WO2002038159A1

WO2002038159A1 - Remedies for endometrial hyperplasia

Info

Publication number: WO2002038159A1
Application number: PCT/JP2001/009764
Authority: WO
Inventors: Yukoku Tamaoka
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2000-11-10
Filing date: 2001-11-08
Publication date: 2002-05-16

Abstract

Intrauterine preparations for endometrial hyperplasia, in particular heterotypical endometrial hyperplasia, containing danazol. Because of being administered directly to the uterine cavity, these preparation have a high safety with relieved side effects. For the convenience in taking out, such a preparation can be provided with a string. It is also possible that danazol is released from the other end of the string too, thereby exposing the uterus externally and internally to danazol.

Description

Akira Endometriosis therapeutic agent Technical field

The present invention relates to a danazol-containing preparation for intrauterine administration for the treatment of endometriosis. Background art

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). .

However, all of these apply danazol to danazol in patients with endometriosis, and there is no disclosure of the efficacy of danazol for endometriosis, which is the object of the present invention.

On the other hand, Obstetrics and Gynecology, pp. 1199-1992 (1443), pp. 1747-1754, report the efficacy of danazol therapy for endometrial hyperplasia.

However, this report only evaluates oral danazol. It is also argued here that "danazol therapy cannot be expected for atypical hyperplasia."

Here, endometriosis and endometriosis are described. 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. In the ectopic area (eg, ovary or pelvic peritoneum) Refers to the condition. On the other hand, 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. According to the rules for the treatment of endometrial cancer, 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).

In other words, 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.

Furthermore, in the context of cancer, endometriosis is unlikely to become cancerous, but endometriosis is likely to become cancerous, with 1.1% simple growth and complex growth. Literature reporting 3.5%, simple variant hyperplasia 8.3%, complex variant hyperplasia 21.4% (Journal of the Japan Society of Obstetrics and Gynecology, September 1999, September 3 4 4 — 3 4 5).

Thus, the fact that the endometrial tissue itself is abnormal and that it may become cancerous means that endometrial hyperplasia is a condition that is clearly distinguished from endometriosis. it can.

At present, there is no effective drug for endometrial hyperplasia, especially for atypical hyperplasia, and it has been desired to provide such a drug. Disclosure of the invention The present inventors have found that the use of a preparation for intrauterine administration containing danazol improves the symptoms of endometrial hyperplasia, and completed the present invention. The gist of the present invention is as follows.

1. A preparation for intrauterine administration for endometrial hyperplasia, comprising a danazol and a pharmaceutically acceptable carrier.

2. The above-mentioned preparation for intrauterine administration, which comprises 50 to 1000 mg of danazol, silicone rubber and a surfactant.

3. The above-mentioned preparation for intrauterine administration, wherein the release amount of danazol is maintained in the range of 50 to 150 [Ig Z days].

4. The above intrauterine administration preparation, wherein the endometrial hyperplasia is atypical endometrial hyperplasia.

5. The above preparation for intrauterine administration, wherein the preparation for intrauterine administration has a ring-like, "T" -like or "7" -like shape.

6. The above intrauterine preparation, wherein the string is attached to the intrauterine preparation.

7. The preparation for intrauterine administration, wherein the preparation for intrauterine administration also releases danazole from the other end of the string attached to the preparation for intrauterine administration. The name “danazol” refers to the compound name 17 α-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 (hereinafter, referred to as the preparation 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, and a non-ring shape is a “T” -like or “7” -like shape. Although the preparation of the present invention is inserted into the uterine cavity of a patient for a certain period of time, it must be removed when it is no longer necessary to insert the preparation. For convenience at this time, 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.

In the preparation of the present invention, 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. As the base, a polymer compound approved for medical use can be used, and silicone rubber or the like is preferable. Further, 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. Also, 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. BRIEF DESCRIPTION OF THE FIGURES

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. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples do not limit the present invention. Danazol used was commercially available danazol (trade name: Bonzol (manufactured by Mitsubishi Pharma Corporation)). Example 1 (Preparation of the present invention)

30 Omg of 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.

Example 2 (Formulation 2 of the present invention)

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.

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. Using the preparation of the present invention after 2 months of use, 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).

Example 4 (Clinical test for patients with endometrial hyperplasia)

Nine female patients diagnosed with endometrial hyperplasia by endometrial biopsy were enrolled in this clinical study. At the first visit, all patients complained of irregular uterine bleeding, 2 had dysmenorrhea and prolonged menstruation, and 5 had menorrhagia. Eight of the nine patients were diagnosed with endometrial hyperplasia, and one was diagnosed with endometrial atypia. Biopsy samples were taken regardless of menstrual phase (endometriotic or secretory phase). To treat patients by inserting the preparation of the present invention into the uterus for 3 to 12 months, and to evaluate the direct effect of danazol on proliferative disease when removing the preparation of the present invention, the endometrium of 8 patients Samples were taken by biopsy. In one case of endometrial atypical hyperplasia, 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.

table 1

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.

When the patient was treated with the preparation of the present invention for 3 months, uterine bleeding stopped 20 days after insertion of the ring of the present invention. The cessation of irregular uterine bleeding was maintained during the treatment, and normal menstruation began after removal of the preparation of the present invention. Endometrial samples collected before treatment (Fig. 2A) show a back-to-back appe- arance and a Swiss cheese-like pattern characteristic of endometriosis. In contrast, endometrial samples collected after treatment (Fig. 2B) had disappeared.

In addition, histopathological findings before treatment in one patient with atypical endometrial hyperplasia showed that the amount of chromatin increased in the nucleus, the swelling of the nucleolus, and the size of the cells were characteristic of atypical endometrial hyperplasia. However, the healing and proliferation of gland ducts, irregular infiltration of gland ducts, and marked papillary structure were observed, but after 3 months of treatment, epithelial regeneration was altered, pseudodecidualization and gland atrophy were shown, and endometrial proliferation was observed No findings of the disease were observed (FIG. 3B), and the atypical hyperplasia did not recur even after 9 months from the start of treatment with the preparation of the present invention. Industrial applicability

It was revealed that the preparation of the present invention has a remarkable effect on endometrial hyperplasia. It was also found to be effective against atypical hyperplasia. It should be noted that danazol exerts an anticancer effect (atypical hyperplasia is synonymous with endometrial cancer stage 0).

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.

From the above, 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.

Claims

The scope of the claims

1 A formulation for intrauterine administration for endometrial hyperplasia comprising danazol and a pharmaceutically acceptable carrier.

2. The formulation for intrauterine administration according to claim 1, comprising 50 to 1000 mg of Danazol, silicone rubber and a surfactant.

3. The preparation for intrauterine administration according to claim 1 or 2, wherein the release amount of Danazol is maintained in the range of 50 to 1500 days.

4. The preparation for intrauterine administration according to claim 1, wherein the endometrial hyperplasia is atypical endometrial hyperplasia.

5. The preparation for intrauterine administration according to claim 1, wherein the preparation for intrauterine administration containing danazol has a ring-like, "T" -like or "7" -like shape. 6. The preparation for intrauterine administration according to claim 1, wherein a string is attached to the preparation for intrauterine administration.

7. The preparation for intrauterine administration containing danazole according to claim 6, wherein danazole is also released from the other end of the string attached to the preparation for intrauterine administration.