WO2018212256A1 - THERAPEUTIC AGENT USING ESTROGEN RECEPTOR β PARTIAL AGONIST HAVING ESTROGEN RECEPTOR α INHIBITING EFFECT, FOR PAIN AND/OR STRUCTURAL LESION FROM GYNECOLOGICAL DISORDER SUCH AS ENDOMETRIOSIS AND UTERUS ADENOMYOSIS - Google Patents
THERAPEUTIC AGENT USING ESTROGEN RECEPTOR β PARTIAL AGONIST HAVING ESTROGEN RECEPTOR α INHIBITING EFFECT, FOR PAIN AND/OR STRUCTURAL LESION FROM GYNECOLOGICAL DISORDER SUCH AS ENDOMETRIOSIS AND UTERUS ADENOMYOSIS Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- the present invention relates to a therapeutic agent for pain and / or organic lesions in gynecological diseases such as endometriosis and adenomyosis using an estrogen receptor ⁇ partial agonist having an estrogen receptor ⁇ inhibitory effect.
- Gynecological diseases include diseases caused by abnormalities such as estrogen and progesterone.
- diseases caused by abnormalities such as estrogen and progesterone.
- endometriosis, uterine adenomyosis, uterine fibroids and the like can be mentioned.
- Tamoxifen registered trademark: Norbadex
- SERM selective estrogen receptor modulator
- This drug is said to have an antagonistic action on the mammary gland to antagonistically inhibit the binding of estrogen to the receptor.
- this drug itself causes endometrial cancer, uterine sarcoma or endometriosis, and is not used for the treatment of estrogen-dependent diseases including endometriosis.
- the mechanism of action of this drug on the endometrium is considered to have an intrinsic partial agonistic action on the estrogen receptor.
- fulvestrant registered trademark: Fesodex
- this drug does not show an intrinsic partial agonistic action on the estrogen receptor, and is said to show a pure antagonistic action.
- this drug since this drug has a low gastrointestinal absorption rate, it must be administered intramuscularly, and its dosage form is an intramuscular preparation. Therefore, it is not used as an oral drug for the treatment of estrogen-dependent diseases.
- raloxifene registered trademark: Evista
- Evista raloxifene
- this drug is a therapeutic agent for osteoporosis whose mechanism of action is the increase in bone mass due to the action of estrogen receptor partial agonist present in bone, and it worsens the recurrence of endometriosis, an estrogen-dependent disease. Therefore, it is not used for the treatment of gynecological diseases such as uterine fibroids, uterine adenomyosis, and endometriosis.
- Dynagest registered trademark
- This drug causes a large number of irregular bleedings, which is a big problem for patients.
- Non-patent documents 1 to 7 are further cited as documents relating to these.
- An object of the present invention is to provide a drug for treating pain associated with gynecological diseases and / or treating organic lesions due to gynecological diseases.
- the present inventor has surprisingly been synthesized and clinically studied for the purpose of treating breast cancer.
- the present invention provides the following specific embodiments (1) to (5).
- (1) Accompanying gynecological diseases containing an estrogen receptor ⁇ -inhibiting ⁇ partial agonist represented by the following structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient
- the therapeutic agent according to (1) above, wherein the gynecological disease is an estrogen-dependent gynecological disease.
- the therapeutic agent according to (1) or (2) above, wherein the gynecological disease is endometriosis and / or uterine adenomyosis.
- the therapeutic agent according to any one of (1) to (3), wherein the pain is menstrual pain and / or pelvic pain associated with the gynecological disease.
- the therapeutic agent according to any one of (1) to (4) above, wherein the organic lesion is ovarian chocolate cyst, Douglas fossa induration, and / or uterine mobility limitation.
- the present invention also provides the following specific embodiments (6) to (10).
- (6) The estrogen receptor ⁇ -inhibiting ⁇ partial agonist represented by the structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof is administered as an active ingredient, A method for treating pain associated with a gynecological disease before menopause and / or an organic lesion caused by the gynecological disease before menopause.
- the estrogen receptor ⁇ -inhibiting ⁇ partial agonist represented by the structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof is administered as an active ingredient, A method for reducing pain associated with a gynecological disease before menopause and / or improving an organic lesion caused by the gynecological disease before menopause.
- estrogen receptor ⁇ -inhibiting ⁇ represented by the above structural formula (a) Use of a partial agonist, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
- a drug for treating pain associated with gynecological diseases and / or organic lesions due to gynecological diseases can be provided.
- Example 4 is a graph showing an evaluation result by VAS of pelvic pain in Test Example 1.
- 6 is a graph showing the evaluation result of pelvic pain score by the total value of Test Example 2.
- 10 is a graph showing evaluation results of pelvic pain scores according to the degree of pelvic pain in Test Example 3.
- 10 is a graph showing the evaluation results of pelvic pain score by use of the analgesic in Test Example 4.
- 10 is a graph showing the evaluation results of menstrual pain score based on the total value of Test Example 5.
- 10 is a graph showing evaluation results of menstrual pain scores according to the degree of menstrual pain in Test Example 6.
- 12 is a graph showing evaluation results of menstrual pain scores by use of analgesics in Test Example 7.
- 10 is a graph showing the evaluation results of ovarian chocolate cysts in Test Example 8.
- Estrogen receptor ⁇ inhibition, estrogen receptor ⁇ partial agonist The compound represented by the following structural formula (a) used in the present invention is orally active and has an estrogen receptor ⁇ inhibitory action and an estrogen receptor ⁇ partial agonist action.
- the compound represented by the structural formula (a) used in the present invention can be used as a free form, a pharmaceutically acceptable salt, or a hydrate thereof.
- the pharmaceutically acceptable salt is not particularly limited, but is an inorganic acid salt such as hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc .; acetate, trifluoroacetate, lactate, propion Acid, tartrate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, silica
- organic acid salts such as cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, and salicylate.
- organic acid salts are preferable, and more preferable.
- Citrate, fumarate, succinate, benzoate, malonate, and more preferably citrate hereinafter, the citrate of the compound may be abbreviated as “SR16234”).
- the compound represented by the structural formula (a) used in the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof can be produced, for example, according to the methods described in Patent Documents 1 and 2. it can.
- the compounds represented by the structural formula (a), pharmaceutically acceptable salts thereof, and hydrates thereof are different from each other such as ovary chocolate cyst (chocolate cyst of ovary) as shown in Examples described later. It has the effect of suppressing the growth of the intrinsic endometrial tissue, and the growth inhibitory effect is stable for a long time. It can be administered orally, does not cause drug-related adverse events, and can be used safely even in premenopausal patients.
- the drug of the present invention is particularly useful as a therapeutic agent for pain associated with gynecological diseases and / or organic lesions due to gynecological diseases.
- gynecological diseases it is useful as a therapeutic agent for estrogen-dependent gynecological diseases.
- Estrogen-dependent diseases include, for example, endometriosis, adenomyosis uteri, deep endometriosis, endometrial hyperplasia, mastopathy ( mastopathy) and the like.
- Pain includes menstrual pain, dysmenorrhea, and / or pelvic pain.
- Gynecological diseases and organic lesions include cysts and cysts caused by ectopic endometrial growth; Douglas crypts caused by ectopic endometrial growth, limited uterine mobility And the like.
- Specific examples of cysts caused by ectopic endometrial proliferation include, for example, ovarian chocolate cysts that occur in the ovaries.
- medical agent of this invention has the reduction effect, disappearance effect, and improvement effect with respect to the gynecological disease and organic lesion which were mentioned above.
- endometrial tissue grows other than endometrium, for example, muscles and ligaments of uterus and surrounding tissues, ovary , Douglas fossa, rectum, peritoneum, fallopian tube, vagina, cervix, bladder, ureter, lung, navel, buttocks and the like.
- the therapeutic agent for pain associated with gynecological diseases and / or organic lesions due to gynecological diseases is represented by the structural formula (a) as an active ingredient. Contains at least a compound.
- the therapeutic agent may contain other components as necessary. Other components include, but are not limited to, stabilizers, surfactants, plasticizers, lubricants, solubilizers, buffers, sweeteners, base materials, adsorbents, corrigents, binders, suspending agents.
- Agents antioxidants, brighteners, coating agents, flavoring agents, fragrances, wetting agents, wetting regulators, antifoaming agents, chewing agents, cooling agents, coloring agents, sugar-coating agents, tonicity agents, pH adjustment Agent, softener, emulsifier, adhesive, adhesion enhancer, thickener, thickener, foaming agent, excipient, dispersant, propellant, disintegrant, disintegration aid, fragrance, moisture-proofing agent, antiseptic And pharmaceutical additives such as agents, preservatives, soothing agents, solvents, solubilizers, solubilizers, fluidizing agents, and the like.
- the dosage form of the therapeutic agent may be appropriately selected according to the patient's age, weight, disease, symptom and degree thereof, and is not particularly limited.
- tablets including sublingual tablets and orally disintegrating tablets
- Administration injection (subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.), suppository (including rectal suppository, vaginal suppository), inhalant, transdermal absorption agent, eye drop
- Parenteral administration such as nasal preparations and nasal drops.
- These may be controlled-release preparations such as immediate-release preparations and sustained-release preparations.
- oral administration by oral administration is preferable from the viewpoints of easy administration, easy compliance with medication, and easy cost reduction.
- tablets, liquids and syrups are preferable, and tablets are more preferable.
- the dosage of this therapeutic agent is appropriately determined according to the age, sex, weight, disease, symptom and degree of the patient. Although it is not particularly limited as long as it is a pharmaceutically effective amount, it is in the range of 1 to 200 mg (0.25 to 50 mg / kg body weight) per day for oral administration in terms of free form of the compound represented by the structural formula (a). More preferably, it is 4 to 120 mg (1 to 30 mg / kg body weight) per day, more preferably 8 to 60 mg (2 to 15 mg / kg body weight), and particularly preferably 10 to 40 mg (2.5 to 2.5 mg / kg body weight) per day. 10 mg / kg body weight).
- a range of 0.001 to 10 mg / kg body weight per day is preferable, more preferably 0.01 to 5 mg / kg body weight per day, and further preferably 0.5 to 2 mg / kg per day.
- the range of weight is preferable, more preferably 0.01 to 5 mg / kg body weight per day, and further preferably 0.5 to 2 mg / kg per day.
- this therapeutic agent can be administered once or divided into a plurality of times.
- the total dose is usually 0.1 to 5000 mg, and it is desirable to use a single dose or divided doses.
- additives known in the art can be blended, and methods known in the art, such as the methods described in the 16th revision Japanese Pharmacopoeia, etc. can be applied.
- methods known in the art such as the methods described in the 16th revision Japanese Pharmacopoeia, etc.
- active ingredients are solvents such as purified water and ethanol, solubilizers, suspending agents, tonicity agents, flavoring agents, buffering agents, stabilizers, flavoring agents.
- a liquid preparation, a syrup preparation, etc. can be manufactured by carrying out dispensing preparation etc. according to a conventional method. Furthermore, when preparing an injection, after adding a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. to the active ingredient, it is aseptically sealed in a container according to a conventional method. Thus, an injection for subcutaneous, intramuscular, intravenous injection or the like can be produced. Moreover, when preparing a rectal suppository, it can be formulated by adding excipients, surfactants and the like to the active ingredient, and then mixing and molding according to a conventional method.
- the active ingredient is blended with bases such as white petrolatum and paraffin, stabilizers, wetting agents, preservatives such as methyl parahydroxybenzoate, What is necessary is just to mix according to a conventional method.
- bases such as white petrolatum and paraffin, stabilizers, wetting agents, preservatives such as methyl parahydroxybenzoate, What is necessary is just to mix according to a conventional method.
- the ointment, cream, gel, paste or the like may be applied to a support such as a woven fabric, a nonwoven fabric, or a plastic film by a conventional method.
- This therapeutic agent is intended for the treatment of pain associated with gynecological diseases and / or organic lesions due to gynecological diseases.
- it since it has an action of suppressing the growth of estrogen-dependent tumors, particularly ectopic endometrial tissue, it is preferable to target endometriosis and uterine adenomyosis. More preferably, the disease is targeted.
- side effects such as bone loss are weak, even premenopausal patients can be used safely.
- symptoms such as excessive menstruation, irregular organ bleeding, dysmenorrhea, and compression symptoms caused by these diseases can be alleviated or treated.
- Evaluation item (1) Primary evaluation item: Pelvic pain measured by Visual Analogue Scale (VAS) (2) Secondary evaluation items: Pelvic pain score, menstrual pain score, objective findings (size of ovarian chocolate cyst , Consolidation of Douglas fossa, restriction of uterine mobility), and physical findings
- Study design and study outline This study is an uncontrolled, open-label study.
- the study consists of a screening phase and a 12-week treatment phase.
- screening tests were conducted within 6 weeks before the start of study drug administration, and it was confirmed that the above-mentioned selection criteria were satisfied and the above-mentioned exclusion criteria were not violated. Thereafter, in the treatment period, the test drug was administered for 12 weeks, and the evaluation items were evaluated.
- test drug 40 mg of the test drug (SR16234) was orally administered once a day for 12 weeks after breakfast.
- VAS Visual Analogue Scale
- the subject evaluated the pelvic pain score according to the evaluation criteria shown in Table 1 below.
- the pelvic pain score can be evaluated by the pelvic pain score based on the sum of the degree of pelvic pain and the use of analgesics, the pelvic pain score based only on the degree of pelvic pain, and the pelvic pain score based only on the use of analgesics, respectively. .
- the pelvic pain score before administration which is a reference for evaluation, was a score based on the degree of pelvic pain and / or the use of analgesics during the period from the start of the previous menstrual period to the day before the next menstrual period.
- the pelvic pain score after the start of administration was the score of the degree of pelvic pain and / or the use of analgesics during each period every 4 weeks after the start of administration.
- menstrual Pain Score (1) The subject himself evaluated according to the evaluation criteria for menstrual pain score shown in Table 2 below.
- the menstrual pain score can be evaluated by the menstrual pain score based on the sum of the degree of menstrual pain and the use of analgesics, the menstrual pain score based only on the degree of menstrual pain, and the menstrual pain score based only on the use of analgesics, respectively. .
- the menstrual pain score before administration which is the reference for evaluation, was a score based on the degree of menstrual pain and / or the use of analgesics during the period from the most recent menstruation start date to the next day before menstruation start.
- the menstrual pain score after the start of administration was the score of the degree of menstrual pain and / or the use of analgesics during each period of 4 weeks after the start of administration.
- Test Example 1 Evaluation result of pelvic pain by VAS Table 5 shows the results of VAS before administration (Baseline) and the amount of change from Baseline at each time point. As shown in FIG. In addition, unless there is particular notice in a present Example, the evaluation result has shown the average value of the result of ten subjects.
- Test Example 2 Evaluation result of pelvic pain score based on the total value of the degree of pelvic pain and the use of analgesics About the pelvic pain score based on the total value, the value before administration and the amount of change from Baseline at each time point The results are shown in Table 6, and the results are shown in FIG.
- Test Example 3 Evaluation result of pelvic pain score according to the degree of pelvic pain About the pelvic pain score according to the degree of pelvic pain, the values before administration and the results of change from Baseline at each time point are shown in Table 7. The result is shown in a graph in FIG.
- Test Example 4 Results of evaluation of pelvic pain score by use of analgesics
- Table 8 shows the results of the pelvic pain score by use of analgesics and the amount of change from Baseline at each time point before administration. The result is shown in a graph in FIG.
- Test Example 5 Evaluation result of the menstrual pain score based on the total value of the degree of menstrual pain and the use of analgesics About the menstrual pain score based on the total value, the value before administration and the amount of change from Baseline at each time point The results are shown in Table 9, and the results are shown in FIG.
- Test Example 6 Evaluation result of menstrual pain score according to the degree of menstrual pain About the menstrual pain score according to the degree of menstrual pain, the values before administration and the results of change from Baseline at each time point are shown in Table 10. The result is shown in a graph in FIG.
- Test Example 7 Results of evaluation of menstrual pain score by use of analgesics Table 11 shows the results of menstrual pain scores by use of analgesics and the amount of change from baseline at each time point. The result is shown in a graph in FIG.
- Test Example 8 Evaluation results of ovarian chocolate cysts Table 12 shows the values before administration and the measurement results at each time point for the volume (mm 3 ) of ovarian chocolate cysts. It is shown in FIG. This measurement result shows the result of one subject.
- Test Example 9 Evaluation result of Douglas fossa induration Table 13 shows the pre-dose values and evaluation results at 12 weeks for the Douglas fossa induration severity score. Is shown in FIG. This measurement result has shown the result of nine subjects.
- Test Example 10 Evaluation result of restriction of uterine mobility Regarding the score of severity of restriction of uterine mobility, values before administration and evaluation results at 12 weeks are shown in Table 14, and this result is shown in a graph. The result is shown in FIG. This measurement result has shown the result of nine subjects.
- Test Example 11 Adverse Event Evaluation Results Table 15 shows the adverse event results observed during the clinical trial. All of these adverse events are judged by the study physician to be unrelated to study drug administration.
- SR16234 was orally administered and statistically significantly improved compared to Baseline (Test Examples 5 to 7).
- the estrogen receptor ⁇ -inhibiting ⁇ partial agonist of the present invention can be administered orally, has low toxicity, and is excellent in safety. Therefore, it is suitable for estrogen-dependent gynecological diseases such as endometriosis and adenomyosis. It can be used widely and effectively as a drug to be used.
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Abstract
[Problem] To provide a pharmaceutical agent for treatment of pain associated with a gynecological disorder and/or treatment of a structural lesion caused by a gynecological disorder. [Solution] A therapeutic agent for pain associated with a gynecological disorder and/or a structural lesion caused by the gynecological disorder, the therapeutic agent containing an estrogen receptor α inhibiting β partial agonist represented by structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an effective component.
Description
本発明は、エストロゲン受容体α阻害作用を有するエストロゲン受容体βパーシャルアゴニストを用いた、子宮内膜症、子宮腺筋症等の婦人科疾患の疼痛、及び／又は器質的病変の治療剤に関する。
The present invention relates to a therapeutic agent for pain and / or organic lesions in gynecological diseases such as endometriosis and adenomyosis using an estrogen receptor β partial agonist having an estrogen receptor α inhibitory effect.
婦人科疾患として、エストロゲンやプロゲステロン等の異常に起因する疾患がある。例えば、子宮内膜症、子宮腺筋症、子宮筋腫等が挙げられる。
Gynecological diseases include diseases caused by abnormalities such as estrogen and progesterone. For example, endometriosis, uterine adenomyosis, uterine fibroids and the like can be mentioned.
このような疾患の治療としては、外科的切除等の手術療法が現在も第一選択とされている。薬物療法としては、ゴナドトロピンアゴニスト（ＧｎＲＨアゴニスト）として使用されているリュープリン又はスプレキュアの投与が知られている。これらは黄体形成ホルモン（ＬＨ）／卵胞刺激ホルモン（ＦＳＨ）からなる性腺刺激ホルモンの分泌抑制によって、エストロゲン量を低下させることを作用機序とする。しかしながら、これらの薬剤は、骨塩量（骨量）減少や卵巣機能欠落症状等の副作用があることから使用期間が制限されており、長期的な使用が困難である。
For the treatment of such diseases, surgical treatment such as surgical resection is still the first choice. As pharmacotherapy, administration of leuprin or spray cure used as a gonadotropin agonist (GnRH agonist) is known. The mechanism of action is to reduce the amount of estrogen by suppressing the secretion of gonadotropin hormone consisting of luteinizing hormone (LH) / follicle stimulating hormone (FSH). However, since these drugs have side effects such as bone mineral density (bone mass) decrease and ovarian function deficiency symptoms, the period of use is limited and long-term use is difficult.
そのため、子宮内膜症、子宮腺筋症等の婦人科疾患による、疼痛及び器質的病変の治療薬として、長期的に使用可能な薬剤が求められている。
Therefore, there is a demand for drugs that can be used for a long time as a treatment for pain and organic lesions due to gynecological diseases such as endometriosis and adenomyosis.
従来、選択的エストロゲン受容体モジュレーター（以下、「ＳＥＲＭ」と略す。）として、タモキシフェン（登録商標：ノルバデックス）が、国内では１９８０年代より乳癌を適応症として、使用されている。この薬剤は、乳腺に対しては、エストロゲンの受容体への結合を拮抗的に阻害するアンタゴニスト作用を有するとされている。しかしながら、この薬剤は、それ自体が子宮体癌、子宮肉腫或いは子宮内膜症を引き起こすとの報告があり、子宮内膜症を含むエストロゲン依存性疾患の治療に使われることはない。なお、この薬剤の子宮内膜に対する増殖作用の作用機序は、エストロゲン受容体に対して内因性のパーシャルアゴニスト作用を持つためであるとされている。
Conventionally, Tamoxifen (registered trademark: Norbadex) has been used as a selective estrogen receptor modulator (hereinafter abbreviated as “SERM”) in Japan since 1980s as an indication for breast cancer. This drug is said to have an antagonistic action on the mammary gland to antagonistically inhibit the binding of estrogen to the receptor. However, it has been reported that this drug itself causes endometrial cancer, uterine sarcoma or endometriosis, and is not used for the treatment of estrogen-dependent diseases including endometriosis. The mechanism of action of this drug on the endometrium is considered to have an intrinsic partial agonistic action on the estrogen receptor.
その後、エストロゲン受容体拮抗剤として、フルベストラント（登録商標：フェソロデックス）が、閉経後乳癌の治療剤として承認されている。この薬剤は、タモキシフェンとは異なり、エストロゲン受容体に対して内因性のパーシャルアゴニスト作用は示さず、ピュアアンタゴニスト作用を示すとされている。しかしながら、この薬剤は、消化管吸収率が低いことから、筋肉内に投与する必要があり、その剤形は筋注製剤とされている。したがって、エストロゲン依存性疾患の治療のための経口薬として用いられることはない。
Subsequently, fulvestrant (registered trademark: Fesodex) was approved as a therapeutic agent for postmenopausal breast cancer as an estrogen receptor antagonist. Unlike tamoxifen, this drug does not show an intrinsic partial agonistic action on the estrogen receptor, and is said to show a pure antagonistic action. However, since this drug has a low gastrointestinal absorption rate, it must be administered intramuscularly, and its dosage form is an intramuscular preparation. Therefore, it is not used as an oral drug for the treatment of estrogen-dependent diseases.
また、他のＳＥＲＭとして、ラロキシフェン（登録商標：エビスタ）が、骨粗しょう症治療を適応症として承認されている。しかしながら、この薬剤は、骨に存在するエストロゲン受容体パーシャルアゴニスト作用による骨量増加を作用機序とする骨粗しょう症治療薬であって、エストロゲン依存性疾患である子宮内膜症の再発を悪化させたとの報告もあることから、子宮筋腫、子宮腺筋症、子宮内膜症等の婦人科疾患の治療に用いられることはない。
Also, as another SERM, raloxifene (registered trademark: Evista) has been approved for the treatment of osteoporosis. However, this drug is a therapeutic agent for osteoporosis whose mechanism of action is the increase in bone mass due to the action of estrogen receptor partial agonist present in bone, and it worsens the recurrence of endometriosis, an estrogen-dependent disease. Therefore, it is not used for the treatment of gynecological diseases such as uterine fibroids, uterine adenomyosis, and endometriosis.
またさらに、他のＳＥＲＭとしては、乳癌治療剤として開発された（７α）－２１－［４－［（ジエチルアミノ）メチル］－２－メトキシフェノキシ］－７－メチル－１９－ノルプレグナ－１，３，５（１０）－トリエン－３－オール又はその薬学的に許容される塩が知られている（特許文献１及び２参照）。
As another SERM, (7α) -21- [4-[(diethylamino) methyl] -2-methoxyphenoxy] -7-methyl-19-norpregna-1,3, developed as a breast cancer therapeutic agent 5 (10) -trien-3-ol or a pharmaceutically acceptable salt thereof is known (see Patent Documents 1 and 2).
さらには、プロゲステロン受容体アゴニストとして、ディナゲスト（登録商標）が子宮内膜症の治療に用いられている。しかしながら、この薬剤は高頻度で不正出血を引き起こすことが患者にとって大きな問題であるとされている。
Furthermore, Dynagest (registered trademark) is used as a progesterone receptor agonist for the treatment of endometriosis. However, it is said that this drug causes a large number of irregular bleedings, which is a big problem for patients.
これらに関する文献としては、さらに非特許文献１～７が挙げられる。
Non-patent documents 1 to 7 are further cited as documents relating to these.
本発明の目的は、婦人科疾患に伴う疼痛の治療、及び／又は婦人科疾患による器質的病変の治療をする薬剤を提供することにある。
An object of the present invention is to provide a drug for treating pain associated with gynecological diseases and / or treating organic lesions due to gynecological diseases.
本発明者は、上記課題に対し子宮内膜症又は子宮腺筋症患者で臨床研究を実施した結果、まったく意外なことに、乳癌治療の目的で合成され臨床研究された下記構造式（ａ）で表される化合物が、エストロゲン受容体α阻害βパーシャルアゴニストとして機能し、子宮内膜症及び子宮腺筋症からなるエストロゲン依存性の婦人科疾患患者で、優れた疼痛の治療効果、及び器質的変化を改善する効果を奏することを見出し、本発明を完成するに至った。
As a result of conducting clinical studies on endometriosis or adenomyosis patients with respect to the above-mentioned problems, the present inventor has surprisingly been synthesized and clinically studied for the purpose of treating breast cancer. Is an estrogen receptor α-inhibiting β-partial agonist, and has an excellent therapeutic effect on pain and organic properties in patients with estrogen-dependent gynecological diseases consisting of endometriosis and adenomyosis. It has been found that there is an effect of improving the change, and the present invention has been completed.
本発明は、以下に示す（１）～（５）の具体的態様を提供する。
（１）下記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する、婦人科疾患に伴う疼痛、及び／又は前記婦人科疾患による器質的病変の治療剤。 The present invention provides the following specific embodiments (1) to (5).
(1) Accompanying gynecological diseases containing an estrogen receptor α-inhibiting β partial agonist represented by the following structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient A therapeutic agent for pain and / or an organic lesion caused by the gynecological disease.
（１）下記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する、婦人科疾患に伴う疼痛、及び／又は前記婦人科疾患による器質的病変の治療剤。 The present invention provides the following specific embodiments (1) to (5).
(1) Accompanying gynecological diseases containing an estrogen receptor α-inhibiting β partial agonist represented by the following structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient A therapeutic agent for pain and / or an organic lesion caused by the gynecological disease.
（２）前記婦人科疾患が、エストロゲン依存性婦人疾患である、上記（１）に記載の治療剤。
（３）前記婦人科疾患が、子宮内膜症、及び／又は子宮腺筋症である、上記（１）又は（２）に記載の治療剤。
（４）前記疼痛が、前記婦人科疾患に伴う、月経痛、及び／又は骨盤痛である、上記（１）～（３）のいずれか一項に記載の治療剤。
（５）前記器質的病変が、卵巣チョコレート嚢胞、ダグラス窩の硬結、及び／又は子宮可動性の制限である、上記（１）～（４）のいずれか一項に記載の治療剤。 (2) The therapeutic agent according to (1) above, wherein the gynecological disease is an estrogen-dependent gynecological disease.
(3) The therapeutic agent according to (1) or (2) above, wherein the gynecological disease is endometriosis and / or uterine adenomyosis.
(4) The therapeutic agent according to any one of (1) to (3), wherein the pain is menstrual pain and / or pelvic pain associated with the gynecological disease.
(5) The therapeutic agent according to any one of (1) to (4) above, wherein the organic lesion is ovarian chocolate cyst, Douglas fossa induration, and / or uterine mobility limitation.
（３）前記婦人科疾患が、子宮内膜症、及び／又は子宮腺筋症である、上記（１）又は（２）に記載の治療剤。
（４）前記疼痛が、前記婦人科疾患に伴う、月経痛、及び／又は骨盤痛である、上記（１）～（３）のいずれか一項に記載の治療剤。
（５）前記器質的病変が、卵巣チョコレート嚢胞、ダグラス窩の硬結、及び／又は子宮可動性の制限である、上記（１）～（４）のいずれか一項に記載の治療剤。 (2) The therapeutic agent according to (1) above, wherein the gynecological disease is an estrogen-dependent gynecological disease.
(3) The therapeutic agent according to (1) or (2) above, wherein the gynecological disease is endometriosis and / or uterine adenomyosis.
(4) The therapeutic agent according to any one of (1) to (3), wherein the pain is menstrual pain and / or pelvic pain associated with the gynecological disease.
(5) The therapeutic agent according to any one of (1) to (4) above, wherein the organic lesion is ovarian chocolate cyst, Douglas fossa induration, and / or uterine mobility limitation.
また、本発明は、以下（６）～（１０）の具体的態様を提供する。
（６）上記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物を有効成分として投与することを特徴とする、閉経前の婦人科疾患に伴う疼痛、及び／又は閉経前の前記婦人科疾患による器質的病変の治療方法。
（７）上記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物を有効成分として投与することを特徴とする、閉経前の婦人科疾患に伴う疼痛の軽減、及び／又は閉経前の前記婦人科疾患による器質的病変の改善方法。
（８）閉経前の婦人科疾患に伴う疼痛、及び／又は閉経前の前記婦人科疾患による器質的病変の治療のための；上記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物の使用。
（９）閉経前の婦人科疾患に伴う疼痛、及び／又は閉経前の前記婦人科疾患による器質的病変の治療用薬剤の製造のための；上記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物の使用。
（１０）上記（１）に記載の治療剤は、経口投与で用いることが好ましい。 The present invention also provides the following specific embodiments (6) to (10).
(6) The estrogen receptor α-inhibiting β partial agonist represented by the structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof is administered as an active ingredient, A method for treating pain associated with a gynecological disease before menopause and / or an organic lesion caused by the gynecological disease before menopause.
(7) The estrogen receptor α-inhibiting β partial agonist represented by the structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof is administered as an active ingredient, A method for reducing pain associated with a gynecological disease before menopause and / or improving an organic lesion caused by the gynecological disease before menopause.
(8) For the treatment of pain associated with gynecological diseases before menopause and / or organic lesions due to the gynecological diseases before menopause; estrogen receptor α-inhibiting β represented by the above structural formula (a) Use of a partial agonist, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(9) For the manufacture of a medicament for the treatment of pain associated with gynecological diseases before menopause and / or organic lesions due to the gynecological diseases before menopause; estrogen receptor represented by the above structural formula (a) Use of a body α-inhibiting β partial agonist, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(10) The therapeutic agent described in (1) above is preferably used by oral administration.
（６）上記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物を有効成分として投与することを特徴とする、閉経前の婦人科疾患に伴う疼痛、及び／又は閉経前の前記婦人科疾患による器質的病変の治療方法。
（７）上記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物を有効成分として投与することを特徴とする、閉経前の婦人科疾患に伴う疼痛の軽減、及び／又は閉経前の前記婦人科疾患による器質的病変の改善方法。
（８）閉経前の婦人科疾患に伴う疼痛、及び／又は閉経前の前記婦人科疾患による器質的病変の治療のための；上記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物の使用。
（９）閉経前の婦人科疾患に伴う疼痛、及び／又は閉経前の前記婦人科疾患による器質的病変の治療用薬剤の製造のための；上記構造式（ａ）で表される、エストロゲン受容体α阻害βパーシャルアゴニスト、その薬学的に許容される塩、又はそれらの水和物の使用。
（１０）上記（１）に記載の治療剤は、経口投与で用いることが好ましい。 The present invention also provides the following specific embodiments (6) to (10).
(6) The estrogen receptor α-inhibiting β partial agonist represented by the structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof is administered as an active ingredient, A method for treating pain associated with a gynecological disease before menopause and / or an organic lesion caused by the gynecological disease before menopause.
(7) The estrogen receptor α-inhibiting β partial agonist represented by the structural formula (a), a pharmaceutically acceptable salt thereof, or a hydrate thereof is administered as an active ingredient, A method for reducing pain associated with a gynecological disease before menopause and / or improving an organic lesion caused by the gynecological disease before menopause.
(8) For the treatment of pain associated with gynecological diseases before menopause and / or organic lesions due to the gynecological diseases before menopause; estrogen receptor α-inhibiting β represented by the above structural formula (a) Use of a partial agonist, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(9) For the manufacture of a medicament for the treatment of pain associated with gynecological diseases before menopause and / or organic lesions due to the gynecological diseases before menopause; estrogen receptor represented by the above structural formula (a) Use of a body α-inhibiting β partial agonist, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(10) The therapeutic agent described in (1) above is preferably used by oral administration.
本発明によれば、婦人科疾患に伴う疼痛、及び／又は婦人科疾患による器質的病変を治療するための薬剤を提供することができる。
According to the present invention, a drug for treating pain associated with gynecological diseases and / or organic lesions due to gynecological diseases can be provided.
以下、本発明の実施の形態について詳細に説明するが、以下の実施の形態は、本発明を説明するための例示であり、本発明はこれらに限定されるものではなく、その要旨を逸脱しない範囲内で任意に変更して実施することができる。なお、本明細書において、例えば「１～１００」との数値範囲の表記は、その上限値「１」及び下限値「１００」の双方を包含するものとする。また、他の数値範囲の表記も同様である。
Hereinafter, embodiments of the present invention will be described in detail. However, the following embodiments are examples for explaining the present invention, and the present invention is not limited thereto, and does not depart from the gist thereof. Any change can be made within the range. In this specification, for example, the description of a numerical range of “1 to 100” includes both the upper limit value “1” and the lower limit value “100”. This also applies to other numerical range notations.
［エストロゲン受容体α阻害、エストロゲン受容体βパーシャルアゴニスト］
本発明で用いられる下記構造式（ａ）で表される化合物は、経口的に活性であり、エストロゲン受容体α阻害作用、及びエストロゲン受容体βパーシャルアゴニスト作用を有する。 [Estrogen receptor α inhibition, estrogen receptor β partial agonist]
The compound represented by the following structural formula (a) used in the present invention is orally active and has an estrogen receptor α inhibitory action and an estrogen receptor β partial agonist action.
本発明で用いられる下記構造式（ａ）で表される化合物は、経口的に活性であり、エストロゲン受容体α阻害作用、及びエストロゲン受容体βパーシャルアゴニスト作用を有する。 [Estrogen receptor α inhibition, estrogen receptor β partial agonist]
The compound represented by the following structural formula (a) used in the present invention is orally active and has an estrogen receptor α inhibitory action and an estrogen receptor β partial agonist action.
本発明で用いる上記構造式（ａ）で表される化合物は、フリー体、薬学的に許容される塩、又は、その水和物として用いることができる。薬学的に許容される塩としては、特に限定されないが、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩等の無機酸塩；酢酸塩、トリフルオロ酢酸塩、乳酸塩、プロピオン酸塩、酒石酸塩、グリコール酸塩、ピルビン酸塩、シュウ酸塩、リンゴ酸塩、マロン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、安息香酸塩、ケイ皮酸塩、マンデル酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ｐ－トルエンスルホン酸塩、サリチル酸塩等の有機酸塩等が挙げられるが、これらの中でも有機酸塩が好ましく、より好ましくはクエン酸塩、フマル酸塩、コハク酸塩、安息香酸塩、マロン酸塩であり、さらに好ましくはクエン酸塩である（以下、当該化合物のクエン酸塩を「ＳＲ１６２３４」と略す場合もある。）。
The compound represented by the structural formula (a) used in the present invention can be used as a free form, a pharmaceutically acceptable salt, or a hydrate thereof. The pharmaceutically acceptable salt is not particularly limited, but is an inorganic acid salt such as hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc .; acetate, trifluoroacetate, lactate, propion Acid, tartrate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, silica Examples thereof include organic acid salts such as cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, and salicylate. Among these, organic acid salts are preferable, and more preferable. Citrate, fumarate, succinate, benzoate, malonate, and more preferably citrate (hereinafter, the citrate of the compound may be abbreviated as “SR16234”). .
本発明で用いる上記構造式（ａ）で表される化合物、その薬学的に許容される塩、又はそれらの水和物は、例えば特許文献１及び２に記載の方法に準じて製造することができる。
The compound represented by the structural formula (a) used in the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof can be produced, for example, according to the methods described in Patent Documents 1 and 2. it can.
上記構造式（ａ）で表される化合物、その薬学的に許容される塩、及びそれらの水和物は、後述する実施例で示すように、卵巣チョコレート嚢胞（chocolate cyst of ovary）等の異所性子宮内膜組織の増殖を抑制する作用を有し、当該増殖抑制作用は長期間安定である。また、経口投与が可能であり、薬剤関連有害事象を起こさず、閉経前患者であっても安全に使用可能である。
The compounds represented by the structural formula (a), pharmaceutically acceptable salts thereof, and hydrates thereof are different from each other such as ovary chocolate cyst (chocolate cyst of ovary) as shown in Examples described later. It has the effect of suppressing the growth of the intrinsic endometrial tissue, and the growth inhibitory effect is stable for a long time. It can be administered orally, does not cause drug-related adverse events, and can be used safely even in premenopausal patients.
すなわち、本発明の薬剤は、婦人科疾患に伴う疼痛、及び／又は婦人科疾患による器質的病変の治療剤として殊に有用である。婦人科疾患の中でも、エストロゲン依存性の婦人科疾患の治療剤として有用である。エストロゲン依存性の疾患としては、例えば、子宮内膜症（endometriosis）、子宮腺筋症（adenomyosis uteri）、子宮深部内膜症（deep endometriosis）、子宮内膜増殖症（endometrial hyperplasia）、乳腺症（mastopathy）等が挙げられる。これらの中でも、子宮内膜症、子宮腺筋症に伴う疼痛、及び／又は子宮内膜症、子宮腺筋症による器質的病変の治療剤として特に有用に用いられる。
That is, the drug of the present invention is particularly useful as a therapeutic agent for pain associated with gynecological diseases and / or organic lesions due to gynecological diseases. Among gynecological diseases, it is useful as a therapeutic agent for estrogen-dependent gynecological diseases. Estrogen-dependent diseases include, for example, endometriosis, adenomyosis uteri, deep endometriosis, endometrial hyperplasia, mastopathy ( mastopathy) and the like. Among these, it is particularly useful as a therapeutic agent for endometriosis, pain associated with uterine adenomyosis, and / or organic lesions due to endometriosis and uterine adenomyosis.
疼痛としては、月経痛（menstrual pain, dysmenorrhea）、及び／又は骨盤痛（pelvic pain）が挙げられる。
婦人科疾患及び器質的病変としては、異所性の子宮内膜の増殖に伴って引き起こされる嚢胞、嚢腫；異所性の子宮内膜の増殖に起因するダグラス窩の硬結、子宮可動性の制限；等が挙げられる。異所性の子宮内膜の増殖に伴って引き起こされる嚢胞の具体例としては、例えば、卵巣に生じる卵巣チョコレート嚢胞が挙げられる。そして、本発明の薬剤は、上述した婦人科疾患及び器質的病変に対する縮小効果、消失効果、改善効果を奏するものである。なお、本明細書において、異所性の子宮内膜組織の増殖とは、子宮内膜の組織が、子宮内膜以外で増殖することをいい、例えば、子宮及び周辺組織の筋肉及び靭帯、卵巣、ダグラス窩、直腸、腹膜、卵管、膣、子宮頸管、膀胱、尿管、肺、臍、鼠蹊部等で増殖するものが挙げられる。 Pain includes menstrual pain, dysmenorrhea, and / or pelvic pain.
Gynecological diseases and organic lesions include cysts and cysts caused by ectopic endometrial growth; Douglas crypts caused by ectopic endometrial growth, limited uterine mobility And the like. Specific examples of cysts caused by ectopic endometrial proliferation include, for example, ovarian chocolate cysts that occur in the ovaries. And the chemical | medical agent of this invention has the reduction effect, disappearance effect, and improvement effect with respect to the gynecological disease and organic lesion which were mentioned above. In the present specification, ectopic growth of endometrial tissue means that endometrial tissue grows other than endometrium, for example, muscles and ligaments of uterus and surrounding tissues, ovary , Douglas fossa, rectum, peritoneum, fallopian tube, vagina, cervix, bladder, ureter, lung, navel, buttocks and the like.
婦人科疾患及び器質的病変としては、異所性の子宮内膜の増殖に伴って引き起こされる嚢胞、嚢腫；異所性の子宮内膜の増殖に起因するダグラス窩の硬結、子宮可動性の制限；等が挙げられる。異所性の子宮内膜の増殖に伴って引き起こされる嚢胞の具体例としては、例えば、卵巣に生じる卵巣チョコレート嚢胞が挙げられる。そして、本発明の薬剤は、上述した婦人科疾患及び器質的病変に対する縮小効果、消失効果、改善効果を奏するものである。なお、本明細書において、異所性の子宮内膜組織の増殖とは、子宮内膜の組織が、子宮内膜以外で増殖することをいい、例えば、子宮及び周辺組織の筋肉及び靭帯、卵巣、ダグラス窩、直腸、腹膜、卵管、膣、子宮頸管、膀胱、尿管、肺、臍、鼠蹊部等で増殖するものが挙げられる。 Pain includes menstrual pain, dysmenorrhea, and / or pelvic pain.
Gynecological diseases and organic lesions include cysts and cysts caused by ectopic endometrial growth; Douglas crypts caused by ectopic endometrial growth, limited uterine mobility And the like. Specific examples of cysts caused by ectopic endometrial proliferation include, for example, ovarian chocolate cysts that occur in the ovaries. And the chemical | medical agent of this invention has the reduction effect, disappearance effect, and improvement effect with respect to the gynecological disease and organic lesion which were mentioned above. In the present specification, ectopic growth of endometrial tissue means that endometrial tissue grows other than endometrium, for example, muscles and ligaments of uterus and surrounding tissues, ovary , Douglas fossa, rectum, peritoneum, fallopian tube, vagina, cervix, bladder, ureter, lung, navel, buttocks and the like.
［婦人科疾患に伴う疼痛、及び／又は婦人科疾患による器質的病変の治療剤］
本発明の婦人科疾患に伴う疼痛、及び／又は婦人科疾患による器質的病変の治療剤（以降、「本治療剤」と称する。）は、有効成分として上記構造式（ａ）で表される化合物を少なくとも含有する。本治療剤は、必要に応じてその他の成分を含有していてもよい。その他の成分としては、特に限定されないが、安定剤、界面活性剤、可塑剤、滑沢剤、可溶化剤、緩衝剤、甘味剤、基材、吸着剤、矯味剤、結合剤、懸濁化剤、抗酸化剤、光沢化剤、コーティング剤、着香剤、香料、湿潤剤、湿潤調整剤、消泡剤、咀嚼剤、清涼化剤、着色剤、糖衣剤、等張化剤、ｐＨ調節剤、軟化剤、乳化剤、粘着剤、粘着増強剤、粘稠剤、粘稠化剤、発泡剤、賦形剤、分散剤、噴射剤、崩壊剤、崩壊補助剤、芳香剤、防湿剤、防腐剤、保存剤、無痛化剤、溶剤、溶解剤、溶解補助剤、流動化剤等の医薬品添加剤が挙げられる。 [Therapeutic agent for pain associated with gynecological diseases and / or organic lesions due to gynecological diseases]
The therapeutic agent for pain associated with gynecological diseases and / or organic lesions caused by gynecological diseases of the present invention (hereinafter referred to as “the present therapeutic agent”) is represented by the structural formula (a) as an active ingredient. Contains at least a compound. The therapeutic agent may contain other components as necessary. Other components include, but are not limited to, stabilizers, surfactants, plasticizers, lubricants, solubilizers, buffers, sweeteners, base materials, adsorbents, corrigents, binders, suspending agents. Agents, antioxidants, brighteners, coating agents, flavoring agents, fragrances, wetting agents, wetting regulators, antifoaming agents, chewing agents, cooling agents, coloring agents, sugar-coating agents, tonicity agents, pH adjustment Agent, softener, emulsifier, adhesive, adhesion enhancer, thickener, thickener, foaming agent, excipient, dispersant, propellant, disintegrant, disintegration aid, fragrance, moisture-proofing agent, antiseptic And pharmaceutical additives such as agents, preservatives, soothing agents, solvents, solubilizers, solubilizers, fluidizing agents, and the like.
本発明の婦人科疾患に伴う疼痛、及び／又は婦人科疾患による器質的病変の治療剤（以降、「本治療剤」と称する。）は、有効成分として上記構造式（ａ）で表される化合物を少なくとも含有する。本治療剤は、必要に応じてその他の成分を含有していてもよい。その他の成分としては、特に限定されないが、安定剤、界面活性剤、可塑剤、滑沢剤、可溶化剤、緩衝剤、甘味剤、基材、吸着剤、矯味剤、結合剤、懸濁化剤、抗酸化剤、光沢化剤、コーティング剤、着香剤、香料、湿潤剤、湿潤調整剤、消泡剤、咀嚼剤、清涼化剤、着色剤、糖衣剤、等張化剤、ｐＨ調節剤、軟化剤、乳化剤、粘着剤、粘着増強剤、粘稠剤、粘稠化剤、発泡剤、賦形剤、分散剤、噴射剤、崩壊剤、崩壊補助剤、芳香剤、防湿剤、防腐剤、保存剤、無痛化剤、溶剤、溶解剤、溶解補助剤、流動化剤等の医薬品添加剤が挙げられる。 [Therapeutic agent for pain associated with gynecological diseases and / or organic lesions due to gynecological diseases]
The therapeutic agent for pain associated with gynecological diseases and / or organic lesions caused by gynecological diseases of the present invention (hereinafter referred to as “the present therapeutic agent”) is represented by the structural formula (a) as an active ingredient. Contains at least a compound. The therapeutic agent may contain other components as necessary. Other components include, but are not limited to, stabilizers, surfactants, plasticizers, lubricants, solubilizers, buffers, sweeteners, base materials, adsorbents, corrigents, binders, suspending agents. Agents, antioxidants, brighteners, coating agents, flavoring agents, fragrances, wetting agents, wetting regulators, antifoaming agents, chewing agents, cooling agents, coloring agents, sugar-coating agents, tonicity agents, pH adjustment Agent, softener, emulsifier, adhesive, adhesion enhancer, thickener, thickener, foaming agent, excipient, dispersant, propellant, disintegrant, disintegration aid, fragrance, moisture-proofing agent, antiseptic And pharmaceutical additives such as agents, preservatives, soothing agents, solvents, solubilizers, solubilizers, fluidizing agents, and the like.
本治療剤の投与形態は、患者の年齢、体重、疾患、症状及びその程度等に応じて適宜選択すればよく、特に限定されない。例えば錠剤（舌下錠、口腔内崩壊錠を含む。）、顆粒剤、散剤、液剤、シロップ剤（ドライシロップ剤を含む。）、ゼリー剤、カプセル剤（ソフトカプセル、マイクロカプセルを含む。）等による経口投与；注射剤（皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤等）、坐剤（直腸坐剤、膣坐剤を含む。）、吸入剤、経皮吸収剤、点眼剤、点鼻剤等による非経口投与が挙げられる。これらは、速放性製剤や徐放性製剤などの放出制御製剤であってもよい。これらの中でも、投薬が簡便で服薬コンプライアンス遵守が容易であり、低コスト化も容易であるとの観点から、経口投与による経口剤が好ましい。経口剤としては錠剤、液剤、シロップ剤が好ましく、より好ましくは錠剤である。
The dosage form of the therapeutic agent may be appropriately selected according to the patient's age, weight, disease, symptom and degree thereof, and is not particularly limited. For example, tablets (including sublingual tablets and orally disintegrating tablets), granules, powders, liquids, syrups (including dry syrups), jellies, capsules (including soft capsules and microcapsules) orally. Administration: injection (subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.), suppository (including rectal suppository, vaginal suppository), inhalant, transdermal absorption agent, eye drop Parenteral administration such as nasal preparations and nasal drops. These may be controlled-release preparations such as immediate-release preparations and sustained-release preparations. Among these, oral administration by oral administration is preferable from the viewpoints of easy administration, easy compliance with medication, and easy cost reduction. As the oral preparation, tablets, liquids and syrups are preferable, and tablets are more preferable.
本治療剤の投与量は、患者の年齢、性別、体重、疾患、症状及びその程度等に応じて適宜決定される。薬学的有効量であれば特に限定されないが、上記構造式（ａ）で表される化合物のフリー体換算で、経口投与では１日あたり１～２００ｍｇ（０．２５～５０ｍｇ／ｋｇ体重）の範囲が好ましく、より好ましくは１日あたり４～１２０ｍｇ（１～３０ｍｇ／ｋｇ体重）、さらに好ましくは８～６０ｍｇ（２～１５ｍｇ／ｋｇ体重）、特に好ましくは１日あたり１０～４０ｍｇ（２．５～１０ｍｇ／ｋｇ体重）の範囲である。一方、非経口投与では１日あたり０．００１～１０ｍｇ／ｋｇ体重の範囲が好ましく、より好ましくは１日あたり０．０１～５ｍｇ／ｋｇ体重、さらに好ましくは１日あたり０．５～２ｍｇ／ｋｇ体重の範囲である。
The dosage of this therapeutic agent is appropriately determined according to the age, sex, weight, disease, symptom and degree of the patient. Although it is not particularly limited as long as it is a pharmaceutically effective amount, it is in the range of 1 to 200 mg (0.25 to 50 mg / kg body weight) per day for oral administration in terms of free form of the compound represented by the structural formula (a). More preferably, it is 4 to 120 mg (1 to 30 mg / kg body weight) per day, more preferably 8 to 60 mg (2 to 15 mg / kg body weight), and particularly preferably 10 to 40 mg (2.5 to 2.5 mg / kg body weight) per day. 10 mg / kg body weight). On the other hand, in the case of parenteral administration, a range of 0.001 to 10 mg / kg body weight per day is preferable, more preferably 0.01 to 5 mg / kg body weight per day, and further preferably 0.5 to 2 mg / kg per day. The range of weight.
なお、本治療剤は、１回又は複数回に分けて投与することができる。この場合、総投与量は通常０．１～５０００ｍｇとし、単回投与或いは分割投与とすることが望ましい。
In addition, this therapeutic agent can be administered once or divided into a plurality of times. In this case, the total dose is usually 0.1 to 5000 mg, and it is desirable to use a single dose or divided doses.
本治療剤の製剤化において、当業界で公知の添加剤を配合することができ、また、当業界で公知の方法、例えば第十六改正日本薬局方に記載の方法等を適用することができる。例えば、経口用固形製剤を調製する場合、有効成分に賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味剤、矯臭剤等を加えた後、常法にしたがって成形、造粒、カプセル化等することで、被覆錠剤、顆粒剤、散剤、カプセル剤等を製造することができる。また、経口用液状製剤を調製する場合には、有効成分に精製水やエタノール等の溶剤、溶解補助剤、懸濁化剤、等張化剤、矯味剤、緩衝剤、安定化剤、矯臭剤等を加えた後、常法にしたがって調液分包等することで、内服液剤、シロップ剤等を製造することができる。さらに、注射剤を調製する場合には、有効成分にｐＨ調整剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤等を添加した後、常法にしたがって容器内に無菌封入等することで、皮下、筋肉内、静脈内用注射剤等を製造することができる。また、直腸坐剤を調製する場合には、有効成分に賦形剤、界面活性剤等を加えた後、常法にしたがって混和及び成型等することで、製剤化することができる。軟膏剤、例えばペースト、クリーム及びゲルの形態に調製する際には、有効成分に白色ワセリンやパラフィン等の基剤、安定化剤、湿潤剤、パラオキシ安息香酸メチル等の保存剤等を配合し、常法にしたがって混合等すればよい。また、貼付剤を調製する場合には、織布、不織布、プラスチックフィルム等の支持体に、上記軟膏、クリーム、ゲル、ペースト等を常法により塗布すればよい。
In formulating this therapeutic agent, additives known in the art can be blended, and methods known in the art, such as the methods described in the 16th revision Japanese Pharmacopoeia, etc. can be applied. . For example, when preparing an oral solid preparation, after adding excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, flavoring agents, etc. to the active ingredients, molding and granulation according to conventional methods By encapsulating, coated tablets, granules, powders, capsules and the like can be produced. When preparing oral liquid preparations, active ingredients are solvents such as purified water and ethanol, solubilizers, suspending agents, tonicity agents, flavoring agents, buffering agents, stabilizers, flavoring agents. After adding, etc., a liquid preparation, a syrup preparation, etc. can be manufactured by carrying out dispensing preparation etc. according to a conventional method. Furthermore, when preparing an injection, after adding a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. to the active ingredient, it is aseptically sealed in a container according to a conventional method. Thus, an injection for subcutaneous, intramuscular, intravenous injection or the like can be produced. Moreover, when preparing a rectal suppository, it can be formulated by adding excipients, surfactants and the like to the active ingredient, and then mixing and molding according to a conventional method. When preparing ointments such as pastes, creams and gels, the active ingredient is blended with bases such as white petrolatum and paraffin, stabilizers, wetting agents, preservatives such as methyl parahydroxybenzoate, What is necessary is just to mix according to a conventional method. When preparing a patch, the ointment, cream, gel, paste or the like may be applied to a support such as a woven fabric, a nonwoven fabric, or a plastic film by a conventional method.
本治療剤は、婦人科疾患に伴う疼痛、及び／又は婦人科疾患による器質的病変の治療を対象とする。上述したとおり、エストロゲン依存性の腫瘍、中でも異所性の子宮内膜組織の増殖を抑制する作用を有することから、子宮内膜症、子宮腺筋症を対象とすることが好ましく、子宮内膜症を対象とすることがより好ましい。さらに、骨量減少等の副作用が弱いことから、閉経前患者であっても安全に使用可能である。また、これらの疾患に起因する過多月経、不正性器出血、月経困難症、圧迫症状等の症状を緩和又は治療することもできる。
This therapeutic agent is intended for the treatment of pain associated with gynecological diseases and / or organic lesions due to gynecological diseases. As described above, since it has an action of suppressing the growth of estrogen-dependent tumors, particularly ectopic endometrial tissue, it is preferable to target endometriosis and uterine adenomyosis. More preferably, the disease is targeted. Furthermore, since side effects such as bone loss are weak, even premenopausal patients can be used safely. In addition, symptoms such as excessive menstruation, irregular organ bleeding, dysmenorrhea, and compression symptoms caused by these diseases can be alleviated or treated.
以下、各種試験結果に基づいて、本発明をさらに詳細に説明するが、本発明はこれらにより何ら限定されるものではない。
Hereinafter, the present invention will be described in more detail based on various test results, but the present invention is not limited thereto.
［試験例：子宮内膜症・子宮腺筋症患者の疼痛及び器質的病変の抑制作用の確認］
＜子宮内膜症・子宮腺筋症患者での臨床試験プロトコール＞
［１］評価項目
（１）主要評価項目：Visual Analogue Scale（ＶＡＳ）により測定された骨盤痛
（２）副次的評価項目：骨盤痛スコア、月経痛スコア、他覚所見（卵巣チョコレート嚢胞の大きさ、ダグラス窩の硬結、子宮可動性の制限）、及び身体所見 [Test example: Confirmation of pain and organic lesion inhibitory effect in patients with endometriosis and adenomyosis]
<Clinical trial protocol in patients with endometriosis and adenomyosis>
[1] Evaluation item (1) Primary evaluation item: Pelvic pain measured by Visual Analogue Scale (VAS) (2) Secondary evaluation items: Pelvic pain score, menstrual pain score, objective findings (size of ovarian chocolate cyst , Consolidation of Douglas fossa, restriction of uterine mobility), and physical findings
＜子宮内膜症・子宮腺筋症患者での臨床試験プロトコール＞
［１］評価項目
（１）主要評価項目：Visual Analogue Scale（ＶＡＳ）により測定された骨盤痛
（２）副次的評価項目：骨盤痛スコア、月経痛スコア、他覚所見（卵巣チョコレート嚢胞の大きさ、ダグラス窩の硬結、子宮可動性の制限）、及び身体所見 [Test example: Confirmation of pain and organic lesion inhibitory effect in patients with endometriosis and adenomyosis]
<Clinical trial protocol in patients with endometriosis and adenomyosis>
[1] Evaluation item (1) Primary evaluation item: Pelvic pain measured by Visual Analogue Scale (VAS) (2) Secondary evaluation items: Pelvic pain score, menstrual pain score, objective findings (size of ovarian chocolate cyst , Consolidation of Douglas fossa, restriction of uterine mobility), and physical findings
［２］臨床試験対象者の選択基準
以下の条件を満たす１０名の子宮内膜症・子宮腺筋症患者を、臨床試験対象者とした。
・２０歳以上の外来患者
・月経周期を有する患者
・臨床的に子宮内膜症又は子宮腺筋症と診断された患者
・子宮内膜症に伴う骨盤痛を有する患者 [2] Selection criteria for clinical trial subjects Ten endometriosis and adenomyosis patients who satisfy the following conditions were clinical trial subjects.
・ Outpatients over 20 years old ・ Patients with menstrual cycle ・ Patients clinically diagnosed with endometriosis or adenomyosis ・ Patients with pelvic pain associated with endometriosis
以下の条件を満たす１０名の子宮内膜症・子宮腺筋症患者を、臨床試験対象者とした。
・２０歳以上の外来患者
・月経周期を有する患者
・臨床的に子宮内膜症又は子宮腺筋症と診断された患者
・子宮内膜症に伴う骨盤痛を有する患者 [2] Selection criteria for clinical trial subjects Ten endometriosis and adenomyosis patients who satisfy the following conditions were clinical trial subjects.
・ Outpatients over 20 years old ・ Patients with menstrual cycle ・ Patients clinically diagnosed with endometriosis or adenomyosis ・ Patients with pelvic pain associated with endometriosis
［３］臨床試験対象者の除外基準
但し、以下の条件のいずれかに該当する患者は、臨床試験対象者に組み入れないこととした。
・エストロゲン依存性腫瘍（例えば乳癌、子宮体癌）、子宮頸癌又はその疑いのある患者長径３ｃｍ以上の子宮筋腫と診断された患者
・診断の確定していない異常性器出血のある患者
・骨粗しょう症、骨量減少又はその他の代謝性骨疾患の病歴ある患者 [3] Exclusion criteria for clinical trial subjects However, patients who meet any of the following conditions will not be included in clinical trial subjects.
・ Estrogen-dependent tumors (eg, breast cancer, endometrial cancer), cervical cancer, or suspected patients Diagnosed with uterine fibroids with a major axis of 3 cm or more ・ Patients with abnormal genital bleeding that have not been confirmed Patients with a history of symptom, bone loss or other metabolic bone disease
但し、以下の条件のいずれかに該当する患者は、臨床試験対象者に組み入れないこととした。
・エストロゲン依存性腫瘍（例えば乳癌、子宮体癌）、子宮頸癌又はその疑いのある患者長径３ｃｍ以上の子宮筋腫と診断された患者
・診断の確定していない異常性器出血のある患者
・骨粗しょう症、骨量減少又はその他の代謝性骨疾患の病歴ある患者 [3] Exclusion criteria for clinical trial subjects However, patients who meet any of the following conditions will not be included in clinical trial subjects.
・ Estrogen-dependent tumors (eg, breast cancer, endometrial cancer), cervical cancer, or suspected patients Diagnosed with uterine fibroids with a major axis of 3 cm or more ・ Patients with abnormal genital bleeding that have not been confirmed Patients with a history of symptom, bone loss or other metabolic bone disease
［４］試験デザイン、及び試験アウトライン
本試験は、非対照、非盲検試験である。
本試験はスクリーニング期と、１２週間の治療期とからなる。スクリーニング期では、試験薬投与開始前６週間以内にスクリーニング検査を行い、上述した選択基準を満たし、上述した除外基準に抵触しないことを確認した。その後、治療期では、１２週間の間、試験薬の投与を行い、上記評価項目の評価を行った。 [4] Study design and study outline This study is an uncontrolled, open-label study.
The study consists of a screening phase and a 12-week treatment phase. In the screening period, screening tests were conducted within 6 weeks before the start of study drug administration, and it was confirmed that the above-mentioned selection criteria were satisfied and the above-mentioned exclusion criteria were not violated. Thereafter, in the treatment period, the test drug was administered for 12 weeks, and the evaluation items were evaluated.
本試験は、非対照、非盲検試験である。
本試験はスクリーニング期と、１２週間の治療期とからなる。スクリーニング期では、試験薬投与開始前６週間以内にスクリーニング検査を行い、上述した選択基準を満たし、上述した除外基準に抵触しないことを確認した。その後、治療期では、１２週間の間、試験薬の投与を行い、上記評価項目の評価を行った。 [4] Study design and study outline This study is an uncontrolled, open-label study.
The study consists of a screening phase and a 12-week treatment phase. In the screening period, screening tests were conducted within 6 weeks before the start of study drug administration, and it was confirmed that the above-mentioned selection criteria were satisfied and the above-mentioned exclusion criteria were not violated. Thereafter, in the treatment period, the test drug was administered for 12 weeks, and the evaluation items were evaluated.
［５］試験薬の用法、用量、及び投与期間
本試験では、４０ｍｇの試験薬（ＳＲ１６２３４）を１日１回朝食後に１２週間、経口投与した。 [5] Usage, dose, and administration period of test drug In this test, 40 mg of the test drug (SR16234) was orally administered once a day for 12 weeks after breakfast.
本試験では、４０ｍｇの試験薬（ＳＲ１６２３４）を１日１回朝食後に１２週間、経口投与した。 [5] Usage, dose, and administration period of test drug In this test, 40 mg of the test drug (SR16234) was orally administered once a day for 12 weeks after breakfast.
［６］骨盤痛のVisual Analogue Scale（ＶＡＳ）による評価方法
以下の方法により骨盤痛のＶＡＳを測定した。
（１）ＶＡＳは１００ｍｍの直線の目盛の無いスケールであり、直線の左端には「痛みなし」と表示され、右端には「今まで経験した最も強い痛み」と表示されている。「今まで経験した最も強い痛みを」を１００ｍｍ、「痛み無し」を０ｍｍとした。このスケールに従い、評価期間ごとの骨盤痛のＶＡＳを被験者自身が評価を行った。
（２）評価の基準となる投与前の骨盤痛のＶＡＳは、直前の月経開始前から次の月経開始前日までの期間中で最も強い骨盤痛を評価した。
（３）投与開始後の骨盤痛のＶＡＳは、投与開始後４週間ごとの各期間中で最も強い骨盤痛を評価した。 [6] Evaluation method of pelvic pain by Visual Analogue Scale (VAS) VAS of pelvic pain was measured by the following method.
(1) VAS is a 100 mm straight scale without a scale, and “no pain” is displayed at the left end of the straight line, and “the strongest pain experienced so far” is displayed at the right end. “The strongest pain experienced so far” was 100 mm, and “no pain” was 0 mm. According to this scale, the subject himself evaluated the pelvic pain VAS for each evaluation period.
(2) VAS of pelvic pain before administration, which is a reference for evaluation, evaluated the strongest pelvic pain during the period from immediately before the start of menstruation until the next day before the start of the next menstruation.
(3) VAS of pelvic pain after the start of administration evaluated the strongest pelvic pain in each period every 4 weeks after the start of administration.
以下の方法により骨盤痛のＶＡＳを測定した。
（１）ＶＡＳは１００ｍｍの直線の目盛の無いスケールであり、直線の左端には「痛みなし」と表示され、右端には「今まで経験した最も強い痛み」と表示されている。「今まで経験した最も強い痛みを」を１００ｍｍ、「痛み無し」を０ｍｍとした。このスケールに従い、評価期間ごとの骨盤痛のＶＡＳを被験者自身が評価を行った。
（２）評価の基準となる投与前の骨盤痛のＶＡＳは、直前の月経開始前から次の月経開始前日までの期間中で最も強い骨盤痛を評価した。
（３）投与開始後の骨盤痛のＶＡＳは、投与開始後４週間ごとの各期間中で最も強い骨盤痛を評価した。 [6] Evaluation method of pelvic pain by Visual Analogue Scale (VAS) VAS of pelvic pain was measured by the following method.
(1) VAS is a 100 mm straight scale without a scale, and “no pain” is displayed at the left end of the straight line, and “the strongest pain experienced so far” is displayed at the right end. “The strongest pain experienced so far” was 100 mm, and “no pain” was 0 mm. According to this scale, the subject himself evaluated the pelvic pain VAS for each evaluation period.
(2) VAS of pelvic pain before administration, which is a reference for evaluation, evaluated the strongest pelvic pain during the period from immediately before the start of menstruation until the next day before the start of the next menstruation.
(3) VAS of pelvic pain after the start of administration evaluated the strongest pelvic pain in each period every 4 weeks after the start of administration.
［７］骨盤痛スコアによる評価方法
（１）以下の表１に示した骨盤痛スコアの評価基準に従い、被験者自身が評価を行った。骨盤痛スコアは、骨盤痛の程度と鎮痛薬の使用との合計値による骨盤痛スコア、骨盤痛の程度のみによる骨盤痛スコア、鎮痛薬の使用のみによる骨盤痛スコアによって、それぞれ評価することができる。
（２）評価の基準となる投与前の骨盤痛スコアは、直前の月経開始前から次の月経開始前日までの期間中の骨盤痛の程度及び／又は鎮痛薬の使用によるスコアとした。
（３）投与開始後の骨盤痛スコアは、投与開始後４週間ごとの各期間中における骨盤痛の程度及び／又は鎮痛薬の使用によるスコアとした。 [7] Evaluation Method Based on Pelvic Pain Score (1) The subject evaluated the pelvic pain score according to the evaluation criteria shown in Table 1 below. The pelvic pain score can be evaluated by the pelvic pain score based on the sum of the degree of pelvic pain and the use of analgesics, the pelvic pain score based only on the degree of pelvic pain, and the pelvic pain score based only on the use of analgesics, respectively. .
(2) The pelvic pain score before administration, which is a reference for evaluation, was a score based on the degree of pelvic pain and / or the use of analgesics during the period from the start of the previous menstrual period to the day before the next menstrual period.
(3) The pelvic pain score after the start of administration was the score of the degree of pelvic pain and / or the use of analgesics during each period every 4 weeks after the start of administration.
（１）以下の表１に示した骨盤痛スコアの評価基準に従い、被験者自身が評価を行った。骨盤痛スコアは、骨盤痛の程度と鎮痛薬の使用との合計値による骨盤痛スコア、骨盤痛の程度のみによる骨盤痛スコア、鎮痛薬の使用のみによる骨盤痛スコアによって、それぞれ評価することができる。
（２）評価の基準となる投与前の骨盤痛スコアは、直前の月経開始前から次の月経開始前日までの期間中の骨盤痛の程度及び／又は鎮痛薬の使用によるスコアとした。
（３）投与開始後の骨盤痛スコアは、投与開始後４週間ごとの各期間中における骨盤痛の程度及び／又は鎮痛薬の使用によるスコアとした。 [7] Evaluation Method Based on Pelvic Pain Score (1) The subject evaluated the pelvic pain score according to the evaluation criteria shown in Table 1 below. The pelvic pain score can be evaluated by the pelvic pain score based on the sum of the degree of pelvic pain and the use of analgesics, the pelvic pain score based only on the degree of pelvic pain, and the pelvic pain score based only on the use of analgesics, respectively. .
(2) The pelvic pain score before administration, which is a reference for evaluation, was a score based on the degree of pelvic pain and / or the use of analgesics during the period from the start of the previous menstrual period to the day before the next menstrual period.
(3) The pelvic pain score after the start of administration was the score of the degree of pelvic pain and / or the use of analgesics during each period every 4 weeks after the start of administration.
［８］月経痛スコアによる評価方法
（１）以下の表２に示した月経痛スコアの評価基準に従い、被験者自身が評価を行った。月経痛スコアは、月経痛の程度と鎮痛薬の使用との合計値による月経痛スコア、月経痛の程度のみによる月経痛スコア、鎮痛薬の使用のみによる月経痛スコアによって、それぞれ評価することができる。
（２）評価の基準となる投与前の月経痛スコアは、直近の月経開始日から次の月経開始前日までの期間中の月経痛の程度及び／又は鎮痛薬の使用によるスコアとした。
（３）投与開始後の月経痛スコアは、投与開始後４週間ごとの各期間中における月経痛の程度及び／又は鎮痛薬の使用によるスコアとした。 [8] Evaluation Method Based on Menstrual Pain Score (1) The subject himself evaluated according to the evaluation criteria for menstrual pain score shown in Table 2 below. The menstrual pain score can be evaluated by the menstrual pain score based on the sum of the degree of menstrual pain and the use of analgesics, the menstrual pain score based only on the degree of menstrual pain, and the menstrual pain score based only on the use of analgesics, respectively. .
(2) The menstrual pain score before administration, which is the reference for evaluation, was a score based on the degree of menstrual pain and / or the use of analgesics during the period from the most recent menstruation start date to the next day before menstruation start.
(3) The menstrual pain score after the start of administration was the score of the degree of menstrual pain and / or the use of analgesics during each period of 4 weeks after the start of administration.
（１）以下の表２に示した月経痛スコアの評価基準に従い、被験者自身が評価を行った。月経痛スコアは、月経痛の程度と鎮痛薬の使用との合計値による月経痛スコア、月経痛の程度のみによる月経痛スコア、鎮痛薬の使用のみによる月経痛スコアによって、それぞれ評価することができる。
（２）評価の基準となる投与前の月経痛スコアは、直近の月経開始日から次の月経開始前日までの期間中の月経痛の程度及び／又は鎮痛薬の使用によるスコアとした。
（３）投与開始後の月経痛スコアは、投与開始後４週間ごとの各期間中における月経痛の程度及び／又は鎮痛薬の使用によるスコアとした。 [8] Evaluation Method Based on Menstrual Pain Score (1) The subject himself evaluated according to the evaluation criteria for menstrual pain score shown in Table 2 below. The menstrual pain score can be evaluated by the menstrual pain score based on the sum of the degree of menstrual pain and the use of analgesics, the menstrual pain score based only on the degree of menstrual pain, and the menstrual pain score based only on the use of analgesics, respectively. .
(2) The menstrual pain score before administration, which is the reference for evaluation, was a score based on the degree of menstrual pain and / or the use of analgesics during the period from the most recent menstruation start date to the next day before menstruation start.
(3) The menstrual pain score after the start of administration was the score of the degree of menstrual pain and / or the use of analgesics during each period of 4 weeks after the start of administration.
［９］超音波検査
卵巣チョコレート嚢胞の有無を経膣超音波検査により観察した。観察は、投与開始前と、投与開始後４週間ごとの計４回行った。卵巣チョコレート嚢胞が「あり」の場合は、３方向（Ｄ１，Ｄ２，Ｄ３）又は２方向（Ｄ１，Ｄ２）の径（ｍｍ）を測定した。得られた径から、卵巣チョコレート嚢胞の容積を算出した。 [9] Ultrasonography The presence or absence of ovarian chocolate cysts was observed by transvaginal ultrasound. Observation was performed a total of 4 times before the start of administration and every 4 weeks after the start of administration. When the ovary chocolate cyst was “present”, the diameter (mm) in three directions (D1, D2, D3) or two directions (D1, D2) was measured. From the obtained diameter, the volume of the ovarian chocolate cyst was calculated.
卵巣チョコレート嚢胞の有無を経膣超音波検査により観察した。観察は、投与開始前と、投与開始後４週間ごとの計４回行った。卵巣チョコレート嚢胞が「あり」の場合は、３方向（Ｄ１，Ｄ２，Ｄ３）又は２方向（Ｄ１，Ｄ２）の径（ｍｍ）を測定した。得られた径から、卵巣チョコレート嚢胞の容積を算出した。 [9] Ultrasonography The presence or absence of ovarian chocolate cysts was observed by transvaginal ultrasound. Observation was performed a total of 4 times before the start of administration and every 4 weeks after the start of administration. When the ovary chocolate cyst was “present”, the diameter (mm) in three directions (D1, D2, D3) or two directions (D1, D2) was measured. From the obtained diameter, the volume of the ovarian chocolate cyst was calculated.
［１０］内診（ダグラス窩の硬結）
以下の表３に示した評価基準に従い、内診によるダグラス窩の硬結の評価を行った。
[10] Internal examination (concretion of Douglas fossa)
According to the evaluation criteria shown in Table 3 below, the induration of Douglas fossa was evaluated by internal examination.
以下の表３に示した評価基準に従い、内診によるダグラス窩の硬結の評価を行った。
According to the evaluation criteria shown in Table 3 below, the induration of Douglas fossa was evaluated by internal examination.
［１１］内診（子宮可動性の制限）
以下の表４に示した評価基準に従い、内診による子宮可動性の制限の評価を行った。
[11] Internal examination (restriction of uterine mobility)
According to the evaluation criteria shown in Table 4 below, the restriction of uterine mobility by internal examination was evaluated.
以下の表４に示した評価基準に従い、内診による子宮可動性の制限の評価を行った。
According to the evaluation criteria shown in Table 4 below, the restriction of uterine mobility by internal examination was evaluated.
［１２］身体所見
試験薬投与後に問診・診察を行い、その結果について、試験薬投与前と比較して臨床的に有意な事象を有害事象として評価した。 [12] Physical findings Interviews / examinations were conducted after administration of the study drug, and clinically significant events were evaluated as adverse events compared to those before administration of the study drug.
試験薬投与後に問診・診察を行い、その結果について、試験薬投与前と比較して臨床的に有意な事象を有害事象として評価した。 [12] Physical findings Interviews / examinations were conducted after administration of the study drug, and clinically significant events were evaluated as adverse events compared to those before administration of the study drug.
＜子宮内膜症・子宮腺筋症患者での臨床試験結果＞
［１］試験例１：骨盤痛のＶＡＳによる評価結果
ＶＡＳについて、投与前（Baseline）の値、及び各時点のBaselineからの変化量の結果を表５に、この結果をグラフに表したものを図１に示す。なお、本実施例において特に断りのない限り、評価結果は１０名の対象者の結果の平均値を示している。 <Results of clinical trials in patients with endometriosis and adenomyosis>
[1] Test Example 1: Evaluation result of pelvic pain by VAS Table 5 shows the results of VAS before administration (Baseline) and the amount of change from Baseline at each time point. As shown in FIG. In addition, unless there is particular notice in a present Example, the evaluation result has shown the average value of the result of ten subjects.
［１］試験例１：骨盤痛のＶＡＳによる評価結果
ＶＡＳについて、投与前（Baseline）の値、及び各時点のBaselineからの変化量の結果を表５に、この結果をグラフに表したものを図１に示す。なお、本実施例において特に断りのない限り、評価結果は１０名の対象者の結果の平均値を示している。 <Results of clinical trials in patients with endometriosis and adenomyosis>
[1] Test Example 1: Evaluation result of pelvic pain by VAS Table 5 shows the results of VAS before administration (Baseline) and the amount of change from Baseline at each time point. As shown in FIG. In addition, unless there is particular notice in a present Example, the evaluation result has shown the average value of the result of ten subjects.
［２］試験例２：骨盤痛の程度と鎮痛薬の使用との合計値による骨盤痛スコアの評価結果
合計値による骨盤痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表６に、この結果をグラフに表したものを図２に示す。 [2] Test Example 2: Evaluation result of pelvic pain score based on the total value of the degree of pelvic pain and the use of analgesics About the pelvic pain score based on the total value, the value before administration and the amount of change from Baseline at each time point The results are shown in Table 6, and the results are shown in FIG.
合計値による骨盤痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表６に、この結果をグラフに表したものを図２に示す。 [2] Test Example 2: Evaluation result of pelvic pain score based on the total value of the degree of pelvic pain and the use of analgesics About the pelvic pain score based on the total value, the value before administration and the amount of change from Baseline at each time point The results are shown in Table 6, and the results are shown in FIG.
［３］試験例３：骨盤痛の程度による骨盤痛スコアの評価結果
骨盤痛の程度による骨盤痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表７に、この結果をグラフに表したものを図３に示す。 [3] Test Example 3: Evaluation result of pelvic pain score according to the degree of pelvic pain About the pelvic pain score according to the degree of pelvic pain, the values before administration and the results of change from Baseline at each time point are shown in Table 7. The result is shown in a graph in FIG.
骨盤痛の程度による骨盤痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表７に、この結果をグラフに表したものを図３に示す。 [3] Test Example 3: Evaluation result of pelvic pain score according to the degree of pelvic pain About the pelvic pain score according to the degree of pelvic pain, the values before administration and the results of change from Baseline at each time point are shown in Table 7. The result is shown in a graph in FIG.
［４］試験例４：鎮痛薬の使用による骨盤痛スコアの評価結果
鎮痛薬の使用による骨盤痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表８に、この結果をグラフに表したものを図４に示す。 [4] Test Example 4: Results of evaluation of pelvic pain score by use of analgesics Table 8 shows the results of the pelvic pain score by use of analgesics and the amount of change from Baseline at each time point before administration. The result is shown in a graph in FIG.
鎮痛薬の使用による骨盤痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表８に、この結果をグラフに表したものを図４に示す。 [4] Test Example 4: Results of evaluation of pelvic pain score by use of analgesics Table 8 shows the results of the pelvic pain score by use of analgesics and the amount of change from Baseline at each time point before administration. The result is shown in a graph in FIG.
［５］試験例５：月経痛の程度と鎮痛薬の使用との合計値による月経痛スコアの評価結果
合計値による月経痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表９に、この結果をグラフに表したものを図５に示す。 [5] Test Example 5: Evaluation result of the menstrual pain score based on the total value of the degree of menstrual pain and the use of analgesics About the menstrual pain score based on the total value, the value before administration and the amount of change from Baseline at each time point The results are shown in Table 9, and the results are shown in FIG.
合計値による月経痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表９に、この結果をグラフに表したものを図５に示す。 [5] Test Example 5: Evaluation result of the menstrual pain score based on the total value of the degree of menstrual pain and the use of analgesics About the menstrual pain score based on the total value, the value before administration and the amount of change from Baseline at each time point The results are shown in Table 9, and the results are shown in FIG.
［６］試験例６：月経痛の程度による月経痛スコアの評価結果
月経痛の程度による月経痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表１０に、この結果をグラフに表したものを図６に示す。 [6] Test Example 6: Evaluation result of menstrual pain score according to the degree of menstrual pain About the menstrual pain score according to the degree of menstrual pain, the values before administration and the results of change from Baseline at each time point are shown in Table 10. The result is shown in a graph in FIG.
月経痛の程度による月経痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表１０に、この結果をグラフに表したものを図６に示す。 [6] Test Example 6: Evaluation result of menstrual pain score according to the degree of menstrual pain About the menstrual pain score according to the degree of menstrual pain, the values before administration and the results of change from Baseline at each time point are shown in Table 10. The result is shown in a graph in FIG.
［７］試験例７：鎮痛薬の使用による月経痛スコアの評価結果
鎮痛薬の使用による月経痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表１１に、この結果をグラフに表したものを図７に示す。 [7] Test Example 7: Results of evaluation of menstrual pain score by use of analgesics Table 11 shows the results of menstrual pain scores by use of analgesics and the amount of change from baseline at each time point. The result is shown in a graph in FIG.
鎮痛薬の使用による月経痛スコアについて、投与前の値、及び各時点のBaselineからの変化量の結果を表１１に、この結果をグラフに表したものを図７に示す。 [7] Test Example 7: Results of evaluation of menstrual pain score by use of analgesics Table 11 shows the results of menstrual pain scores by use of analgesics and the amount of change from baseline at each time point. The result is shown in a graph in FIG.
［８］試験例８：卵巣チョコレート嚢胞の評価結果
卵巣チョコレート嚢胞の容積（ｍｍ3）について、投与前の値、及び各時点の測定結果を表１２に、この結果をグラフに表したものを図８に示す。この測定結果は、１名の対象者の結果を示している。 [8] Test Example 8: Evaluation results of ovarian chocolate cysts Table 12 shows the values before administration and the measurement results at each time point for the volume (mm 3 ) of ovarian chocolate cysts. It is shown in FIG. This measurement result shows the result of one subject.
卵巣チョコレート嚢胞の容積（ｍｍ3）について、投与前の値、及び各時点の測定結果を表１２に、この結果をグラフに表したものを図８に示す。この測定結果は、１名の対象者の結果を示している。 [8] Test Example 8: Evaluation results of ovarian chocolate cysts Table 12 shows the values before administration and the measurement results at each time point for the volume (mm 3 ) of ovarian chocolate cysts. It is shown in FIG. This measurement result shows the result of one subject.
［９］試験例９：ダグラス窩の硬結の評価結果
ダグラス窩の硬結の重症度のスコアについて、投与前の値、及び１２週時点の評価結果を表１３に、この結果をグラフに表したものを図９に示す。この測定結果は、９名の対象者の結果を示している。 [9] Test Example 9: Evaluation result of Douglas fossa induration Table 13 shows the pre-dose values and evaluation results at 12 weeks for the Douglas fossa induration severity score. Is shown in FIG. This measurement result has shown the result of nine subjects.
ダグラス窩の硬結の重症度のスコアについて、投与前の値、及び１２週時点の評価結果を表１３に、この結果をグラフに表したものを図９に示す。この測定結果は、９名の対象者の結果を示している。 [9] Test Example 9: Evaluation result of Douglas fossa induration Table 13 shows the pre-dose values and evaluation results at 12 weeks for the Douglas fossa induration severity score. Is shown in FIG. This measurement result has shown the result of nine subjects.
［１０］試験例１０：子宮可動性の制限の評価結果
子宮可動性の制限の重症度のスコアについて、投与前の値、及び１２週時点の評価結果を表１４に、この結果をグラフに表したものを図１０に示す。この測定結果は、９名の対象者の結果を示している。 [10] Test Example 10: Evaluation result of restriction of uterine mobility Regarding the score of severity of restriction of uterine mobility, values before administration and evaluation results at 12 weeks are shown in Table 14, and this result is shown in a graph. The result is shown in FIG. This measurement result has shown the result of nine subjects.
子宮可動性の制限の重症度のスコアについて、投与前の値、及び１２週時点の評価結果を表１４に、この結果をグラフに表したものを図１０に示す。この測定結果は、９名の対象者の結果を示している。 [10] Test Example 10: Evaluation result of restriction of uterine mobility Regarding the score of severity of restriction of uterine mobility, values before administration and evaluation results at 12 weeks are shown in Table 14, and this result is shown in a graph. The result is shown in FIG. This measurement result has shown the result of nine subjects.
［１１］試験例１１：有害事象の評価結果
臨床試験中に観察された有害事象の結果を表１５に示す。これらの有害事象はいずれも試験薬投与とは関連無いものであると試験実施医師により判断されている。 [11] Test Example 11: Adverse Event Evaluation Results Table 15 shows the adverse event results observed during the clinical trial. All of these adverse events are judged by the study physician to be unrelated to study drug administration.
臨床試験中に観察された有害事象の結果を表１５に示す。これらの有害事象はいずれも試験薬投与とは関連無いものであると試験実施医師により判断されている。 [11] Test Example 11: Adverse Event Evaluation Results Table 15 shows the adverse event results observed during the clinical trial. All of these adverse events are judged by the study physician to be unrelated to study drug administration.
［１２］考察
表５及び図１に示すように、ＶＡＳにより測定された骨盤痛は、１日あたり４０ｍｇのＳＲ１６２３４の経口投与により、Baselineに比較して統計的に有意に改善された（試験例１）。
また、表６及び図２、表７及び図３、並びに表８及び図４にそれぞれ示すように、合計値、骨盤痛の程度、及び鎮痛薬の使用による骨盤痛スコアは、１日あたり４０ｍｇのＳＲ１６２３４の経口投与により、Baselineに比較して統計的に有意に改善された（試験例２～４）。
また、表９及び図５、表１０及び図６、並びに表１１及び図７にそれぞれ示すように、合計値、月経痛の程度、及び鎮痛薬の使用による月経痛スコアは、１日あたり４０ｍｇのＳＲ１６２３４の経口投与により、Baselineに比較して統計的に有意に改善された（試験例５～７）。 [12] Discussion As shown in Table 5 and FIG. 1, pelvic pain measured by VAS was statistically significantly improved by oral administration of 40 mg of SR16234 per day as compared to Baseline (Test Example). 1).
In addition, as shown in Table 6 and FIG. 2, Table 7 and FIG. 3, and Table 8 and FIG. 4, respectively, the total value, the degree of pelvic pain, and the pelvic pain score due to the use of analgesics are 40 mg per day. SR16234 was orally administered and statistically significantly improved compared to Baseline (Test Examples 2 to 4).
In addition, as shown in Table 9 and FIG. 5, Table 10 and FIG. 6, and Table 11 and FIG. 7, respectively, the total value, the degree of menstrual pain, and the menstrual pain score due to the use of analgesics are 40 mg per day. SR16234 was orally administered and statistically significantly improved compared to Baseline (Test Examples 5 to 7).
表５及び図１に示すように、ＶＡＳにより測定された骨盤痛は、１日あたり４０ｍｇのＳＲ１６２３４の経口投与により、Baselineに比較して統計的に有意に改善された（試験例１）。
また、表６及び図２、表７及び図３、並びに表８及び図４にそれぞれ示すように、合計値、骨盤痛の程度、及び鎮痛薬の使用による骨盤痛スコアは、１日あたり４０ｍｇのＳＲ１６２３４の経口投与により、Baselineに比較して統計的に有意に改善された（試験例２～４）。
また、表９及び図５、表１０及び図６、並びに表１１及び図７にそれぞれ示すように、合計値、月経痛の程度、及び鎮痛薬の使用による月経痛スコアは、１日あたり４０ｍｇのＳＲ１６２３４の経口投与により、Baselineに比較して統計的に有意に改善された（試験例５～７）。 [12] Discussion As shown in Table 5 and FIG. 1, pelvic pain measured by VAS was statistically significantly improved by oral administration of 40 mg of SR16234 per day as compared to Baseline (Test Example). 1).
In addition, as shown in Table 6 and FIG. 2, Table 7 and FIG. 3, and Table 8 and FIG. 4, respectively, the total value, the degree of pelvic pain, and the pelvic pain score due to the use of analgesics are 40 mg per day. SR16234 was orally administered and statistically significantly improved compared to Baseline (Test Examples 2 to 4).
In addition, as shown in Table 9 and FIG. 5, Table 10 and FIG. 6, and Table 11 and FIG. 7, respectively, the total value, the degree of menstrual pain, and the menstrual pain score due to the use of analgesics are 40 mg per day. SR16234 was orally administered and statistically significantly improved compared to Baseline (Test Examples 5 to 7).
このような子宮内膜症・子宮腺筋症患者における骨盤痛・月経痛軽減効果は、これまでＳＥＲＭ及びエストロゲン受容体拮抗剤では臨床的に証明されておらず、ＳＲ１６２３４の投与により初めて確認された効果である。このように、疼痛を抑制することで、患者の生活の質（ＱＯＬ；Quality of Life）を有意に改善することが可能となった。
The effect of reducing pelvic pain and menstrual pain in patients with endometriosis and adenomyosis has not been clinically proven so far with SERM and estrogen receptor antagonists, and was first confirmed by the administration of SR16234. It is an effect. Thus, it became possible to significantly improve a patient's quality of life (QOL; QualityQualof Life) by suppressing pain.
さらに、表１２及び図８に示すように、卵巣チョコレート嚢胞の容積は、１日あたり４０ｍｇのＳＲ１６２３４の経口投与により、Baselineに比較して著明に改善され、経過と共に縮小して、１２週後には完全に消失した（試験例８）。
Furthermore, as shown in Table 12 and FIG. 8, the volume of ovarian chocolate cysts was significantly improved compared to Baseline by oral administration of 40 mg SR16234 per day, and decreased with time, after 12 weeks. Disappeared completely (Test Example 8).
このような子宮内膜症・子宮腺筋症患者における器質的病変である、卵巣チョコレート嚢胞の改善効果は、これまでＳＥＲＭ及びエストロゲン受容体拮抗剤では臨床的に証明されておらず、ＳＲ１６２３４の投与により初めて確認された効果である。このように、子宮内膜症の器質的な病変を治療することで、患者の生活の質を有意に改善することが可能となった。
The improvement effect of ovarian chocolate cysts, which are organic lesions in patients with endometriosis and uterine adenomyosis, has not been clinically proven so far with SERM and estrogen receptor antagonists, and administration of SR16234 This is the effect confirmed for the first time. Thus, it became possible to significantly improve the quality of life of patients by treating organic lesions of endometriosis.
さらに、表１３及び図９に示すように、ダグラス窩の硬結は、１日あたり４０ｍｇのＳＲ１６２３４の経口投与により、Baselineに比較して統計的に有意に改善された（試験例９）。
Furthermore, as shown in Table 13 and FIG. 9, the consolidation of the Douglas fossa was statistically significantly improved by oral administration of 40 mg of SR16234 per day as compared to Baseline (Test Example 9).
このような子宮内膜症・子宮腺筋症患者における器質的病変である、ダグラス窩の硬結の改善効果は、これまでＳＥＲＭ及びエストロゲン受容体拮抗剤では臨床的に証明されておらず、ＳＲ１６２３４の投与により初めて確認された効果である。このように、子宮内膜症の器質的な病変を治療することで、患者の生活の質を有意に改善することが可能となった。
The effect of improving the consolidation of the Douglas fossa, which is an organic lesion in patients with endometriosis and uterine adenomyosis, has not been clinically proven so far with SERM and estrogen receptor antagonists. This is the first effect confirmed by administration. Thus, it became possible to significantly improve the quality of life of patients by treating organic lesions of endometriosis.
さらに、表１４及び図１０に示すように、子宮可動性の制限は、１日あたり４０ｍｇのＳＲ１６２３４の経口投与により、Baselineに比較して統計的に有意に改善された（試験例１０）。
Furthermore, as shown in Table 14 and FIG. 10, the restriction of uterine mobility was statistically significantly improved by oral administration of 40 mg of SR16234 per day as compared to Baseline (Test Example 10).
このような子宮内膜症・子宮腺筋症患者における器質的病変である子宮可動性の制限の改善効果は、これまでＳＥＲＭ及びエストロゲン受容体拮抗剤では臨床的に証明されておらず、ＳＲ１６２３４の投与により初めて確認された効果である。このように、子宮内膜症の器質的な病変を治療することで、患者の生活の質を有意に改善することが可能となった。
The effect of improving the restriction of uterine mobility, which is an organic lesion in patients with endometriosis and adenomyosis, has not been clinically proven so far with SERM and estrogen receptor antagonists. This is the first effect confirmed by administration. Thus, it became possible to significantly improve the quality of life of patients by treating organic lesions of endometriosis.
またさらに、表１５に示すように、臨床試験中に観察された有害事象は、１日あたり４０ｍｇのＳＲ１６２３４の経口投与によっても極めて軽度の症状であり、ＳＲ１６２３４の投与に関連すると考えられる有害事象は確認されなかった（試験例１１）。
Still further, as shown in Table 15, adverse events observed during clinical trials are also very mild symptoms even after oral administration of 40 mg SR16234 per day, and adverse events considered to be related to SR16234 administration are: It was not confirmed (Test Example 11).
これは、これまでのＧｎＲＨアゴニスト、及びプロゲステロン受容体アゴニストでは、骨量の減少や不正出血等の臨床的に薬剤投与に関連する有害事象が報告されていることとは異なり、ＳＲ１６２３４の投与により初めて確認されたものである。また、骨量に対する影響が無いことから、エストロゲンの補充を行うアドバック療法が不要となるといえる。このようにして、子宮内膜症患者の安全性を損なうことなく、疼痛を抑制し、器質的病変を有意に改善することが可能となった。
Unlike conventional GnRH agonists and progesterone receptor agonists, which reported clinical adverse drug-related events such as bone loss and irregular bleeding, the first administration of SR16234 It has been confirmed. Moreover, since there is no influence on the bone mass, it can be said that an add-back therapy for supplementing estrogen is unnecessary. In this manner, pain can be suppressed and organic lesions can be significantly improved without impairing the safety of endometriosis patients.
本発明のエストロゲン受容体α阻害βパーシャルアゴニストは、経口投与が可能であり、毒性が弱く、安全性に優れることから、子宮内膜症、子宮腺筋症等のエストロゲン依存性の婦人科疾患に用いる薬剤として広く且つ有効に利用可能である。
The estrogen receptor α-inhibiting β partial agonist of the present invention can be administered orally, has low toxicity, and is excellent in safety. Therefore, it is suitable for estrogen-dependent gynecological diseases such as endometriosis and adenomyosis. It can be used widely and effectively as a drug to be used.
Claims (5)
- 下記構造式（ａ）；
- 前記婦人科疾患が、エストロゲン依存性婦人疾患である、
請求項１に記載の治療剤。 The gynecological disease is an estrogen-dependent gynecological disease,
The therapeutic agent according to claim 1. - 前記婦人科疾患が、子宮内膜症、及び／又は子宮腺筋症である、請求項１又は２に記載の治療剤。 The therapeutic agent according to claim 1 or 2, wherein the gynecological disease is endometriosis and / or uterine adenomyosis.
- 前記疼痛が、前記婦人科疾患に伴う、月経痛、及び／又は骨盤痛である、請求項１～３のいずれか一項に記載の治療剤。 The therapeutic agent according to any one of claims 1 to 3, wherein the pain is menstrual pain and / or pelvic pain associated with the gynecological disease.
- 前記器質的病変が、卵巣チョコレート嚢胞、ダグラス窩の硬結、及び／又は子宮可動性の制限である、請求項１～４のいずれか一項に記載の治療剤。 The therapeutic agent according to any one of claims 1 to 4, wherein the organic lesion is an ovarian chocolate cyst, consolidation of Douglas fossa, and / or restriction of uterine mobility.
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| JP2004352663A (en) * | 2003-05-29 | 2004-12-16 | Masao Igarashi | Medicinal composition for treating feminine chronic hypogastralgia of unknown cause |
| JP2005239687A (en) * | 2004-02-27 | 2005-09-08 | Nobuhiko Yui | Intracystic medicine |
| WO2006098371A1 (en) * | 2005-03-16 | 2006-09-21 | Masao Igarashi | Therapeutic agent and prophylactic agent for endometriosis and adenomyosis uteri |
| WO2017010515A1 (en) * | 2015-07-14 | 2017-01-19 | ノーベルファーマ株式会社 | ESTROGEN RECEPTOR β PARTIAL AGONIST HAVING ESTROGEN RECEPTOR α INHIBITORY EFFECT, AND THERAPEUTIC AGENT FOR GYNECOLOGICAL DISORDERS USING SAME |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2004352663A (en) * | 2003-05-29 | 2004-12-16 | Masao Igarashi | Medicinal composition for treating feminine chronic hypogastralgia of unknown cause |
| JP2005239687A (en) * | 2004-02-27 | 2005-09-08 | Nobuhiko Yui | Intracystic medicine |
| WO2006098371A1 (en) * | 2005-03-16 | 2006-09-21 | Masao Igarashi | Therapeutic agent and prophylactic agent for endometriosis and adenomyosis uteri |
| WO2017010515A1 (en) * | 2015-07-14 | 2017-01-19 | ノーベルファーマ株式会社 | ESTROGEN RECEPTOR β PARTIAL AGONIST HAVING ESTROGEN RECEPTOR α INHIBITORY EFFECT, AND THERAPEUTIC AGENT FOR GYNECOLOGICAL DISORDERS USING SAME |
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