BG66128B1 - Pharmaceutical composition and use for the therapeutic management of extrauterine proliferation of endometrial tissue - Google Patents

Abstract

The invention relates to a pharmaceutical composition for the therapeutic control of ectopic endometrial tissue proliferation comprising an LHRH antagonist selected from the group consisting of centrorelix, teverelix, ganyrelix, andit, abarelix and osarelix and optionally one or more active substances selected from a contraceptive , non-steroidal anti-rheumatic agent, analgesic, androgen other than 17-alpha-alkyl substituted testosterone or combinations.

Description

Technical field

The present invention relates to a pharmaceutical composition and to its use for the therapeutic control of ectopic endometrial tissue proliferation.

Endometriosis is one of the most commonly diagnosed pathological cases in patients with gynecological diseases. For example, between 10% and 25% of women with gynecological symptoms in England and the United States are ill. Usually, the clinical diagnosis is made by laparoscopic observation of hemorrhagic and fibrous foci in the pelvic organs. Ectopic endometrial tissue responds to ovarian hormones, undergoing cyclical changes. Cyclic bleeding from endometrial deposition contributes to a local inflammatory response. Endometriosis generally affects women in the years of their childbearing activity, with a prevalence rate of at least 1% (see Shaw, R. W. (1993), An Atlas of Endometriosis. The Parthenon Publishing Group).

Endometriosis is usually classified as endometriosis (genital) internal (adenomyosis), endometriosis genital external and non-genital endometriosis.

Chronic pelvic pain can occur in association with both endometriosis and independent disease.

Fallopian tube occlusion (FTO) is a relatively common disease and accounts for up to 20% of cases of fallopian tube sterility (see Winfield, A.C. et al., Apparent cornual occlusion in hysterosalpingography: Reversal by glucagon. AJR At J Roentgenol 1982; 139: 525 527).

BACKGROUND OF THE INVENTION

Sampson suggests that menstrual flow and subsequent implantation of endometrial tissue by the peritoneum leads to endometriosis (Sampson, J. A. (1927), Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavitey. At. J. Obstet., Gynecol., 14, 422].

Several etiologic factors may be involved in the pathogenesis of endometriosis: Dmowski et al. suggest that genetic and immunological factors lead to endometriosis [Dmowski, W. R., Steele, R. W. and Baker, G. F. (1981). Deficient cellular immunity and endometriosis. At. J. Obstet. Gynecol., 141, 377]

Vascular and lymphatic embolization at various sites has been shown, which explains the (infrequent) detection of endometriosis outside the peritoneal cavity, for example skin, lungs, kidneys.

Cells lining the Mueller canal arise from primitive cells that differentiate into peritoneal cells and into cells on the surface of the ovary. These mature cells are thought to undergo de-differentiation back to their primary source and then transform into endometrial cells [Levander, G. (1941), Bone formation by induction. An experimental study. Arch. Wedge. Chir., 202,497].

Dysmenorrhea, acute or chronic pelvic pain, dyspareunia and sterility are the most commonly reported clinical symptoms.

FTO is a heterogeneous group with pronounced pathology, pre-internal obstruction, or external compression of estrogen-sensitive disorders such as endometriosis, adenomyosis, endosalpingeosis and myoma. FTO is most commonly diagnosed by hysterosalpingography other than laparoscopy.

The first treatment alternative involves laparoscopic removal of endometriotic lesions. This procedure may be followed by treatment with danazol or an LHRH agonist (for a period of six months). Women treated with danazole had gastrointestinal and liver disorders, as well as severe androgenic side effects.

From a theoretical point of view, it is proposed to use direct suppression by treating endometriosis and uterine fibroids by administering an LHRH antagonist to reduce treatment time and to improve subjective symptoms more quickly [Th. Reissmann et al. Human Reproduction vol. 10 No. 8 pp. 1974-1981, (1995)].

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Later, Hodgen proposed in the US 5,658,884 patent regimen for the control of gonadal dependence by reducing the delivery of estrogen by administering a GnRH antagonist for a long period of 6 months, or longer in an amount effective to inhibits endometrial tissue proliferation without essentially stopping the production of endogenous estrogen. To this end, Hodgen offers such a regimen or dose of a GnRH antagonist in which serum estradiol levels are reached in the range of about 25 to 50 and preferably 35 to 45 pg / ml within 24 hours. In addition, Hodgen does not describe levels of serum estradiol ranging from 50 pg / ml to 75 pg / ml. Moreover, Hodgen in US Patent 5,658,884 only offers continuous long-term treatment (daily or periodic, the latter meaning weekly or monthly administration), but not treatment induced for a short period of time from 4 to 12 weeks. Hodgen also does not describe any combination therapy involving the GnRH antagonist in the treatment of endometriosis. Treatment is described for monkeys only and involves the conduct of a costly and repetitive progesterone test to provide, within 24 hours, a mean serum estradiol level of 30 to 50 pg / ml.

WO 1997/027863 A1 discloses a combination pharmaceutical composition comprising an LHRH antagonist, for example, an antide and cetrorelix and antiestrogens. Said antiestrogens have a tissue-selective estrogenic effect. The use of the combined pharmaceutical preparation for the treatment of gynecological disorders, in particular endometriosis and fibroids, has also been disclosed.

WO 1998/055470 A1 discloses combination therapy of an LHRH antagonist with various other active agents such as estrogens and contraceptives for the treatment of sex hormone and other conditions such as endometriosis and fibroids.

Therefore, effective drug therapy should immediately limit the ectopic endometrial tissue that appears after surgical laparoscopic surgery. The duration of therapy should be only 4 to 12 weeks, without any symptoms, mainly associated with hormone deficiency and ovarian cyst formation.

LHRH antagonists exert a direct attack on hormonal suppression, and therefore benign gynecologic tumors, such as uterine fibrosis, decrease over a short period of time [Human Reproduction, 1998, B].

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising an LHRH antagonist suitable for the therapeutic control of ectopic endometrial tissue proliferation.

The application of these pharmaceutical compositions achieves an improvement which consists in:

- immediate restriction of ectotopic endometrial tissue;

- immediate cessation of symptoms, such as severe pain, chronic pelvic pain and dysmenorrhea;

- prevention of any development of the disease;

- elimination of symptoms related to hormone deficiency;

- prevention of the formation of ovarian cysts, demineralization of the bones, as well as gastrointestinal or hepatic disorders, with use starting from the first to the third day of the cycle. While using a pharmaceutical composition comprising the LHRH antagonist, serum estradiol concentration levels are maintained between 35 µg / ml and 80 µg / ml, preferably between 45-75 µg / ml, more preferably between 50-75 µg / ml. The LHRH antagonist is administered for only 4 to 12 weeks (use induced for a short period of time) or by daily, weekly, or monthly use. According to the present invention, contraceptive, non-steroidal, antirheumatic, analgesic androgenic but other than 17-alpha-alkyl substituted testosterone, or any combination thereof, is provided after use induced for a short period of time.

Therapeutic treatment of ectopic endometrial tissue with the LHRH antagonist begins in the menstrual cycle from first to third

66128 Bl day. Before using the pharmaceutical composition containing the LHRH antagonist, diagnosis is made by laparoscopy.

In cases of severe pain, use of the composition containing the LHRH antagonist may be started without prior laparoscopy.

The therapy will continue until the clinical symptoms of the disease disappear and endometrial proliferation is no longer observed. Due to the direct onset of suppression of the gonadotropic LH and FSH, as well as the steroidal sex hormones estradiol and progesterone, further endometrial proliferation is stopped. Benign tumors, or other lesions dependent on endometriosis-like steroid hormones, decrease within four to twenty weeks of therapy. Because therapy is not performed for a short period of time, ovarian cysts do not develop.

In addition, no hormone deficiency symptoms are observed if estradiol values are maintained in the range of the early follicular phase from 35 to 80 µg / ml, preferably between 45-75 µg / ml, more preferably between 50 -75 microg / ml, without further increase or decrease. No dose titration is required from the LHRH antagonist, for example, by controlling the costly progesterone test.

Accordingly, according to the present invention, the improvement of the method for the therapeutic control of ectopic endometrial tissue proliferation by the use of pharmaceutical compositions comprising the LHRH antagonist comprises:

- immediate restriction of ectopic endometrial tissue;

- prevention of any development of the disease;

- elimination of symptoms related to hormone deficiency;

- prevention of ovarian cyst formation, bone demineralization as well as gastrointestinal or hepatic disorders, starting from the first to third days of the cycle and maintaining estradiol levels in the early follicular phase throughout the treatment, using the pharmaceutical composition of the antagonist of

LHRH, wherein the antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, or abarelix. The antagonist may also be an antagonist of LHRH D-63153 (Ac-D-Nal-D-pCl-Phe-D-Pal-Ser-N-Me-Tyr-DHci-Nle-Arg-Pro-D-Ala-NH2 ), as described in German patent application No. 199 11 771.3, filed March 11, 1999.

The pharmaceutical composition comprising the LHRH antagonist may be used for 4 to 12 weeks with a weekly dose of 3 to 10 mg per week or 4 to 12 weeks with a daily dose of 0.25 mg to 0.5 mg / day.

It is also possible to administer the pharmaceutical composition comprising the LHRH antagonist for 4 to 12 weeks with a monthly dose of 12 to 40 mg per month.

For re-treatment, the pharmaceutical composition containing the LHRH antagonist is given for 4 to 12 weeks and treatment is repeated two or three times a year, with no re-treatment immediately following treatment induced for a short period of time. Typically, the period of weeks, or months, during which the LHRH antagonist containing the pharmaceutical composition is not used is the time between the end of use of the pharmaceutical composition induced for a short period of time and the start of reuse of the pharmaceutical composition.

To demonstrate the ability to maintain low estradiol secretion, 3 mg of cetrorelix acetate subcutaneously was administered to nine patients with confirmed endometriosis with the regulated use of a pharmaceutical composition comprising an LHRH antagonist so as to observe therapeutic suppression without disappearing symptoms. which is administered weekly for 8 weeks. When the patient's condition is excellent and when there are no hot flashes or other symptoms, and when no disease development is confirmed, which is confirmed by a second laparoscopy, the mean of serum estradiol concentrations ranges between 37 pg / ml and 64 pg / ml, preferably between 45-75 pg / ml, more preferably between 50-75 pg / ml. Histological biopsies do not show endometrial proliferation and no ovarian cysts are formed at the end of pharma use

66128 Bl of the composition.

Figure 1 shows the continuous suppression of estradiol to early follicular phase values (range from 37 pg / ml to 80 pg / ml, preferably between 45-75 pg / ml, more preferably between 50-75 pg / ml, obtained at patients with endometriosis at a weekly dose of 3 mg cetrorelix for 8 weeks A rapid and prolonged suppression of estradiol levels was obtained without any signals of disease symptoms associated with estradiol deficiency and without endometrial proliferation.

Figure 2 shows the levels of serum estradiol after the use of cetrorelix with a weekly dose of 1 mg, or 3 mg once a week. Serum estradiol levels are between about 37 pg / ml - 80 pg / ml, preferably between 45-75 pg / ml, more preferably between 50-75 pg / ml.

The patient with endometriosis with characteristic symptomatic pain suffers from a chronic disease. Surgical methods for treatment therapy as well as drug therapy for patients to suppress steroid hormone secretion only lead to temporary improvement. The incidence of recurrence of the disease is very high and is approximately 70% within 5 years of completion of therapy (Schweppe, 1999).

At the same time, radical surgery and suppression of estrogen secretion have significant side effects. Radical surgical therapy, in the sense of hysterectomy with bilateral adnectomy, is not adequate therapy for younger premenopausal women. Chronic estrogen deficiency leads to the following vegetative symptoms: heat attacks, sweating, vaginal drying, depressed moods, and also the risk of osteoporosis. Alternative therapy with the synthetic steroid compound Danazol may lead to symptoms characteristic of secondary male sexual characteristics due to its androgenic effect.

The goal of drug therapy in patients with endometriosis with symptomatic pain is to achieve treatment that is not accompanied by side effects, especially to eliminate the negative effects of estrogen suppression and treatment that has a long-lasting effect after completion of therapy. The specific pharmacological mode of action of the LHRH antagonist leads to new avenues for the treatment of endometriosis.

Weekly administration of an adequate dose of an LHRH antagonist pharmaceutical composition, for example 3 mg Cetrotide® subcutaneously / week, for a period of eight weeks, results in a controlled suppression of estrogen secretion so that serum concentrations of about 35 pg / ml are obtained and about 80 pg / ml, preferably between 45-75 pg / ml, and even more preferably between 50-75 pg / ml. No vegetative symptoms occur in this range of serum concentration. The development of osteoporosis may also be avoided. Symptomatic pain will be effectively suppressed in all stages of the disease (rAFS i-IV). In rAFS stages I-II, clinical regression of the disease is noted in the sense of reducing the implantation area (Felberbaum et al., 2000).

In a preferred embodiment of this invention, after this treatment period of 8 to 12 weeks, the patient may take a contraceptive, preferably an oral contraceptive, preferably together with gestagenic components if pregnancy is not desired. Combinations of Lynestronol 2 mg with 0.04 mg ethinylestradiol or 2.5 mg Lynestronol with 0.05 mg ethinylestradiol (eg Yermonil®, Lynratiopharm-Sequenz®) should be mentioned in this connection.

Combination therapy with androgens other than 17-alphaalkyl substituted testosterone such as danazol may also be used, following short-term induction with the LHRH antagonist, either alone or in combination with non-steroidal antirheumatic agents and / or analgesics. One example of a suitable androgen is halotestin® (fluoximsterone).

The use of a contraceptive, preferably an oral contraceptive containing predominantly progestogens, should be continued individually as long as the sensation of typical pain persists. At this stage, the patient will have relatively little menstrual bleeding as an effect of the gestagenic component of this contraceptive, preferably oral contraceptive. Also, in particular as protection for critical premenstrual and menstrual days, in relation to

66128 Pain relief during this period may be given concomitantly with appropriate non-steroidal anti-rheumatic agents, for example, diclofenac, ibuprofen, indomethacin, oxicam derivatives, or acetylsalicylic acid. An analgesic such as flupirtine maleate (Katadolon®) may also be used.

If further symptoms of pain persist during combination therapy with gestagenic contraceptives, it is preferable to repeat oral contraceptives, daily, weekly or monthly, with an adequate dose of an LHRH antagonist. If the patient does not feel any pain, treatment may be changed with a gestagenic contraceptive, preferably oral contraceptive, in combination with appropriate non-steroidal anti-rheumatic drugs, or analgesics.

This therapy, which periodically uses a pharmaceutical composition containing the LHRH antagonist, results in new and changed, without limitation treatment, without side effects and significantly reduces the patient overload due to treatment.

Therefore, the present invention provides pharmaceutical compositions based on an LHRH antagonist that are suitable for the therapeutic control of ectopic endometrial tissue proliferation, chronic pelvic pain, and obstruction of fallopian tubes, which may be:

a) acetate salt compositions at a concentration of 1 mg / 1 ml or lower, where the powder can be dissolved in water for injection (Wfl) or in gluconic acid (GA);

b) acetate salt compositions at a concentration of 1.5 mg / 1 ml to 5.0 mg / 1 ml, preferably 2.5 mg / 1 ml, where the powder can be dissolved in water for injection (Wfl) or in gluconic acid (GA) ;

c) compositions of pamoate salt at a concentration of 10 mg / 1 ml to 30 mg / 1 ml, preferably 15 mg / 1 ml, where the lyophilized powder can be dissolved in gluconic acid (GA) or in water for injection (Wfl ).

According to one embodiment of the present invention, the use of the pharmaceutical composition mentioned above is for the therapeutic treatment of ectopic endometrial tissue proliferation, chronic pelvic pain, and fallopian tube (FTO) blockage, which includes the use of an LHRH antagonist for treatment induced for a short period of time of about 4 to 12 weeks, after which the use of the antagonist is stopped, meaning that the use may be between about 28 to about 84 days, or from about 1 to about three months.

Suitable excipients and dosage forms, for example, are described by the CN. Bauer, KN. Fromming and S. Fuhrer, Lehrbueh der Pharmazeutischen Technologie, 6 ^th edition, Stuttgart 1999, pages 163-186 (excipients) and pages 227 386 (formulations herein incorporated by reference.

The pharmaceutical compositions of the LHRH antagonist may be administered, for example, subcutaneously (s.c.), intramuscularly (i.m.), or by inhalation. Agents selected from the group consisting of contraceptives, preferably oral contraceptives, non-steroidal antirheumatic agents, analgesics, androgens other than 17-alpha-alkyl substituted testosterone, or any combination thereof, may be administered, as is known in the art (see (e.g., German, European, or US pharmacopoeia), preferably orally or by inhalation.

According to one aspect of the present invention, there is provided a pharmaceutical composition as mentioned above, wherein the LHRH antagonist is administered such that the serum estrogen concentration level is between about 35 pg / ml and about 80 pg / ml, preferably between about 45-75 pg / ml, more preferably about 50-75 pg / ml.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above, where, following treatment induced for a short period with the LHRH antagonist, contraceptive administration, preferably oral contraceptive, is followed.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above, where, after treatment induced for a short period with the LHRH antagonist, a non-steroidal anti-rheumatic agent is administered.

According to another aspect of the present iso

66128 B1b, a pharmaceutical composition is provided, as mentioned above, where analgesic treatment is followed after treatment induced for a short period with the LHRH antagonist.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above, where after treatment induced for a short period with the LHRH antagonist, an androgen other than 17-alpha-alkyl substituted testosterone is administered.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above, where after treatment induced for a short period with the LHRH antagonist, the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17-alpha-alkyl substituted testosterone, and any combination thereof.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above, wherein the use of the LHRH antagonist begins in the early to middle follicular phase, preferably in the first to third days of the cycle.

According to another aspect of the present invention there is provided a pharmaceutical composition as mentioned above wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganyrelix, antide, abarelix and D-63153.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above wherein the LHRH antagonist is administered during treatment induced for a short period of 4 to 12 weeks with a weekly dose of 3 to 10 mg per week.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above, wherein the LHRH antagonist is administered during treatment induced for a short period of 4 to 12 weeks at a daily dose of 0.25 mg to 0.5 mg / day.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above wherein the LHRH antagonist is administered during treatment induced for a short period of 4 to 12 weeks at a monthly dose of 12 to 40 mg of month.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above wherein the LHRH antagonist is administered to induce treatment for a period of 4 to 12 weeks and treatment is repeated two or three times a year.

According to another aspect of the present invention, there is provided a pharmaceutical composition as mentioned above, wherein one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal antirheumatic agent, an analgesic, an androgen, other than of 17-alpha-alkyl substituted testosterone, or any combination thereof, are in the same or separate dosage form.

Claims (20)

Claims A pharmaceutical composition for the therapeutic control of ectopic endometrial tissue proliferation, chronic pelvic pain and / or fallopian tube (FTO) obstruction, characterized in that it contains an LHRH antagonist selected from the group consisting of cetrorelix, teverelix, ganirelix , abarelix and ozarelix (D63153) with serum estrogen concentration levels between 35 and 80 pg / ml. Pharmaceutical composition according to claim 1, characterized in that the serum estrogen concentration level is between 45 and 75 pg / ml. Pharmaceutical composition according to claim 1, characterized in that the serum estrogen concentration level is between 50 and 75 pg / ml. 4. Use of an LHRH antagonist selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and osarelix (D63153) for therapeutic control of endometrial tissue extracellular proliferation, chronic pelvic pain and / or obstruction 66128 Bl of Folopie Tube (FTO), administering the LHRH antagonist for 4 to 12 weeks induced short-term treatment, repeating treatment two or three times a year, and administering the LHRH antagonist so that the serum level the estrogen concentration is between 35 and 80 pg / ml. Use according to claim 4, characterized in that the LHRH antagonist is administered such that the serum estrogen concentration level is between 45 and 75 pg / ml. Use according to claim 4, characterized in that the LHRH antagonist is administered such that the serum estrogen concentration level is between 50 and 75 pg / ml. Use of an LHRH antagonist and one or more active agents selected from the group consisting of a contraceptive, a non-steroidal anti-rheumatic agent, an anaesthetics, an androgen other than 17-alpha-alkyl substituted testosterone, or any combination thereof for the therapeutic control of ectopic endometrial proliferation , chronic pelvic pain, and / or fallopian tube obstruction (FTO), with the LHRH antagonist administered as a short-term treatment of 4 to 12 weeks, repeated twice or three times a year, LHRH an antagonist is discontinued and one or more active agents selected from the group consisting of a contraceptive, a non-steroidal antirheumatic agent, an analgesic, an androgen other than 17-alpha-alkyl substituted testosterone, or any combination thereof, such that the level of serum estrogen concentration is administered is between 35 and 80 pg / ml. Use according to claim 7, characterized in that the LHRH antagonist is administered such that the serum estrogen concentration level is between 45 and 75 pg / ml. Use according to claim 7, characterized in that the LHRH antagonist is administered such that the serum estrogen concentration level is between 50 and 75 pg / ml. Use according to any one of claims 4 to 7, characterized in that the LHRH antagonist-induced short-term treatment is followed by the administration of a contraceptive. Use according to claim 7, characterized in that the oral contraceptive is used as a contraceptive. Use according to any one of claims 4 to 7, characterized in that the short-term induced LHRH antagonist treatment is followed by a non-steroidal anti-rheumatic agent. Use according to any one of claims 4 to 7, characterized in that the LHRH antagonist induced for a short period is followed by an analgesic. Use according to any one of claims 4 to 7, characterized in that the short-term induced LHRH antagonist treatment is followed by 17-alpha-alkyl substituted testosterone. Use according to any one of the preceding claims, characterized in that the administration of the LHRH antagonist is initiated in the beginning to the middle of the follicular phase. Use according to claim 15, characterized in that the LHRH antagonist is administered over a cycle of one to three days. Use according to any one of claims 7 to 16, characterized in that the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganyrelix, antide, abarelix and D63153. Use according to any one of the preceding claims, characterized in that during the short-period induced treatment with the LHRH antagonist is administered at a weekly dose of 3 to 10 mg. Use according to any one of the preceding claims, characterized in that during the short-term induced LHRH antagonist treatment is administered at a daily dose of 0.25 mg to 0.5 mg / day. Use according to any one of the preceding claims, characterized in that during the short-term induced LHRH antagonist treatment is administered at a monthly dose of 12 mg to 40 mg per month.