transdermally administered is preferably a patch. This is because the pharmaceutical composition can be prepared in the form of a dose unit containing a specific amount of the active ingredient, which makes it easier to administer medication and medication.

In the pharmaceutical composition or the therapeutic / preventive method of the present invention, the pharmaceutical composition may be formulated into a dosage unit dosage form. The dose unit means a physically separate unit suitable as a dose unit for a subject to which the pharmaceutical composition is administered, and each unit has been calculated to produce the desired effect. It contains a predetermined amount of the active ingredient and is optionally included with the appropriate pharmaceutical carrier. The dosage form of the dose unit may be one dose of one dose per day or multiple doses per day (for example, two doses per day and three doses per day). When multiple doses per day are used, the unit dose may be the same or different for each dose. In addition, the dosage form of the above-mentioned dose unit is 1 time on 2 days, 1 time on 3 days, 1 time on 4 days, 1 time on 5 days, 1 time on 6 days, 1 time a week, 2 times a week, The dose may be once every two weeks, once a month, once in February, etc.

Hereinafter, a test example including an evaluation of an example (evaluation of a test drug (eplerenone (+) or esakiselenone (+))) and an evaluation of a comparative example (control evaluation (eplerenone (-) or esakiselenone (-))) will be shown. Although the content of the invention will be specifically described, the scope of the present invention is not limited to these test examples.

In the following test examples 1 to 4, the following items were set in common. Menstruation in Test Examples 1 and 3 should be read as bleeding in Test Examples 2 and 4 because the subject is postmenopausal.

Menstruation (bleeding) cycle: The period from the previous menstruation (bleeding) start date to the day before the next menstruation (bleeding) start was defined as the menstruation (bleeding) cycle. Then, of the two menstrual (bleeding) cycles, the preceding menstrual (bleeding) cycle is defined as the first menstrual (bleeding) cycle, the subsequent menstrual (bleeding) cycle is defined as the second menstrual (bleeding) cycle, and the first menstrual cycle (bleeding). Menstruation (bleeding) that begins immediately after the (bleeding) cycle is called the first menstruation (bleeding), and menstruation (bleeding) that starts immediately after the second menstruation (bleeding) cycle is called the second menstruation (bleeding).

Scheduled menstruation (bleeding) date: In the 1st menstruation (bleeding) cycle, the scheduled start date of the 1st menstruation (bleeding) (1st scheduled date of menstruation (bleeding)) and in the 2nd menstruation (bleeding) cycle 2 Estimate the scheduled start date of menstruation (bleeding) for each subject in consideration of the sexual cycle of each subject, and start administration of various drugs based on each scheduled date. I set a day / rest day.

Evaluation order: Control evaluation (eplerenone (-) or esakiselenone (-)) was performed in the 1st menstrual (bleeding) cycle, and test drug evaluation (eplerenone (+) or esakiselenone (+)) was performed in the 2nd menstrual (bleeding) cycle. ..

Test method: In the same subject, both control evaluation (eplerenone (-) or esakiselenone (-)) and test drug evaluation (eplerenone (+) or esakiselenone (+)) were performed in the order of early evaluation, and the results were evaluated. Compared.

Test evaluation items: Various discomforts (irritability, depression, nausea, headache, lower abdominal pain, lower back pain, chest tightness, breast tension, swelling of lower limbs) are diagnosed based on the report from the subject, and the degree is diagnosed. It was scored in 4 stages as shown below.
-: No symptom +: Weak symptom ++: Moderate symptom +++: Strong symptom

Evaluation date: The day before the scheduled menstrual period (bleeding) was set as the evaluation date for both the control evaluation (eplerenone (-) or esakiselenone (-)) and the test drug evaluation (eplerenone (+) or esakiselenone (+)). The subjects recorded the test endpoints every day from 10 days before the scheduled menstruation (bleeding) date until the actual start of menstruation (bleeding), but the menstruation (bleeding) was after the scheduled menstruation (bleeding) date. If it started, the evaluation date was set as described above, and if menstruation (bleeding) started before the scheduled menstruation (bleeding) date, the day before the actual menstruation (bleeding) started was set as the evaluation date.

Test example 1: Effectiveness and side effects of eplerenone administration for various discomforts associated with PMS

The efficacy and side effects of eplerenone administration for various discomforts associated with premenstrual syndrome were evaluated by the following procedure.

Subject: 2 patients diagnosed with premenstrual syndrome.

Test drug and its dosage and administration: Celara Tablets 25 mg (containing 25 mg / tablet of eplerenone) (Pfizer Japan Inc.) was orally administered once a day.

Details of test method (see FIG. 1): For control evaluation (eplerenone (-)), subjects did not administer Celara tablets during the relevant menstrual cycle and controlled the results of the test evaluation items on the evaluation date. The result of the evaluation (eplerenone (-)) was used. For test drug evaluation (eplerenone (+)), 14 days from 14 days before the scheduled menstruation date to the day before the scheduled menstruation date (until that point if the actual menstruation started before the scheduled menstruation date), Celara tablets 25 mg was orally administered once a day, and the results of the test evaluation items on the evaluation day were used as the results of the test drug evaluation (eplerenone (+)).

The results of Test Example 1 are shown in Table 1.
[Table 1]

In the table, "eplerenone administration", (-) means a control evaluation (eplerenone (-)) without administration of Celara tablets, and (+) means a test drug evaluation (eplerenone (+)) with Celara tablets.

Subjects with headache associated with premenstrual syndrome complained of moderate to severe headache in the control evaluation (eplerenone (-)) without administration of the test drug Celara tablets, but the test drug evaluation with the test drug Celara tablets ( With eplerenone (+)), this headache completely disappeared in all subjects. In addition, during the test period, no side effects were observed due to the administration of Celara tablets.

Test example 2: Eplerenone administration efficacy and side effects for various discomforts associated with menopausal estrogen / progesterone combination therapy

The efficacy and side effects of eplerenone administration for various discomforts associated with menopausal estrogen / progesterone combination therapy were evaluated by the following procedure.

Subject: 16 patients who were diagnosed as menopausal disorder because they exhibited premenstrual syndrome within 1 year after menopause, were receiving estrogen / progesterone combination therapy, and had various discomforts.

Estrogen / progesterone combination therapy (drug and its usage / dose and administration pattern (see Fig. 2)): Estrogen tape 0.72 mg (containing 17β-estradiol 0.72 mg / sheet) (Hisamitsu Pharmaceutical Co., Ltd.) 1 time 1 sheet, pasted every 2 days. In addition, as a progesterone preparation, Provera Tablets 2.5 mg (containing 2.5 mg / tablet of medroxyprogesterone acetate) (Pfizer Japan Inc.) and 1 tablet once a day were orally administered. The administration pattern was a continuous method of periodic combination method. That is, in order to continuously increase estrogen regardless of the bleeding cycle, continue to apply estrana tape, and in order to form a periodic luteal phase in which progesterone increases, Provera tablets are applied on the scheduled bleeding date. Oral administration was performed for a limited period of 12 days from 1 day to 2 days before.

Details of test method (see Figure 2): For control evaluation (eplerenone (-)), subjects did not receive Celara tablets during the relevant bleeding cycle and controlled the results of the test endpoints on the evaluation date. The result of the evaluation (eplerenone (-)) was used. Regarding the evaluation of the test drug (eplerenone (+)), 14 days from the day before the start of administration of Provera tablets (corresponding to 14 days before the scheduled bleeding date) to the day after the end of administration (corresponding to the day before the scheduled bleeding date) ( If the actual bleeding begins before the scheduled bleeding date, administer 25 mg of Celara tablets orally once a day, and evaluate the test evaluation items on the evaluation date (eplerenone (eplerenone (eplerenone)). It was the result of +)).

The results of Test Example 2 are shown in Table 2.
[Table 2]

Subjects with various discomforts associated with estrogen / progesterone combination therapy due to menopause complained of various discomforts as shown in the table in the control evaluation (eplerenone (-)) without administration of the test drug Celara tablets. However, in the test drug evaluation (eplerenone (+)) in which the test drug Celara tablets were administered, all discomforts disappeared completely in all subjects. In addition, during the test period, no side effects were observed due to the administration of Celara tablets.

Test example 3: Efficacy and side effects of Esakiselone administration for various discomforts associated with PMS

The efficacy and side effects of esakiselone administration for various discomforts associated with premenstrual syndrome were evaluated by the following procedure.

Subject: One patient diagnosed with PMS.

Test drug and its dosage and administration: Minebro tablets 2.5 mg (containing 2.5 mg / tablet of esakiselenone) (Daiichi Sankyo Co., Ltd.) was orally administered once a day.

Details of test method (see FIG. 1): For control evaluation (esaxelenone (-)), subjects did not administer Minebro tablets during the relevant menstrual cycle and controlled the results of the test evaluation items on the evaluation date. The result of the evaluation (Esaki selenone (-)) was used. Regarding the evaluation of the test drug (Esakiselon (+)), 14 days from 14 days before the scheduled menstrual period to the day before the scheduled menstrual period (until that point if the actual menstruation started before the scheduled menstrual period), Minebro tablets 2.5 mg was orally administered once a day, and the results of the test evaluation items on the evaluation day were used as the results of the test drug evaluation (esaxelenone (+)).

The results of Test Example 3 are shown in Table 3.
[Table 3]

In the table, "administration of esaxelenone", (-) means a control evaluation without minebro tablets (esaxelenone (-)), and (+) means a test drug evaluation with minebro tablets (esaxelenone (+)).

Subjects with depression associated with premenstrual syndrome complained of moderate depression in the control evaluation (Esakiselonone (-)) without administration of the test drug Minebro tablets, but the test drug evaluation (Esakiselenone) in which the test drug Minebro tablets were administered. In (+)), this depression completely disappeared in the subject. In addition, during the test period, no side effects were observed due to the administration of Minebro tablets.

Test example 4: Estrogen / progesterone combination therapy for menopause Effectiveness and side effects of administration of esakiselenone for various discomforts associated with it

The efficacy and side effects of esakiselenone administration for various discomforts associated with menopausal estrogen / progesterone combination therapy were evaluated by the following procedure.

Subject: 5 patients who were diagnosed as menopausal disorder because they exhibited premenstrual syndrome within 1 year after menopause, were receiving estrogen / progesterone combination therapy, and had various discomforts.

Details of test method (see Figure 2): For control evaluation (Esakiselenone (-)), subjects did not receive Minebro tablets during the relevant bleeding cycle and controlled the results of the test evaluation items on the evaluation date. The result of the evaluation (Esaki selenone (-)) was used. Regarding the evaluation of the test drug (Esakiselone (+)), 14 days from the day before the start of administration of Provera tablets (corresponding to 14 days before the scheduled bleeding date) to the day after the end of administration (corresponding to the day before the scheduled bleeding date) ( If the actual bleeding begins before the scheduled bleeding date (until that point), Minebro tablets 2.5 mg, orally administered once a day, and the results of the test evaluation items on the evaluation date are evaluated as the test drug (Esakiselone (Esakiselone) It was the result of +)).

The results of Test Example 4 are shown in Table 4.
[Table 4]

Subjects with menopausal disorders and various discomforts associated with estrogen / progesterone combination therapy complained of various discomforts as shown in the table in the control evaluation (Esakiselon (-)) without administration of the test drug Minebro tablets. However, in the test drug evaluation (esaxelenone (+)) in which the test drug Minebro tablets were administered, all discomforts disappeared completely in all subjects. In addition, during the test period, no side effects were observed due to the administration of Minebro tablets.

(Summary)
During the luteal phase from about 14 days before the onset of menstruation to the onset of menstruation, luteal hormones increase physiologically, which may cause discomfort (premenstrual syndrome / premenstrual dysphoric disorder). In addition, when menopausal disorder receives estrogen / progesterone combination therapy to treat and prevent it, progesterone increases due to external administration, and discomfort may appear accordingly. When a selective mineralocorticoid receptor antagonist, eplerenone or esakiselenone, was administered to a patient who complained of discomfort associated with such an increase in progesterone, all the discomfort disappeared completely. In addition, during the test period, no side effects were observed due to the administration of eplerenone or esakiselenone.

The therapeutic / preventive pharmaceutical composition and the therapeutic / preventive method in the present invention are highly effective and have few side effects, and are premenstrual luteal syndrome, premenstrual syndrome or premenstrual discomfort disorder, and menopausal estrogen / progesterone combination therapy. It can be used to treat and prevent discomfort associated with an increase in progesterone, such as discomfort associated with. The therapeutic / preventive pharmaceutical composition and the therapeutic / preventive method can be used in the pharmaceutical industry and the healthcare industry.

Claims

A pharmaceutical composition for treating / preventing discomfort associated with an increase in progesterone, which contains a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical composition according to claim 1, wherein the increase in the progesterone is premenstrual luteal phase, premenstrual syndrome or premenstrual dysphoric disorder.
The pharmaceutical composition according to claim 1, wherein the increase in the progesterone is a menopausal disorder estrogen / progesterone combination therapy.
The pharmaceutical composition according to any one of claims 1 to 3, wherein the selective mineralocorticoid receptor antagonist is eplerenone or esakiselenone.
The selective mineralocorticoid receptor antagonist is eplerenone, which is at least 1 day or more from 5 days after the start of the previous menstruation to the day before the start of the next menstruation, and eplerenone is 2 mg / day or more, 400. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is administered at mg / day or less.
The selective mineralocorticoid receptor antagonist is eplerenone, and the period from 5 days before the start of administration of the progesterone preparation to 5 days after the end of administration is at least 1 day or more, and eplerenone is 2 mg / day or more, 400. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is administered at mg / day or less.
The selective mineralocorticoid receptor antagonist is esakiselenone, and the period from 5 days after the start of the previous menstruation to the day before the start of the next menstruation is at least 1 day or more, and esakiselenone is 0.1 mg / day or more, 20 The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is administered at mg / day or less.
The selective mineralocorticoid receptor antagonist is esakiselenone, and the period from 5 days before the start of administration of the progesterone preparation to 5 days after the end of administration is at least 1 day or more, and esakiselenone is 0.1 mg / day or more, 20 The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is administered at mg / day or less.
A method for treating / preventing discomfort associated with an increase in progesterone by administering a pharmaceutical composition containing a selective mineralocorticoid receptor antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
The treatment / prevention method according to claim 9, wherein the increase in the progesterone is the premenstrual luteal phase, premenstrual syndrome, or premenstrual dysphoric disorder.
The treatment / prevention method according to claim 9, wherein the increase in the progesterone is a menopausal disorder estrogen / progesterone combination therapy.
The treatment / prevention method according to any one of claims 9 to 11, wherein the selective mineralocorticoid receptor antagonist is eplerenone or esakiselenone.
The selective mineralocorticoid receptor antagonist is eplerenone, at least 1 day or more from 5 days after the start of the previous menstruation to the day before the start of the next menstruation, and eplerenone is 2 mg / day or more, 400. The treatment / prevention method according to claim 10, wherein the drug is administered at mg / day or less.
The selective mineralocorticoid receptor antagonist is eplerenone, and the period from 5 days before the start of administration of the progesterone preparation to 5 days after the end of administration is at least 1 day or more, and eplerenone is 2 mg / day or more, 400. The treatment / prevention method according to claim 11, wherein the drug is administered at mg / day or less.
The selective mineralocorticoid receptor antagonist is esakiselenone, and the period from 5 days after the start of the previous menstruation to the day before the start of the next menstruation is at least 1 day or more, and esakiselenone is 0.1 mg / day or more, 20 The treatment / prevention method according to claim 10, wherein the drug is administered at mg / day or less.
The selective mineralocorticoid receptor antagonist is esakiselenone, and the period from 5 days before the start of administration of the progesterone preparation to 5 days after the end of administration is at least 1 day, and esakiselenone is 0.1 mg / day or more, 20 The treatment / prevention method according to claim 11, wherein the drug is administered at mg / day or less.