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WO2002038159A1 - Medicaments pour l'hyperplasie endometriale - Google Patents

Medicaments pour l'hyperplasie endometriale Download PDF

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Publication number
WO2002038159A1
WO2002038159A1 PCT/JP2001/009764 JP0109764W WO0238159A1 WO 2002038159 A1 WO2002038159 A1 WO 2002038159A1 JP 0109764 W JP0109764 W JP 0109764W WO 0238159 A1 WO0238159 A1 WO 0238159A1
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WO
WIPO (PCT)
Prior art keywords
preparation
danazol
present
endometrial
hyperplasia
Prior art date
Application number
PCT/JP2001/009764
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English (en)
Japanese (ja)
Inventor
Yukoku Tamaoka
Original Assignee
Mitsubishi Pharma Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mitsubishi Pharma Corporation filed Critical Mitsubishi Pharma Corporation
Publication of WO2002038159A1 publication Critical patent/WO2002038159A1/fr

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Classifications

    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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

Definitions

  • the present invention relates to a danazol-containing preparation for intrauterine administration for the treatment of endometriosis.
  • Danazol is a widely used oral treatment for mastopathy and endometriosis. Also, preparations for parenteral administration of danazol for the treatment of endometriosis, such as intrauterine and intravaginal preparations, are already known (Japanese Patent Application Laid-Open No. 1221318). .
  • Endometriosis is defined as abnormalities in the endometrioid-like tissue at its original normal position (it is considered to be a mistake in the “different position”), that is, tissue or organs other than the inside of the uterine cavity.
  • tissue or organs other than the inside of the uterine cavity In the ectopic area (eg, ovary or pelvic peritoneum) Refers to the condition.
  • endometrial hyperplasia is often seen in cases of ovarian dysfunction, administration of estrogen drugs, and estrogen-producing tumors, and the number of endometrial glands is histologically increased and irregular.
  • endometrial hyperplasia and endometrial hyperplasia are classified according to the degree of atypia, and simple (cystic gland) hyperplasia, complex (adenomatous) hyperplasia and Divided into atypical hyperplasia.
  • Endometrial carcinoma in the international clinical stage classification is treated synonymously with atypical hyperplasia and intraepithelial adenocarcinoma in stage 0 (edited by the Japanese Society of Obstetrics and Gynecology, Glossary of Obstetrics and Gynecology, 2nd Edition, 1997) Year, pp. 76—77, published by Kimbara).
  • endometriosis is a condition in which the endometrioid (like) tissue itself is normal, but endometrioid-like tissue develops in abnormal places.
  • Endometrial hyperplasia has abnormalities in the endometrial tissue itself (internal glands have increased in number and have an irregular form), but endometrial tissue is located in a normal place (uterus). It refers to a condition that multiplies.
  • endometrial hyperplasia is a condition that is clearly distinguished from endometriosis. it can.
  • a preparation for intrauterine administration for endometrial hyperplasia comprising a danazol and a pharmaceutically acceptable carrier.
  • the above-mentioned preparation for intrauterine administration which comprises 50 to 1000 mg of danazol, silicone rubber and a surfactant.
  • danazol refers to the compound name 17 ⁇ -2,4-predanadiene-20—ino [2,3—d] isoxazo relay 17—ol (17 2,4-p regnad i en- 20-yno [2, 3-d] is oxazo l-17-ol), which is sold under various trade names. Danazol used in the present invention is not limited to a sales company.
  • the preparation for intrauterine administration of the present invention may be any commonly used shape suitable for local administration in the uterine cavity, and may be a ring shape or a non-ring shape. it can.
  • a specific example of the ring shape is an Ota ring shape
  • a non-ring shape is a “T” -like or “7” -like shape.
  • a string can be attached to the preparation of the present invention. That is, the preparation of the present invention can be easily removed from the uterine cavity by pulling the string. That is, the shape and material of the strap defined in the present invention are not particularly limited as long as the preparation of the present invention can be removed from the uterine cavity. Examples of the string material used in the present invention include cotton, polyethylene, nylon and the like.
  • danazole can be released also from the other end of the string. This has the effect of exposing danazol not only from within the uterine cavity, but also from outside the uterus.
  • One example of such a method is to attach a red bean-sized base containing danazol to the other end of the string attached to the preparation of the present invention.
  • the content of danazol in the preparation of the present invention is about 50 to about 100 mg, preferably about 100 to about 500 mg.
  • a polymer compound approved for medical use can be used, and silicone rubber or the like is preferable.
  • a surfactant can be used if necessary. Examples of the surfactant that can be used include a glycerin-ester type surfactant, and polyoxyethylene (20) sorbinone monooleate (Tween 80) is preferable.
  • the release of danazol from the formulation of the present invention is from about 50 to about 150 ⁇ g / day, preferably from about 100 to about 750 xg / day, more preferably from about 250 to about 3 0 O ⁇ i gZ days.
  • FIG. 1 shows Danazo from the ring of the present invention into saline when not used (a), after 6 months in the uterine cavity (b) and after 12 months in the uterine cavity (c).
  • FIG. 4 is a diagram showing a change over time in the release of a fuel cell.
  • Figure 2 is a photograph showing endometrial histology before (A) and after (B) treatment of a patient with endometrial hyperplasia without atypia.
  • FIG. 3 is a photograph showing endometrial tissue images of a patient with atypical endometrial hyperplasia before (A) and after (B) treatment.
  • FIG. 4 is a graph showing serum danazol levels when administered orally and when administered intrauterinely using the ring of the present invention.
  • FIG. 5 is a top view (A) and a side view (B) showing one embodiment of a danazol-containing intrauterine ring used in the present invention.
  • danazol based on silicone rubber one-pack type RTV rubber; manufactured by Shin-Etsu Chemical Co., Ltd. (product name: KE44T)
  • polyoxyethylene (20) sorbitan monooleate (Tween 80) 2 as surfactant 5 was added to form a ring (ring weight: 1.24 g) having an outer diameter of 2.3 cm, an inner diameter of 1.2 cm, and a thickness of 3.5 mm.
  • one end After sterilizing a cotton thread of 12 cm in length, folding it in half to make it 6 cm, one end has 300 mg of danazol, and polyoxyethylene (20) sorbitan monooleate (Tween 80) as a surfactant. ) 25 1 added to silicon rubber (one-pack type RTV rubber; manufactured by Shin-Etsu Chemical Co., Ltd. (product name: KE44T)). mm ring (ring weight 1.24 g), and then connect the other end of the thread to 15 mg of danazol, polyoxyethylene (20) sorbitan monooleate (Tween 80) 2 Silicone rubber to which II 1 was added (one-pack type RTV rubber; manufactured by Shin-Etsu Chemical Co., Ltd. (product name: KE44T)) was mixed with 600 mg to obtain a red bean size.
  • silicon rubber one-pack type RTV rubber; manufactured by Shin-Etsu Chemical Co., Ltd. (product name: KE44T)
  • Example 3 (Release of danazol from the preparation of the present invention into physiological saline)
  • the release pattern of danazol from the preparation of the present invention into physiological saline prepared in Example 1 was measured for virgin and 6 months and 1 year in utero.
  • measurement was carried out over 30 days by high performance liquid chromatography over time. The measurement was performed using a Shimadzu Model LC 10 liquid chromatograph, an ultraviolet absorption spectrophotometer (wavelength: 285 nm) and a Ri Chrosorb Si 60 column, and n-hexane'ethanol mixture (24: 1) as the mobile phase. This was performed using As a result, it was found that the release amount of danazole from the preparation of the present invention was maintained in the range of 250 to 300 g / day (see FIG. 1).
  • the preparation of the present invention was replaced once every three months, and each endometrial sample collected at each replacement was subjected to histopathological examination.
  • Table 1 summarizes the pathological findings of each patient. After treatment with the preparation of the present invention, clinical symptoms improved in all patients, and irregular uterine bleeding stopped within one month after insertion of the preparation of the present invention. From the histopathological findings of the endometrium of all patients, Atrophy of the membrane glands was observed in four patients, pseudo-decidual interstitial changes were observed in three patients, or four patients showed normal endometriosis with a normal secretory phase.
  • FIG. 2 shows histopathological findings of one of nine patients with endometrial hyperplasia. This patient had prolonged uterine bleeding for 2 months before starting treatment with the present invention and was proliferated by endometrial thickening (15 mm) or endometrial biopsy, as demonstrated by ultrasonography. Diagnosis was made.
  • Another advantage of using the formulation of the present invention is that the endometrium is exposed to a very large amount of danazol released by the formulation of the present invention.
  • Figure 4 Journal of the Endometriosis Research Group, Vol. 17, 1996, pp. 61-64), which means that there are almost no side effects. That is, orally administered danazole is transported to the liver by blood, where it may be metabolized to cause liver failure.Also, from another aspect, danazole may cause thromboembolism. You do not need to worry about these when using.
  • the present invention can provide a highly safe therapeutic agent for endometrial hyperplasia.
  • the present application was filed with a priority claim of Japanese Patent Application No. 2000-343759.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des préparations intra-utérines contenant du danazol pour traiter l'hyperplasie endométriale, en particulier, l'hyperplasie endométriale hétérotypique. Etant administrées directement dans la cavité utérine, ces préparations sont très sûres et exemptes d'effets secondaires. Pour faciliter leur retrait, on peut doter ces préparations d'un cordon. Le danazol peut également être libéré par l'autre extrémité du cordon, ce qui permet d'exposer l'utérus au danazol de manière à la fois interne et externe.
PCT/JP2001/009764 2000-11-10 2001-11-08 Medicaments pour l'hyperplasie endometriale WO2002038159A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000343759 2000-11-10
JP2000-343759 2000-11-10

Publications (1)

Publication Number Publication Date
WO2002038159A1 true WO2002038159A1 (fr) 2002-05-16

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WO (1) WO2002038159A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011526609A (ja) * 2008-07-03 2011-10-13 バイエル オイ 避妊のための子宮内用送達システム

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330786A1 (fr) * 1988-03-01 1989-09-06 Masao Igarashi Systèmes d'apport de médicaments topiques contenant le danazole

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330786A1 (fr) * 1988-03-01 1989-09-06 Masao Igarashi Systèmes d'apport de médicaments topiques contenant le danazole

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
BULLETTI, C. ET AL, ACTA EUROPAEA FERTILITATIS, vol. 18, no. 3, May 1987 (1987-05-01) - June 1987 (1987-06-01), XP002908832 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE, (BETHESDA, MARYLAND, USA); BULLETTI, C. ET AL.: "Danazol reverses endometrial hyperplasia to normal endometrium", accession no. DIALOG Database accession no. 88147289 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE, (BETHESDA, MARYLAND, USA); GRIO, R. ET AL.: "Danazol in the treatment of endometrial hyperplasia", accession no. DIALOG Database accession no. 94261400 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE, (BETHESDA, MARYLAND, USA); JASONNI, V. ET AL.: "Preliminary report on postmenopausal endometrial hyperplasia treatment with danazol: histological and endocrinological aspects", accession no. DIALOG Database accession no. 86298225 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE, (BETHESDA, MARYLAND, USA); MARIANI, L. ET AL.: "Postmenopausal endometrial hyperplasia: role of danazol therapy", accession no. DIALOG Database accession no. 94259214 *
EIKI SOH ET AL.: "The effect of danazol and tamoxifen on endometrial hyperplasia", JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY (GAN TO KAGAKU RYOUHOU), vol. 16, no. 4, PART II, April 1989 (1989-04-01), pages 1612 - 1622, XP002908829 *
GRIO, R. ET AL, PANMINERVA MEDICA, vol. 35, no. 4, December 1993 (1993-12-01), XP002908830 *
HITOSHI SEZAKI ET AL.: "Drug delivery system", 15 April 1986 (1986-04-15), NANKOUDOU (TOKYO), pages 129, XP002908834 *
JASONNI, V.M. ET AL, CANCER DETECTION AND PREVENTION, vol. 9, 1986, XP002908833 *
KENJI NIWA ET AL.: "Preventive effects of danazol on endometrial carcinogenesis in mice", CANCER LETTERS, vol. 158, no. 2, 1 October 2000 (2000-10-01), pages 133 - 139, XP002908828 *
MARIANI, L. ET AL, INTERNATIONAL JOURNAL OF GYNECOLOGY AND OBSTETRICS, vol. 44, February 1994 (1994-02-01), XP002908831 *
YUKOKU TAMAOKA ET AL.: "Direct effect of danazol on endometrial hyperplasia in adenomyotic women: treatment with danazol containing intrauterine device", HUMAN CELL, vol. 13, no. 3, 10 December 2000 (2000-12-10), pages 127 - 133, XP002908827 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011526609A (ja) * 2008-07-03 2011-10-13 バイエル オイ 避妊のための子宮内用送達システム

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