WO2003017974A1 - Method of treating benign gynaecological disorders and a pharmaceutical kit for use in such method - Google Patents

Abstract

The present invention relates to a method of treating a benign gynaecological disorder in a female mammal, said method comprising intravaginal administration of anti-estrogen to a female mammal suffering from such a disorder in a therapeutically effective dosage to prevent or reduce symptoms of said benign gynaecological disorder. The intravaginal administration of anti-estrogen, in comparison to other routes of administration, achieves the desired clinical levels. The present method is particularly suitable for treating a benign gynaecological disorder selected from the group consisting of uterine leiomyomas, endometriosis, adenomyosis, dysmenorrhea, and functional menorrhagia and metrorrhagia. Another aspect of the invention is concerned with a drug delivery vehicle for intravaginal use, which drug delivery vehicle contains at least 10 νg of an anti-estrogen and a plurality of oral dosage units containing one or more estrogens in an amount equivalent to a daily oral dosage of at least 1 νg ethinyl estradiol.

Description

METHOD OF TREATING BENIGN GYNAECOLOGICAL DISORDERS AND A PHARMACEUTICAL KIT FOR USE IN SUCH METHOD

TECHNICAL FIELD

The present invention relates to a method of treating an estrogen sensitive benign gynaecological disorder in mammal females, especially a benign gynaecological disorder selected from the group consisting of uterine leiomyomas, endometriosis, adenomyosis, dysmenorrhea, and functional menorrhagia and metrorrhagia. More particularly the present invention relates to such a method comprising the administration of a drug delivery vehicle to a female mammal suffering from such a benign gynaecological disorder, said drug delivery vehicle containing an anti-estrogen, wherein the method provides the anti-estrogen in a therapeutically effective dosage to prevent or reduce symptoms of said benign gynaecological disorder.

Another aspect of the invention is concerned with a pharmaceutical kit comprising a drug delivery vehicle that contains at least 10 μg of an anti-estrogen and a plurality of oral dosage units comprising an estrogen in an amount equivalent to a daily oral dosage of at least 1 μg ethinyl estradiol.

BACKGROUND OF THE INVENTION

Uterine leiomyomas (fibroids or myomas), benign clonal tumours, arise from smooth- muscle cells of the human uterus. They are clinically apparent in up to 25% of women and are the single most common indication for hysterectomy. They cause significant morbidity, including prolonged and heavy menstrual bleeding, pelvic pressure and pain, urinary problems, and, in rare cases, reproductive dysfunction.

The pathophysiology of myomas is not well understood. However, both genetic predisposition and steroid hormone concentrations have a role in the development and growth of these benign tumours. In addition, growth factors play an important role in fibrotic processes and angiogenesis. At least two distinct steps to myoma formation can be identified. First, normal myocytes have to be transformed into abnormal myocytes and secondly, these abnormal cells subsequently have to grow into clinically apparent tumours. Microscopic myomas have a high prevalence, meaning that the first process is quite common. The subsequent growth occurs via clonal expansion. A variety of chromosomal subgroups have been found, implying that myomas can be seen as a common phenotype resulting from several different genetic events. Myomas are found submucosally (beneath the endometrium), intramurally (within the myometrium) and subserosally (projecting out of the serosal compartment of the uterus), but mostly are mixed forms of these 3 different types.

The presence of estrogen receptors in leiomyoma cells has been studied by Tamaya et al. (Acta Obstet Gynecol Scand 1985; 64(4);307-9). They have shown that the ratios of estrogen receptor compared to progesterone and androgen receptor levels were higher in leiomyomas than in the corresponding normal myometrium.

Surgery has long been the main treatment for myomas. Women who have completed childbearing often undergo a hysterectomy, because this eliminates both the symptoms and the chance of recurrence. For women who desire future pregnancies or for other reasons wish to retain the uterus, other options are available. Myomectomy (removal of the myomas with uterine conservation) is widely done. However, the disadvantage of this treatment is the risk of new myoma formation.

Medical therapies that have been proposed to treat myomas include administration of a variety of steroids such as the androgenic steroids danazol or gestrinone, GnRH agonists and progestogens. Both danazol and gestrinone induce amenorrhea, thus controlling myoma- related menorrhagia. Gestrinone also has been reported to cause uterine volume reduction. However, both these drugs have pronounced androgenic side effects like weight gain, acne and hirsutism, which explains the diminishing popularity of these drugs. In addition, these drugs produce a hypoestrogenic milieu causing symptoms such as hot flushes and loss of bone mass.

Gonadotrophin releasing hormone (GnRH) agonists (e.g. nafareline, busereline) give a more complete suppression of ovarian activity by down-regulation of LH and FSH receptors. The GnRH agonists produce a significant reduction in uterine size, however, these drugs cause serious hypoestrogenic symptoms, such as hot flushes, sweating, headache, vaginal dryness, and loss of bone mass. In addition, the inactivation of the ovaries does not usually result in complete disappearance of myomas. Once the GnRH agonists are discontinued, the size of the uterus increases to pre-treatment volume. Therefore, the GnRH agonists are primarily used temporarily to facilitate surgery. The newly developed GnRH antagonists suppress ovarian endocrine activity even stronger than the GnRH agonists and cause therefore even more serious hypoestrogenism.

The use of progestogens for the treatment of myomas is ineffective for many women. In addition, progestogens cause many side effects and induce hypoestrogenism too. Because of the induction of a hypoestrogenic status, the aforementioned medical therapies cannot be administered for more than 6 months, in particular not because of the risk of accelerated bone loss resulting in pronounced osteoporosis.

Several studies looked at long term medical therapy of myomas, based on a regimen wherein initially downregulation to a hypogonatropic hypogonadal state is achieved through administration of a GnRH agonist and subsequently an estrogen and a progestogen are administered to sustain the reduction in uterine volume and amenorrhea. A drawback of administering estrogen is that it can cause myoma growth if the dose is too high. The dose that will not give growth of the myomas and counteracts the symptoms of hypoestrogenism varies from person to person. Another drawback of this long term therapy is that it interferes with fertility.

Endometriosis, another well-known gynaecological disorder, affects 10 to 15% of women in the reproductive age. It is a benign disease defined as the presence of viable endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area. In women developing endometriosis, the endometrial cells entering the peritoneal cavity by retrograde menstruation have the capacity to adhere to and invade the peritoneal lining, and are then able to implant and grow. The key question is why endometrial cells adhere and implant in some women and not in others. The implants respond to steroid hormones of the menstrual cycle in a similar way as the endometrium in the uterus. The infiltrating lesions and the blood from these lesions, unable to leave the body, cause inflammation of the surrounding tissue. The most common symptoms of endometriosis are dysmenorrhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the lesions. Some women with severe endometriosis are asymptomatic, while women with mild endometriosis may have severe pain.

Until now, no non-invasive test is available to diagnose endometriosis. Laparoscopy has to be performed to diagnose the disease. Endometriosis is classified according to the 4 stages set up by the American Fertility Society (AFS). Stage I corresponds to minimal disease while stage IN is severe, depending on the location and the extent of the endometriosis. Endometriosis is found in up to 50% of the women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility.

Despite extensive research, the cause of endometriosis is still largely unknown. Several theories for the origin of endometriosis have been proposed, although no single hypothesis explains all cases of the disease completely. However, the key event in all these theories is the occurrence of retrograde menstruation.

The aims of treatment of endometriosis are pain relief, resolution of the endometriotic tissue and restoration of fertility (if desired). The two common treatments are surgery or hormonal therapy or a combination of both.

Surgical treatment removes the endometriotic tissue. Initially, the pain relief using this procedure approaches 70-80%. However, the pain returns in many cases due to re-growth of the endometriotic tissue. At present the most permanent way to treat endometriosis is the removal of the ovaries, thus eliminating the production of estrogens and possible other ovarian factors, which regulate the growth and activity of the endometriotic tissue. The currently available pharmacological treatments of endometriosis are anti- inflammatory and hormonal. In the early stages of endometriosis non-steroidal anti- inflammatory drugs (NSAID's) are often successful in relieving the pelvic pain. Hormonal treatment is given mainly to inhibit the estrogen production by the ovaries. Various drugs are available for suppressing ovarian function as will be explained below.

Endometriosis, like leiomyomas, has been treated with danazol, gestrinone and GnRH agonists. However, the same drawbacks that have been reported above in relation to the use of these drugs in the treatment of myomas have also been observed in the treatment of endometriosis. Progestogens have been used more frequently in the treatment of endometriosis than for treating leiomyomas, because progestogens inhibit endometrial proliferation. Progestogens are administered in a sufficiently high amount to suppress pituitary release of LH and FSH which in turn causes inhibition of endogenous secretion of estrogen resulting in hypoestrogenic symptoms. Examples of progestogens given for endometriosis are medroxyprogesterone acetate, dydrogesterone and lynestrenol. These drugs are also associated with side-effects e.g. serious mood changes and breakthrough bleeding. The treatment of endometriosis with progestogens has not received regulatory approval in the United States. Oral contraceptives, containing both an estrogen and progestogen, are also prescribed for endometriosis. However, this treatment is not optimal, because the stimulatory effect of the estrogenic compound on the endometriotic lesions may not be counteracted effectively enough by the progestogen and because the withdrawal bleeding induced also causes bleeding in endometriotic tissue.

A large percentage of women experience some relief of symptoms while being treated with the hormonal drugs mentioned. However, symptoms remain present and recurrence occurs once administration of the drug is discontinued. None of the aforementioned drugs is suitable for long term treatment of benign gynaecological disorders, because of the severe side-effects which are largely associated with hypoestrogenism. These treatments are therefore in most cases discontinued after a period of 6 months after which recurrence of the symptoms is likely to occur.

It will be evident from the above that there is a great need for a pharmaceutical treatment of uterine leiomyomas and endometriosis, which treatment (1) can suitably be applied for a much longer period of time than the existing hormonal treatments, preferably until such time that the female treated reaches menopause,

(2) is more effective,

(3) causes less side-effects during treatment and/or

(4) has a lower recurrence rate after discontinuation of the therapy. Everything that has been said above in relation to the treatment of uterine leiomyomas and endometriosis equally applies to other benign gynaecological disorders, notably adenomyosis, dysmenorrhoea and functional menorrhagia and metrorrhagia. These benign gynaecological disorders are all estrogen sensitive and are treated in a comparable way as described herein before in relation to uterine leiomyomas and endometriosis. The available pharmaceutical treatments, however, suffer from the same major drawbacks as mentioned above, i.e. they have to be discontinued once the side-effects become more serious than the symptoms to be treated and symptoms reappear after discontinuation of the therapy.

US 6,281,205 relates to novel anti-estrogenic compounds which are useful to treat a variety of disorders, including estrogen-dependent disorders such as breast cancer, ovarian, uterine and pancreatic tumores, galactorrhea, McCune- Albright syndrome, benign breast disease, and endometriosis. In example 46 a vaginal suppository containing 5-25% of an anti- estrogen is described for use in a method of inhibiting vaginal atrophy.

EP-A 0 664 120 describes a medical device for insertion into a vaginal cavity comprising an elastomeric ring containing tamoxifen or a derivative thereof. It is observed in the application that these devices can advantageously be used in the prophylaxis and treatment of breast cancer of diverse origins and to treat pancreatic carcinoma, endometrial carcinoma, ovarian cancer and renal carcinoma.

DE-A 43 29 344 describes a method of treating leiomyomas, using a combination of an anti-progestogen and an anti-estrogen. It is observed that the compounds having anti- progestational and anti-estrogenic activities can be administered enterally or parenterally and that suitable for local application are, for example, vaginal suppositories, gels or rings.

It is noted that the systemic administration of anti-estrogen in the treatment of benign gynaecological disorders such as endometriosis and leiomyomas will cause hypoestrogenism in the female receiving said treatment. Consequently, like the aforementioned pharmaceutical treatments, systemic administration of anti-estrogen will have to be discontinued once the side-effects become more serious than the symptoms to be treated.

Thus, the most important shortcoming of all existing medical therapies for the treatment of estrogen sensitive benign gynaecological disorders is that none of them is curative, i.e. they do not lead to disappearance of the myomas, endometriotic and/or adenomyotic tissue. In addition, they all suffer from side-effects due to hypoestrogenism, which become more pronounced as the duration of the therapy increases.

Consequently there is a need for a long term medical therapy of estrogen sensitive benign gynaecological disorders, particularly for pre- and peri-menopausal females, that does not cause serious side-effects. In addition there is a strong need for a long term medical therapy that will obviate the need for surgical treatments such as hysterectomy and myomectomy.

SUMMARY OF THE INVENTION

The present invention relates to a method of treatment that realises the aforementioned objectives, i.e. it can be applied in the treatment of the aforementioned benign gynaecological disorders for a significantly longer period of time than existing medications, as it causes less side-effects enabling long term therapy thereby avoiding the need for surgical procedures.

Applicants have surprisingly found that the aforementioned objectives may be realised by a method of treatment that comprises intravaginal administration to a female mammal of a therapeutically effective dosage of an anti-estrogen. Although we do not wish to be bound by theory, it is believed that proliferation of myomas, endometriotic, adenomyotic and endometrial tissue is the result of estrogen induced autostimulation (paracryne), i.e. that these tissues are capable of synthesising estrogens and that these estrogens will bind with the estrogen receptors within the same tissue, thereby triggering (further) proliferation. It was found to be possible to effectively stop this cascade of proliferation by the intravaginal administration of anti-estrogen. Moreover, it was observed that this may be achieved without serious interference with the body's hormonal balance.

The particularly good results observed for the intravaginal administration of the anti- estrogen are believed to be largely due to the fact that, unlike all regimens that have been practised so far, the present method does not suppress the pituitary release of follicle stimulating hormone (FSH) and luteinising hormone (LH) and therefore does not inhibit ovarian stimulation. The present method counteracts the proliferative effect of endogenous estrogen on myomas, endometriotic, adenomyotic and endometrial tissue in a very effective way by directly and selectively preventing the interaction of estrogens with the estrogen receptors present in these tissues. The present method achieves a high impact in these tissues without having significant (side-)effects on other estrogen sensitive tissues as estrogens can still interact with the estrogen receptors present in these tissues.

Anti-estrogens are substances which exhibit affinity for the mammalian estrogen receptors without triggering all of the responses that are characteristic of the interaction between estrogens and the same receptors. Thus, when administered in sufficiently high dosage, anti-estrogens will bind in appreciable amounts to estrogen receptors, thereby reducing the estrogen-receptor interaction. Consequently anti-estrogens can suitably be used to reduce or inhibit the impact of estrogens, hence the term "anti-estrogens". The term anti- estrogen as used throughout this document encompasses both anti-estrogens that trigger no estrogen receptor response at all ("true" antagonists) as well as anti-estrogens that are capable of triggering a selective estrogen receptor response. An example of an anti-estrogen capable of triggering a selective estrogen receptor response are so called selective estrogen receptor modulators (SERM's). Examples of suitable anti-estrogens include: tamoxifen, raloxifene, toremifene, idoxifene, droloxifene, nafoxidine, trioxifene, clomiphene, cyclophenil, lasofoxifene, arzoxifene, levormeloxifene, zindoxifene, ICI 164384 and ICI 182780. Walker et al ("Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma"; J Soc Gynecol Investig 2000; 7; 240-56) conducted preclinical studies in the Eker rat model to investigate the efficacy of SERM's as therapeutic agent for fibroids. Treatment with tamoxifen or LY 326315 by a subdermal pellet reduced the incidence of fibroids by 40-60% and reduced the size of the remaining fibroids. It was found that intravaginal administration of an anti-estrogen, in comparison to other routes of administration, achieves the desired clinical effect at lower dosage levels and/or without seriously affecting estrogen blood serum levels. Hence the present method may suitably be applied over a prolonged period of time, thereby significantly increasing the chance of achieving complete disappearance of the uterine leiomyomas, endometriotic or adenomyotic tissue. Furthermore intravaginal administration of the anti-estrogen in accordance with the present invention offers the advantage that it has much less impact on the liver than, for instance, oral administration.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is concerned with a method of treating a benign gynaecological disorder in a female mammal using a drug delivery vehicle, said benign gynaecological disorders being selected from the group consisting of uterine leiomyomas, endometriosis, adenomyosis, dysmenorrhea, and functional menorrhagia and metrorrhagia, the method comprising intravaginal administration of the drug delivery vehicle to the female mammal suffering from the benign gynaecological disorder, said drug delivery vehicle containing an anti-estrogen, wherein the method provides the anti-estrogen in a therapeutically effective dosage to prevent or reduce symptoms of said benign gynaecological disorder.

The present method also encompasses the prophylactic treatment of the aforementioned benign gynaecological disorders. The term "drug delivery vehicle" as used throughout this document encompasses any pharmaceutical dosage systems suitable for delivering a pharmaceutically active principle to a mammal in such a way that the active principle can exert a pharmaceutical effect on said mammal. Because the present drug delivery vehicle is used in a method of intravaginal administration it should be suitable for vaginal insertion. Examples of drug delivery vehicles suitable for intravaginal use include suppositories, tampons, vaginal rings, tablets, capsules, gels, creams, film, pessary, vaginal sponge, lotion, foam, ointment, paste or solution. In a preferred embodiment, said drug delivery vehicle is solid or semi-solid so as to facilitate insertion into the vagina. A preferred example of a solid vehicle is a tablet, capsule, suppository or a vaginal ring. It is noted that the solid drug delivery vehicle does not have to be entirely solid as, for instance, such a vehicle may suitably comprise a solid capsule and a liquid contained within said capsule. The present method may successfully be applied to female mammals. Preferably these mammals include humans, cattle and pets. Most preferably the female mammal is a human female.

The present method provides the anti-estrogen in a therapeutically effective dosage to inhibit growth of uterine leiomyomas, endometriotic, adenomyotic or endometrial tissue. By inhibition of the growth of these tissues is meant that existing leiomyomas, endometriotic, adenomyotic or endometrial tissue does not increase in volume as a result of proliferation and that no new tissues of these sorts are formed. In a particularly preferred embodiment of the present invention the anti-estrogen is provided in a therapeutically effective dosage to achieve atrophy of the aforementioned tissues. Most preferably the method provides said anti-estrogen in a therapeutically effective dosage to achieve full elimination of these tissues.

Examples of 'true' anti-estrogens that may be used in the present method include ICI 164384, ICI 182780, ZM 189154, EM-800, RU 58668, precursors of these anti-estrogens, and mixtures thereof. In addition, anti-estrogens that exert SERM-like activity as well as their precursors may suitably be used in the present method. Such SERM-like anti-estrogens can suitably be selected from the group consisting of tamoxifen, raloxifene, toremifene, idoxifene, droloxifene, nafoxidine, trioxifene, MER 25, EM-652, clomiphene, cyclophenil, lasofoxifene, arzoxifene, levormeloxifene, zindoxifene, LY 117018, LY 326315, ZK 119010, LY 357489, GW 5638, GW 7604, TSE-424, FC1271a and mixtures thereof. It has been reported

(Osteoporosis Conference Scrip No. 1812/13 Apr. 16/20, 1993, p. 29) that raloxifene (6- hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy) benzoyl] benzo[b] thiophene) mimics the favourable action of estrogen on bone and lipids but, unlike estrogen, has minimal uterine stimulatory effect (Breast Cancer Res. Treat. 10(1). 1987 p 31-36 Jordan, V. C. et al.). Preferably the anti-estrogen used in accordance with the invention is selected from the group consisting of ICI 164384, ICI 182789, raloxifene, tamoxifen, precursors of these substances, and mixtures thereof. Most preferably the anti-estrogen is selected from the group consisting of ICI 164384, ICI 182789, precursors of these substances and mixtures thereof, hi accordance with the invention, the anti-estrogen is suitably administered in an amount equivalent to a daily dosage of less than 600 mg raloxifene, preferably of more than 250 μg raloxifene and more preferably in an amount equivalent to a daily dosage of 600 μg to 60 mg raloxifene. In a particularly preferred embodiment the anti-estrogen is administered in an amount which is equivalent to less than 30 mg, more preferably even less than 20 mg raloxifene. The phrase "equivalent to a daily dosage" is not to be interpreted restrictedly. For instance, the above mentioned requirement that the administration of the present drug delivery vehicle is to provide the equivalent of a daily dosage of 600 μg to 60 mg raloxifene, encompasses a protocol wherein raloxifene is administered once a week, provided the weekly dosage is between 4.2 mg and 420 mg, i.e. such that the average daily dose is between 600 μg and 60 mg.

As mentioned herein before, the present method offers the advantage that due to the local (intravaginal) administration it selectively prevents the interaction of estradiol with estrogen receptors in myomas, endometriotic, adenomyotic or endometrial tissue. In contrast, well known methods of treating benign estrogen sensitive gynaecological disorders, completely suppress the endogenous production of estrogen throughout the female's body, giving rise to serious side-effects, particularly after prolonged treatment.

Consequently, in a very preferred embodiment, the present method is carried out in such a fashion that it does not suppress the pituitary release of follicle stimulating hormone (FSH) or luteinising hormone (LH). It will be evident that the present method preferably does not employ active principles that may suppress the pituitary release of FSH or LH. More preferably, the drug delivery vehicle employed in the present method contains virtually no progestogen (e.g. dienogest) or GnRH agonist. Also it is preferred not to co-administer either of these 2 active principles in combination with the present anti-estrogen containing drug delivery vehicle. In another preferred embodiment of the invention the present method comprises co- administration of an estrogen in a therapeutically effective amount to reduce possible symptoms of hypoestrogenism resulting from the administration of the anti-estrogen. As mentioned herein before, the present method offers the advantage that, due to the non- systemic and/or relatively low intravaginal dosage of the anti-estrogen, it will produce significantly less symptoms of hypoestrogenism than known methods for treating estrogen sensitive gynaecological disorders. However, in particular during prolonged treatment, certain symptoms of hypoestrogenism, such as hot flushes, may become manifest. These symptoms may suitably be suppressed by co-administering estrogen in a therapeutically effective dosage to compensate for the estrogen deficiency symptoms occurring at other parts of the body than the pelvis and the uterus, resulting from the intravaginal administration of the anti-estrogen, hi order to minimise any adverse impact on the beneficial effect of the intravaginally administered anti-estrogen, it is preferred to administer the estrogen using a mode of administration which is different from intravaginal or intra-uterine administration. We have unexpectedly found that, in particular if the estrogen is administered systemically (e.g. orally), the blood serum estradiol level may be restored to its usual level, without the administered estrogen having a significant proliferative effect on the myomas, endometriotic, adenoymyotic or endometrial tissue. In a preferred embodiment of the present method estrogen is co-administered with the anti-estrogen so as to maintain the estrogen blood serum level of the female at a level which is equivalent to at least 30 pg 17B- estradiol/ml. Most preferably the 17B-estradiol blood serum level of the female is maintained at a level of at least 30 pg/ml.

The estrogen used in the present method is preferably selected from the group consisting of ethinyl estradiol, mestranol, quinestranol, estradiol, estrone, estran, estriol, conjugated equine estrogens, precursors capable of liberating such an estrogen when used in the present method and mixtures thereof. In a preferred embodiment of the method of the invention the estrogen is selected from the group consisting of ethinyl estradiol, estradiol, precursors of these estrogens and mixtures thereof. The estrogen is suitably administered in an amount equivalent to at least 1 μg ethinyl estradiol, preferably in an amount equivalent to 1- 40 μg ethinyl estradiol (e.g. 0,2-5 mg 17β-estradiol) and more preferably in an amount equivalent to 3-30 μg ethinyl estradiol.

Another embodiment of the present method comprises co-administration of an androgen. The androgen enhances the action of the anti-estrogen, in particular the anti- estrogen's ability to suppress growth, proliferation and viability of endometriotic tissue, adenomyomas, fibroids and endometrial tissue and/or suppresses the undesirable side-effects of said anti-estrogen, particularly those side-effects associated with hypo-estrogenism.

Because androgens are precursors of estrogens, one would expect the administration of androgen to enhance the growth, proliferation and viability of the endometriotic tissue, adenomyomas, fibroids and endometrial tissue, and thus cause a worsening of the disease.

However, surprisingly the androgen component used in accordance with the present invention has an enhancing effect on the anti-proliferative action of the anti-estrogen.

The androgen may exert this effect through activation of androgen receptors. It is known that androgen receptors are present in endometriotic and endometrial tissue, as well as in adenomyosis. Horie et al., "Immunohistochemical localisation of androgen receptor in the human endometrium, decidua, placenta and pathological conditions of the endometrium", Hum. Repr. vol. 7, nr. 10 (1992), pp. 1461-1466 report that although the proliferation and differentiation of endometrium are mediated mainly by estrogen and progesterone receptors, the androgen receptor may play a role in modulating these changes. As yet, however, there is no scientific proof that indeed these androgen receptors play a role in the proliferation of endometriotic tissue, adenomyosis, fibroids and endometrial tissue.

The term "androgen" as used throughout this document relates to steroids that display androgen-like activity. The androgens used in the present method preferably are administered in a dosage where they exert the desired effect, but do not give rise to significant androgenic side-effects such as acne and hirsutism. Preferably the androgen is administered in a dose which leads to an increase in blood serum androgen level of no more than 5 nmole total testosterone equivalent per litre, preferably less than 3 nmole total testosterone equivalent per litre and most preferably less than 1.5 nmole total testosterone equivalent per litre. The total testosterone present in the serum includes both free testosterone and bound testosterone. The androgen used in the present method is preferably selected from the group consisting of dehydroepiandrosterone (DHEA); DHEA-sulphate (DHEAS); testosterone; testosterone esters such as testosterone undecanoate, testosterone propionate, testosterone phenylpropionate, testosterone isohexanoate, testosterone enantate, testosterone bucanate, testosterone decanoate, testosterone buciclate; danazol; gestrinone; methyltestosterone; mesterolon; stanozolol; androstenedione; dihydrotestosterone; androstanediol; metenolon; fluoxymesterone; oxymesterone; methandrostenolol; MENT, precursors capable of liberating these androgens when used in the present method and mixtures thereof. Most preferably the androgen is selected from the group consisting of DHEA, pharmaceutically acceptable testosterone esters such as testosterone undecanoate, danazol, gestrinone, androstenedione, precursors capable of liberating these androgens when used in the present method and mixtures thereof. Preferably the testosterone esters employed in the present method comprise an acyl group which comprises at least 6, more preferably from 8-20 and preferably 9-13 carbon atoms. Most preferably the androgen used in the present method is DHEA and/or testosterone undecanoate. These androgens offer the advantage that they can effectively be used in oral dosage units.

In a preferred embodiment the androgen is provided in an amount equivalent to a daily oral dosage of 5 to 250 mg DHEA, which is equivalent to a daily oral dosage of 1 to 50 mg testosterone undecanoate. More preferably the androgen is provided in an amount equivalent to a daily oral dosage of 20 to 100 mg DHEA, most preferably in an amount equivalent to a daily oral dosage of 40 to 60 mg DHEA. The phrase "equivalent to a daily dosage" should not be interpreted restrictedly. For instance, the above mentioned requirement that the administration of the present medicament is to provide the equivalent of a daily dosage of 5 to 250 mg DHEA, encompasses a protocol wherein DHEA is administered once a week, provided the weekly dosage is between 35 and 1750 mg, i.e. such that the average daily dose is between 5 and 250 mg DHEA.

It is noted that, for instance, DHEA, testosterone undecanoate and androstenedione are precursors of testosterone and that said precursors per se exhibit virtually no affinity for the androgen receptors in the female body. The effectiveness of androgens within the method of the invention is determined by their functionally active form, which may well be different from the form in which they are administered.

In order to obtain the desired impact from the present method it is advisable to administer the medicament at a dosage sufficient to maintain serum androgen concentration of the female mammal within a (physiological) range which is equivalent to between 0.5 and 5.0, preferably to between 0.7 and 4.0, most preferably between 1.0 and 3.0 nanomoles total testosterone per litre. Again, these testosterone concentrations include both free and bound testosterone.

In a particularly preferred embodiment of the invention, the androgen is administered in a systemic fashion. Most preferably the androgen is administered orally. In a particularly preferred embodiment, the present method comprises the combined systemic co- administration of an androgen and an estrogen.

In yet another preferred embodiment of the invention, the method comprises the intravaginal co-administration of an aromatase inhibitor in an amount effective to suppress the endogenous (bio)synthesis of estrogens (especially 17β-estradiol) in the myomas, endometriotic, adenomyotic or endometrial tissue. Aromatase is one of the P-450 enzymes. It catalyses the aromatisation of the A ring of the steroid skeleton in the steroid biosynthetic pathway starting from the cleavage of the side chain of cholesterol. To be more precise: aromatase catalyses the conversion of androstenedione to estrone as well as the conversion of testosterone to estradiol. Hence aromatase is a rate limiting enzyme for the biosynthesis of the latter estrogens.

Aromatase inhibitors are substances capable of inhibiting the catalytic activity of aromatase. In the context of the present invention aromatase inhibitors are substances that may be administered to animals, and especially humans, in non-toxic dosages so as to inhibit estrogen biosynthesis. The combined administration of anti-estrogen and aromatase inhibitor offers the advantage that estrogen induced proliferation of myomas, endometriotic, adenomyotic or endometrial tissue can be suppressed in an extremely effective dual manner. The combined intravaginal administration of anti-estrogen and aromatase inhibitor ensures that on the one hand endogenous biosynthesis of estrogens in the target tissues is reduced to almost zero, whilst the anti-estrogen effectively prevents that any remaining local or circulating estradiol can interact with estrogen receptors in the aforementioned tissues.

At present a range of aromatase inhibitors is available. Aromatase inhibitors primarily find application in methods of treating breast cancer. It has also been suggested that aromatase inhibitors may be used in the treatment of endometriosis.

In principle any known aromatase inhibitor which is suitable for pharmaceutical application can be used in the present method. Examples of aromatase inhibitors which may be used in accordance with the invention are aminoglutethimide, anastrozole, exemestane, vorozole, letrozole, fadrozole, rogletimide, atamestane, formestane, liarozole, finrozole, YM 511, TZA-2237, CGS 16949 A, MEN 11066, precursors of the aforementioned substances, and mixtures thereof. Preferably the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, vorozole, letrozole and formestane, precursors of these substances, and mixtures thereof.

The aromatase inhibitor is preferably administered in an amount equivalent to a daily dosage of less than 100 mg exemestane, preferably of more than 150 μg exemestane and more preferably in an amount equivalent to a daily dosage of 250 μg to 25 mg exemestane. In a particularly preferred embodiment of the invention the aromatase inhibitor is administered in an amount which is equivalent to less than 16 mg, even more preferably less than 8 mg exemestane. In another preferred embodiment the present method comprises co-administration of an anti-progestogen in an effective amount to boost the atrophic effect of the anti-estrogen on the uterine leiomyomas, endometriotic, adenomyotic and endometrial tissue. Although applicants do not wish to be bound by theory it is believed that these tissues, next to estrogen receptors, also express progestogen receptors. Anti-progestogens have been shown to inhibit endometrial proliferation. Thus the combined use of an anti-estrogen and an anti-progestogen is very effective in suppressing such proliferation, but more importantly also in achieving atrophy of the target tissues. In a particularly preferred embodiment also the anti-progestogen is administered intravaginally. Also in case of anti-progestogen the intravaginal administration offers the advantage that, in comparison to systemic administration, the same local climcal effects, with less pronounced side-effects, are achieved at lower systemic blood levels of the anti-progestogen.

The anti-progestogen used in the present method can be a progesterone receptor antagonist or a pharmaceutically suitable agent that counteracts the normal biological activity of progesterone. Examples of anti-progestogens which can be employed in this invention are RU 486 (mifepristone, Roussel Uclaf, Paris; U.S. Pat. No. 4,386,085); Org 31710 [(6.alpha.,l l.beta.,17.beta.)-l l-(4-NMe.sub.2 -phenyl)-6-Me-4',5'-dihydrospiro[oestra-4,9- diene-17,2(3Η)-furan]-3-one]; Org 33628[(ll.beta.,17.alρha.)-(4-acetylρhenyl)- 17,23- epoxy-19,24-dinorchola-4,9,20-trien-3-one]; onapristone (Schering Ag, Berlin; U.S. Pat. No. 4,780,461) and the steroids described in the following patents and patent applications: U.S. Pat. No. 4,609,651, especially the compound lilopristone (1 lβ-(4-dimethylaminophenyl)-17β- hydroxy-17α-(3-hydroxy-prop-l-(Z)-enzyl-4,9(10) estradien-3-one); U.S. application Ser. No. 06/827,050, especially the compounds l lβ-(4-acetylphenyl)-17β-hydroxy-17α-(l-propinyl)- 4,9-estradien-3-one and 1 lβ-(4-acetylphenyl)-17β-hydroxy-17α-(3-hydroxy-l(2)-propenyl)- 4,9-estradien-3-one; U.S. application Ser. No. 07/283,632; published European patent application EP-A 04042831; published PCT application WO 91/14704; and other anti- progestogens, e.g., U.S. Pat. No. 4,891,368. Most preferably the anti-progestogen used in the present method is mifepristone and/or a precursor thereof.

In accordance with the present invention, the anti-progestogen is suitably administered in a daily amount of at least 10 μg. More preferably the minimum daily dosage is equivalent to an intravaginal daily dosage of at least 200 μg, most preferably at least 500 μg mifepristone. The maximum daily dosage of anti-progestogen is preferably equivalent to an intravaginal daily dosage of less than 500 mg mifepristone, more preferably of less than 50 mg mifepristone and most preferably of less than 25 mg mifepristone. The present method is particularly effective when used in the treatment of uterine leiomyomas, endometriosis or adenomyosis as the main symptoms of these disorders are directly related to endometrial proliferation. Best results are obtained when the present method is used in the treatment of uterine leiomyomas, adenomyosis or rectovaginal endometriosis. Throughout this document by precursors of an active ingredient are meant components capable of liberating the active ingredient when used in the present method, particularly after intravaginal and/or, in the case of estrogen and androgen, following oral administration, e.g. as a result of metabolic conversion of the precursor substance.

It is to be understood that the present invention not only encompasses the use of the active principles specifically mentioned in this application, but also the use of metabolites of these components that display comparable functionality. In this context it is noted that, for instance, estriol is a metabolite of 17beta-estradiol.

The drug delivery vehicle used in the present method is preferably administered intravaginally at intervals of between 12 hours and 90 days. More preferably said vehicle is administered between once a day or once a month. It can be advantageous to use a slow release drug delivery vehicle, particularly a vehicle that, following intravaginal administration, is capable of releasing the preferred daily dosage amounts during a period of at least 5, or more preferably at least 10 days, without intermediate replenishment. An important advantage of the present method is that, unlike existing methods, it may be employed for prolonged periods of time, without any serious side-effects. Hence in a preferred embodiment the present method comprises uninterrupted intravaginal administration of the drug delivery vehicle for a period of at least 3 months, preferably at least 6 months. It is noted that with the present method usually a treatment period of at least 3-6 months is necessary to obtain significant atrophy or complete disappearance of the target tissue.

The term "uninterrupted" when used in relation to the administration of one or more active principles, means that said one or more active principles are administered at relatively regular intervals, with no (therapeutically) significant interruptions. Naturally, minor interruptions may occur that do not affect the overall effectiveness of the present method, and indeed such aberrations are encompassed by the present invention. In a preferred embodiment, and more arithmetically, an administration regimen is deemed to be uninterrupted if the longest interval between 2 subsequent administrations is not more than 3.5 times as long as the average interval. Even more preferably said longest interval is not more than 2.5 times as long as the average interval. Estrogen sensitive benign gynaecological disorders are much more frequently observed in pre-menopausal than in postmenopausal women. Hence the benefits of the present method are particularly appreciated when said method is applied to pre- and peri- menopausal females.

Another aspect of the invention is concerned with a pharmaceutical kit comprising a drug delivery vehicle for intravaginal use, comprising at least 10 μg of an anti-estrogen and pharmaceutically acceptable excipient; and a plurality of oral dosage units comprising one or more estrogens in an amount equivalent to a daily oral dosage of at least 1 μg ethinyl estradiol and pharmaceutically acceptable excipient.

Preferably the amount of anti-estrogen exceeds 50 μg. Usually the amount of anti- estogen will not exceed 600 mg, preferably it will not exceed 400 mg, most preferably it will not exceed 200 mg. Most preferably the drug delivery device contains anti-estrogen in an amount equivalent to at least 600 μg raloxifene. The drug delivery vehicle according to the invention may be a tablet, capsule, gel, cream, film, suppository, tampon, vaginal ring, film, pessary, vaginal sponge, lotion, foam, ointment, paste or solution. Preferably the drug delivery vehicle is a suppository, a tampon, a vaginal ring, a capsule, a cream or a gel.

In a preferred embodiment the oral dosage units contain one or more estrogens in an amount equivalent to an oral dosage of at least 1-100 μg ethinyl estradiol, more preferably in an amount equivalent to an oral dosage in the range of 3-30 μg ethinyl estradiol.

In another preferred embodiment the drag delivery vehicle contains an aromatase inhibitor in an amount equivalent to at least 150 μg exemestane, preferably equivalent to at least 250 μg exemestane. The maximum amount of aromatase inhibitor contained in the drug delivery device preferably does not exceed the equivalent of 600 mg exemestane, more preferably it does not exceed the equivalant of 400 mg exemestane, most preferably it does not exceed the equivalent of 200 mg exemestane.

In yet another preferred embodiment the drug delivery vehicle additionally contains at least 10 μg of an anti-progestogen. Preferably the delivery vehicle contains anti-progestogen in an amount equivalent to at least 200 μg, more preferably at least 500 μg mifepristone. Usually the amount of anti-progestogen will not exceed 500 mg, preferably it will not exceed 300 mg, most preferably it will not exceed 200 mg.

The vaginal suppository may suitably be based on a hard fat, preferably a hard fat having a hydroxy value not exceeding 50. The term 'hard fat" means a mixture of glycerides whose constituent fatty acids are straight-chain saturated fatty acids of 8 to 18 carbon atoms, and examples of such hard fat are listed on Martindale The Extra Pharmacopeia, 28ed., p. 1067, London, The Pharmaceutical Press, 1982). The vaginal suppositories according to the present invention may be manufactured by melting the hard fat adding the pharmaceutically active principles, mixing them thoroughly, pouring the composition into suppository moulds in predetermined uniform quantities and cooling them. In another embodiment, the invention provides a tampon device for delivering the anti-estrogen to the vaginal epithelium, said tampon comprising an absorbent material which has been soaked with a pharmaceutically acceptable solution of the anti-estrogen. A retrieval string or tape may be connected to the tampon device so as to facilitate easy removal. When administered the tampon contacts the vaginal epithelium for delivery of the agent. In yet another embodiment the delivery vehicle may be a vaginal ring. Vaginal rings are torous shaped devices designed to deliver a relatively constant dose of drug to the vagina usually over a period of weeks to months. Typically, they are made of a poly EVA elastomer and contain a drug released by diffusion though the elastomer. The most common commercial applications have been to deliver low doses of steroids for post-menopausal vaginal conditions. They have also been under development for use in contraception and hormone replacement therapy. Vaginal rings have also been used to administer spermicides, as well as a variety of locally or systematically active medicaments.

The use of a vaginal ring to deliver drugs requires a ring design that regulates the release rate so as to provide the user with the appropriate daily dose. Among the important factors governing release are the solubility of the drug in the ring elastomer, the surface area of the drug reservoir, the distance the drug must diffuse through the ring body to reach its surface and the molecular weight of the drug.

If very high release rates are desired, they can be attained by a drug load at the ring surface as is characteristic of the homogeneous matrix ring design. This design, however, suffers from rapidly declining release rates as the distance the drug must travel to reach the ring surface increases as the drag load near the surface is depleted. If moderately high release rates are needed to provide the appropriate dose, a design which modulates release rate by imposing a layer of drug-free elastomer between the drag reservoir and the ring exterior is appropriate. This may be attained by coating a homogeneous ring by incorporating a drag-free core. If an even lower release rate is desired, the drug may be confined to a small diameter at the center of the ring ("core ring"). Numerous types of vaginal rings have been described in the patent and non-patent literature alike.

The invention is further illustrated by means of the following examples.

EXAMPLES

Example 1 A clinical efficacy study is conducted in 10 women with uterine fibroids, who have to undergo a myomectomy or a hysterectomy. Each participant receives a daily dosage of 30 mg raloxifene intravaginally. Before the start of the study the number and size of the fibroids is assessed by ultrasonography for each participant. This procedure is repeated every week after the start of the study until the female undergoes myomectomy or hysterectomy. During the period of study participants are recording symptoms of hypoestrogenism in a diary. After 5-16 weeks of vaginally administered raloxifene, the size of the fibroids is reduced in all participants. Reductions in total fibroids volume of up to 75% are observed. Some women experience symptoms of hypoestrogemsm. Example 2

Example 1 is repeated. The participants additionally receive a daily oral dosage of 1 mg 17-β estradiol. The participants receiving the combination of vaginal raloxifene and oral estrogen show significant fibroid atrophy during the treatment, show no endometrial growth in the uterus and record less symptoms of hypoestrogenism than the females described in example 1, who only receive raloxifene.

Example 3

A clinical study is conducted in 20 women with stage 3 or 4 endometriosis, complaining from severe dysmenorrhoea and/or abdominal pain. Ten women receive a daily intravaginal dosage of 30 mg raloxifene. The other ten women receive a daily intravaginal dosage of 30 mg raloxifene together with an oral dosage of 1 mg 17-β estradiol. Both groups are treated for 6 months.

Before the start of the study a laparoscopy is performed. Every 4 weeks the women fill out a questionnaire assessing the level and occurrence of abdominal pain. In addition, the study participants are recording symptoms of hypoestrogenism in a diary. A second laparoscopy is performed after 6 months of treatment or when treatment is discontinued. Results show that all women have a reduction of pain after 6 months of treatment. Within this period, the endometriotic lesions are reduced in all participants. The reduction in size of the endometriotic lesions is similar for both groups. The women receiving 17-β estradiol experience less symptoms of hypoestrogenism.

Example 4

A clinical efficacy study is conducted in 20 women with stage 3 or 4 endometriosis, complaining from severe dysmenorrhoea and or abdominal pain. Ten women receive a daily dosage of 30 mg raloxifene intravaginally. The other 10 women receive a daily dosage of 30 mg raloxifene intravaginally in combination with an oral dosage of 50 mg dehydroepiandrosterone (DHEA). Both groups are treated for 6 months. Before the start of the study a laparoscopy is performed. Every 4 weeks the women fill out a questionnaire assessing the level and occurrence of abdominal pain. During the period of study participants are recording symptoms of hypoestrogenism in a diary. A second laparoscopy is performed after 6 months of treatment or when treatment is discontinued.

Results show that all women have a reduction of pain after 6 months of treatment. Within this period, the endometriotic lesions are reduced in all participants. The women receiving DHEA show a more pronounced reduction in size of the endometriotic lesions compared to the women not receiving DHEA. A few women experience symptoms of hypoestrogenism. Women receiving DHEA appear to have less subjective side effects than the women not receiving DHEA.

Example 5

Example 1 is repeated with the exception that the participants additionally receive a daily intravaginal dosage of 10 mg mifepristone. The participants receiving the combination of raloxifene and mifepristone show a larger reduction of fibroid size than the participant of example 1 who receive only raloxifene.

Example 6

Example 1 is repeated with the exception that the participants additionally receive a daily intravaginal dosage of 12,5 mg exemestane. The participants receiving the combination of raloxifene and exemestane show a larger reduction of fibroid size than the participants of example 1 who receive only raloxifene.

Example 7

Example 1 is repeated with the exception that the participants receive a daily intravaginal dosage of 10 mg tamoxifen instead of 30 mg raloxifene. After 5-16 weeks of vaginally administered tamoxifen, the size of the fibroids is reduced in all participants. Reductions in total fibroids volume of up to 60 % are observed. Some women experience symptoms of hypoestrogenism.

Claims

1. Use of an anti-estrogen in the manufacture of a drag delivery vehicle for use in a method of treating a benign gynaecological disorder in a female mammal, said benign gynaecological disorders being selected from the group consisting of uterine leiomyomas, endometriosis, adenomyosis, dysmenorrhea, and functional menorrhagia and metrorrhagia, the method comprising intravaginal administration of the drug delivery vehicle to the female mammal suffering from the benign gynaecological disorder, wherein the method provides the anti-estrogen in a therapeutically effective dosage to prevent or reduce symptoms of said benign gynaecological disorder.

2. Use according to claim 1, wherein the method does not inhibit ovarian estrogen sythesis.

3. Use according to claim 1 or 2, wherein the method comprises co-administration of estrogen in a therapeutically effective amount to reduce symptoms of hypoestrogenism resulting from the administration of the anti-estrogen.

4. Use according to claim 3, wherein the estrogen is co-administered orally.

5. Use according to any one of claims 1-4, wherein the method comprises the intravaginal administration of the anti-estrogen containing drug delivery vehicle in a sufficient amount to inhibit growth and/or to achieve atrophy of the uterine leiomyomas, adenomyotic, endometriotic or endometrial tissue.

6. Use according to any of claims 1-5, wherein the benign gynaecological disorder is selected from the group consisting of uterine leiomyomas, adenomyosis and endometriosis.

7. Use according to any one of claims 1-6, wherein the method comprises co-administration of androgen in an amount equivalent to a daily oral dosage of 5 to 250 mg DHEA.

8. Use according to any one of claims 1-7, wherein the method comprises co-administration of an aromatase inhibitor in an amount effective to suppress the endogenous synthesis of 17β-estradiol in uterine leiomyomas, endometriotic, adenomyotic or endometrial tissue.

9. Drug delivery vehicle according to any one of claims 1-8, wherein during treatment the blood serum estrogen level of the female is maintained at a level which is equivalent to at least 30 pg 17 β-estradiol /ml.

10. Use according to any one of claims 1-9 wherein the method comprises uninterrupted intravaginal administration of the drug delivery vehicle for a period of at least 3 months, preferably at least 6 months.

11. Use according to any one of claims 1-10, wherein the anti-estrogen is selected from the group ICI 164384, ICI 182789, raloxifene, tamoxifen, precursors of these anti-estrogens, and mixtures thereof.

12. Use according to any one of claims 1-11, wherein the anti-estrogen is administered in an amount equivalent to a daily dosage of 600 μg to 60 mg raloxifene.

13. Pharmaceutical kit comprising a drug delivery vehicle for intravaginal use containing at least 10 μg of an anti-estrogen and pharmaceutically acceptable excipient; and a plurality of oral dosage units containing one or more estrogens in an amount equivalent to a daily oral dosage of at least 1 μg ethinyl estradiol and pharmaceutically acceptable excipient.

14. Pharmaceutical kit according to claim 13, wherein the drug delivery vehicle additionally contains an aromatase inhibitor in an amount equivalent to at least 150 μg exemestane.

15. Pharmaceutical kit according to claim 13 or 14, wherein the drug delivery vehicle additionally contains an anti-progestogen in an amount equivalent to at least 200 μg mifepristone.

16. Pharmaceutical kit according to any one of claims 13-15, wherein the drug delivery vehicle is a suppository, a tampon, a vaginal ring, a capsule, a cream or a gel.