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WO2003017973A1 - Traitement de troubles gynecologiques benins et vecteur d'administration a cet effet - Google Patents

Traitement de troubles gynecologiques benins et vecteur d'administration a cet effet Download PDF

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Publication number
WO2003017973A1
WO2003017973A1 PCT/NL2002/000513 NL0200513W WO03017973A1 WO 2003017973 A1 WO2003017973 A1 WO 2003017973A1 NL 0200513 W NL0200513 W NL 0200513W WO 03017973 A1 WO03017973 A1 WO 03017973A1
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Prior art keywords
seem
estrogen
inhibitors
drug delivery
delivery vehicle
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PCT/NL2002/000513
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English (en)
Inventor
Monique Visser
Herman Jan Tijmen Coelingh Bennink
Joseph Helenus Hubert Thijssen
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Pantarhei Bioscience B.V.
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Priority claimed from EP01203305A external-priority patent/EP1287817A1/fr
Application filed by Pantarhei Bioscience B.V. filed Critical Pantarhei Bioscience B.V.
Publication of WO2003017973A1 publication Critical patent/WO2003017973A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • the present invention relates to a 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, functional menorrhagia and metrorrhagia.
  • 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 a selective estrogen enzyme modulator (SEEM) selected from the group consisting of aromatase inhibitors, cyclo-oxygenase 2 (COX-2) inhibitors, 17 ⁇ -hydroxy steroid dehydrogenase type 1 inhibitors and combinations thereof, wherein the method provides the SEEM in a therapeutically effective dosage to prevent or reduce symptoms of said benign gynaecological disorder.
  • SEEM selective estrogen enzyme modulator
  • SEEMs selective estrogen enzyme modulator
  • SEEMs have in common that they have the capability to inhibit the in vivo biogenesis of estrogens, especially by inhibiting enzymes that are involved in or that affect the last steps of biosynthetic pathways that generate these estrogens.
  • Another aspect of the invention is concerned with a drug delivery vehicle which contains an aromatase inhibitor and/or a 17 ⁇ -hydroxy steroid dehydrogenase type 1 inhibitor, and pharmaceutically acceptable excipient.
  • Uterine leiomyomas benign clonal tumours
  • myomas benign clonal tumours
  • They 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.
  • both genetic predisposition and steroid hormone concentrations have a role in the development and growth of these benign tumours.
  • growth factors play an important role in fibrotic processes and angiogenesis. At least two distinct steps to myoma formation can be identified.
  • 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.
  • 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 hypoestrogemc milieu causing symptoms such as hot flushes and loss of bone mass.
  • Gonadotrophin releasing hormone (GnRH) agonists e.g. nafareline, busereline
  • GnRH agonists produce a significant reduction in uterine size, however, these drugs cause serious hypoestrogemc symptoms, such as hot flushes, sweating, headache, vaginal dryness, and loss of bone mass.
  • the inactivation of the ovaries does not usually result in complete disappearance of myomas.
  • 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.
  • progestogens for the treatment of myomas is ineffective for many women.
  • progestogens cause many side effects and induce hypoestrogenism too.
  • 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.
  • 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 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.
  • 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).
  • AFS American Fertility Society
  • Stage I corresponds to minimal disease while stage IV 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.
  • 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.
  • 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.
  • NSATD's non-steroidal anti- inflammatory drugs
  • 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.
  • 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 hypoestrogemc 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.
  • 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.
  • US 6,274,573 describes a method of reducing the recurrence of uterine leiomyoma comprising administering an effective amount of dienogest (a progestogen). It is observed that dienogest may be used in combination with GnRH agonists, GnRH antagonists, aromatase inhibitors and antiestrogens. It is noted that this method relies on the ability of the dienogest to suppress the pituitary release of FSH and LH and that this method will also cause hypoestrogenism.
  • 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.
  • a method of treatment that comprises intravaginal administration to a female mammal of a therapeutically effective dosage of a selective estrogen enzyme modulator (SEEM) selected from the group consisting of aromatase inhibitors, cyclo-oxygenase 2 (COX-2) inhibitors, 17 ⁇ -hydroxysteroid dehydrogenase type 1 inhibitors and combinations thereof.
  • SEEM selective estrogen enzyme modulator
  • biosynthetic pathways that are involved in the endogenous production of the most important biogenic estrogen, i.e. 17 ⁇ -estradiol may be represented as follows:
  • aromatase and 17 ⁇ -hydroxy steroid dehydrogenase type 1 are key enzymes in the endogenous production of 17 ⁇ -estradiol. This is also believed to be true for the production of 17 ⁇ -estradiol in e.g. myomas or endometriotic tissue. Consequently, the inhibition of aromatase and 17 ⁇ -hydroxysteroid dehydrogenase type 1 in these tissues will automatically reduce the production of 17 ⁇ -estradiol, which in turn will impair proliferation in said tissues.
  • the diagram also shows that prostaglandin PGE2 is capable of stimulating aromatase activity. Consequently, inhibition of cyclo-oxygenase 2 (COX-2), the enzyme responsible for the endogenous production of PGE2 from arachidonic acid, will automatically cause a reduction of aromatase activity and a corresponding decrease in proliferation.
  • COX-2 cyclo-oxygenase 2
  • aromatase inhibitors, cyclo-oxygenase 2 (COX-2) inhibitors as well as 17 ⁇ -hydroxysteroid dehydrogenase type 1 inhibitors may suitably be used to impair endogenous production of estrogens, particularly the endogenous production of 17 ⁇ -estradiol, in myomas, endometriotic, adenomyotic and endometrial tissue.
  • Expression of COX-2 has been observed in endometrial tissue and is suspected in adenomyotic tissue, which serves to illustrate that COX-2 is involved in the estrogen induced proliferation of such tissues.
  • 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.
  • aromatase inhibitors are substances that may be administered to animals, and especially humans, in non-toxic dosages so as to inhibit estrogen biosynthesis.
  • a range of aromatase inhibitors is available and includes substances such as aminoglutethimide, anastrozole, exemestane, vorozole, letrozole, fadrozole, rogletimide, atamestane, formestane, liarozole, YM 511, TZA-2237, CGS 16949A and MEN 11066.
  • Aromatase inhibitors primarily find application in methods of treating breast cancer.
  • aromatase inhibitors may be used in the treatment of endometriosis.
  • Takayama et al. (Fertility Sterility 1998; 69(4);709-13) successfully treated one case of an unusually aggressive recurrent postmenopausal endometriosis with an aromatase inhibitor.
  • All existing therapies with aromatase inhibitors are based on oral or intramuscular administration.
  • Cyclooxygenase (COX) also known as prostaglandin G/H synthase, is a membrane- bound enzyme responsible for the oxidation of arachidonic acid to prostaglandins that was first identified over 20 years ago.
  • COX-1 and COX-2 Two cyclooxygenase isoforms have been identified and are referred to as COX-1 and COX-2.
  • COX-1 enzyme is constitutively expressed and regulates a number of housekeeping functions such as vascular hemostasis and gastroprotection, whereas COX-2 is inducible (i.e., sites of inflammation) by a number of mediators such as growth factors, cytokines and endotoxins.
  • NSAIDs Nonsteroidal anti-inflammatory drugs
  • COX-2 selective inhibitors include: celecoxib; deracoxib; valdecoxib; rofecoxib; parecoxib; etoricoxib; meloxicam; etoldolac; lumiracoxib; nimesulide; leflunomide; tilmacoxib and flosulide.
  • Intravaginal administration of COX-2 inhibitors is mentioned in US 6,086,909 which relates to a method of treating dysmenorrhea.
  • the method described in this US-patent employs intravaginal administration of a pharmaceutical agent selected from the group consisting of a nonsteroidal anti-inflammatory drug, anti-prostaglandin, prostaglandin inhibitor, COX-2 inhibitor, local anesthetic, calcium channel blocker, potassium channel blocker, .beta.-adrenergic agonist, leukotriene blocking agent, smooth muscle inhibitor, vasodilator, and a drug capable of inhibiting dyskinetic muscle contraction.
  • a pharmaceutical agent selected from the group consisting of a nonsteroidal anti-inflammatory drug, anti-prostaglandin, prostaglandin inhibitor, COX-2 inhibitor, local anesthetic, calcium channel blocker, potassium channel blocker, .beta.-adrenergic agonist, leukotriene blocking agent, smooth muscle inhibitor, vasodilator, and a drug
  • Examples of 17 ⁇ -hydroxy steroid dehydrogenase type 1 inhibitors include: N-butyl, N-methyl, 9-[3'17'beta-(dihydroxy)-l',3',5'(10')-estratien-16 alpha-yl]-7 bromononamide; N-butyl, N-methyl, 7-[3',17'beta-dihydroxy-r,3',5'(10')- estratiene-6' beta-yl]-7-thiaheptanamide.
  • the particularly good results observed for the intravaginal administration of SEEM 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 inhibiting the endogenous biosynthesis of estrogens within the aforementioned tissues, thereby preventing stimulation of the estrogen receptors present in these same tissues.
  • intravaginal administration of SEEM 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.
  • 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.
  • intravaginal administration of SEEM in accordance with the present invention offers the advantage that it has much less impact on the liver than, for instance, oral administration.
  • 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, 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 a selective estrogen enzyme modulator (SEEM), wherein the method provides the SEEM in a therapeutically effective dosage to prevent or reduce symptoms of said benign gynaecological disorder, said SEEM being selected from the group consisting of aromatase inhibitors, cyclooxygenase 2 (COX-2) inhibitors, 17 ⁇ -hydroxy steroid dehydrogenase type 1 inhibitors and combinations thereof.
  • SEEM selective estrogen enzyme modulator
  • the present method also encompasses the prophylactic treatment of the aforementioned benign gynaecological disorders.
  • 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 and creams. 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. In principle any known aromatase inhibitor, COX-2 inhibitor or 17 ⁇ -HSD type 1 inhibitor which is suitable for pharmaceutical application can be used in the present method.
  • Aromatase inhibitors which may suitably be used in accordance with the invention are aminoglutethimide, anastrozole, exemestane, vorozole, letrozole, fadrozole, rogletimide, atamestane, formestane, liarozole, finrozole, YM 511, TZA-2237, CGS 16949A, MEN 11066, precursors of the aforementioned substances, and mixtures thereof.
  • the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, vorozole, letrozole and formestane, precursors of these substances, and mixtures thereof.
  • COX-2 inhibitors suitable for use in the present method include the following 5 classes of compounds: carbocycles and heterocycles with vicinal aryl moieties, diary 1- or aryl/heteroaryl-ether and -thioether derivatives, cis-Stilbene derivatives, diaryl and aryl/heteroaryl ketones and compounds with antioxidative moieties.
  • Specific examples of COX-2 inhibitors that may be employed in accordance with the present invention can be found in Dannhardt et al. (Curr Med Chem 2000 Nov; 7(11): 1101-12), which is incorporated herein by reference.
  • the COX-2 inhibitors used in the present method are compounds which are at least 5-fold selective for COX-2 over COX-1 in terms of IC 80 values in the WHMA/COX- 1 determination (Warner TD et al. PNAS 1999; 96(13): 7563).
  • COX-2 inhibitors examples include: celecoxib; deracoxib; valdecoxib; rofecoxib; etoricoxib; parecoxib; meloxicam; etoldolac; lumiracoxib; nimesulide; leflunomide; tilmacoxib; flosulide; diisopropyl fluorophosphates; L745,337; SC-58125; L743337; SC-236; BMS-347070; GW-406381 andE-6087.
  • Preferred 17 ⁇ -HSD type 1 inhibitors for use in the present method are selected from the group consisting of bromoacetoxy derivatives of esfradiol, bromoacetoxy derivatives of estrone, bromoacetoxy derivatives of 4-androstenedione, bromoacetoxy derivatives of progesterone, bromoacetamido derivatives of estrone, aiylazido-beta-alanine derivatives of esfradiol or estrone, 16-methylene-estradiol, 17-beta-propynyl-substitutedprogestin analogs, acetylenic or trifluoromethylacetylenic 14,15-secoestradiols, 16 alpha-(halogenoalkyl) esfradiol derivatives, 6 beta-(thiaheptanamide) derivatives of esfradiol (e.g N-butyl, N-methyl, 7-
  • the main function of the SEEM as used in the present method is to suppress the biosynthesis of biogenic estrogens, notably esfradiol, in the target tissues.
  • biogenic estrogens notably esfradiol
  • administration of the SEEM will lead to a reduction in estrogen-induced proliferation of uterine leiomyomas, endometriotic lesions, adenomyomas and endometrial tissue.
  • the present method may successfully be applied to female mammals.
  • these mammals include humans, cattle and pets.
  • Most preferably the female mammal is a human female.
  • the present method provides the SEEM in a therapeutically effective dosage to inhibit growth of myomas, endometriotic, adenomyotic or endometrial tissue.
  • inhibition of the growth of these tissues is meant that existing myomas, endometriotic, adenomyotic or endometrial tissue do not increase in volume as a result of proliferation and that no new tissues of these sorts are formed.
  • the SEEM is provided in a therapeutically effective dosage to achieve atrophy of the aforementioned tissues. Most preferably the method provides said SEEM in a therapeutically effective dosage to achieve full elimination of these tissues.
  • the present method offers the advantage that due to the local (intravaginal) administration it selectively inhibits the biosynthesis of estrogens, especially 17 ⁇ -estradiol in myomas, endometriotic, adenomyotic or endometrial tissue.
  • 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 inhibit estrogen synthesis by the ovaries or elsewhere in the body due to the low or absent systemic exposure to the SEEM.
  • 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 or GnRH agonist. Also it is preferred not to co-administer either of these 2 active principles in combination with the present SEEM containing drug delivery vehicle.
  • the present method may suitably be applied over a prolonged period of time, thereby significantly increasing the chance of achieving complete disappearance of the leiomyomas, endometriosis and/or adenomyosis.
  • the intravaginal administration of the SEEM occurs in an amount which is therapeutically effective to inhibit the endogenous synthesis of 17 ⁇ -estradiol in the myomas, endometriotic, adenomyotic or endometrial tissue.
  • the intravaginally administered dosage of the SEEM will usually exceed 10 ⁇ g/day.
  • said amount will be in the range of 20 ⁇ g/day to 250 mg/day, more preferably in the range of 50 ⁇ g/day to 100 mg/day.
  • the present method comprises intravaginal administration of the SEEM in an amount which is equivalent to a daily intravaginal dosage of 100 ⁇ g to 250 mg exemestane, preferably of 150 ⁇ g to 100 mg exemestane and more preferably of 250 ⁇ g to 25 mg exemestane.
  • the SEEM is administered in an amount which is equivalent to a daily intravaginal dosage of less than 16 mg, even more preferably of less than 8 mg exemestane.
  • a daily intravaginal dosage of less than 16 mg, even more preferably of less than 8 mg exemestane.
  • the phrase "equivalent to a daily dosage" should not be interpreted restrictedly.
  • the above mentioned requirement that the administration of the present drug delivery vehicle is to provide the equivalent of a daily dosage of 100 ⁇ g to 250 mg exemestane encompasses a protocol wherein exemestane is administered once a week, provided the weekly dosage is between 700 ⁇ g and 1750 mg, i.e. such that the average daily dose is between 100 ⁇ g and 250 mg.
  • the recommended dosages may alternatively be expressed in equivalent daily intravaginal dosages of rofecoxib (a COX-2 inhibitor) in which case the latter dosages are identical to those recited for the aromatase inhibitor exemestane.
  • the SEEM is selected from the group consisting of aromatase inhibitors, COX-2 inhibitors and combinations thereof. Most preferably one or more aromatase inhibitors are employed as the SEEM in the present method. In order to achieve very effective inhibition of endogenous estrogen formation it is advisable to use a combination of SEEMs that each inhibit different pathways of estrogen biosynthesis.
  • a combination comprising an aromatase inhibitor and a COX-2 inhibitor and/or a 17 ⁇ -HSD type 1 inhibitor is employed.
  • a combination comprising an aromatase inhibitor and a COX-2 inhibitor is used.
  • the efficacy of the present method may also be enhanced by the co-administration of a sulphatase inhibitor.
  • the endogenously produced estrogen estrone may be enzymatically converted to 17 ⁇ -estradiol by 17 ⁇ -hydroxy steroid dehydrogenase type 1.
  • estrone may also be converted to estrone sulphate, which is essentially inactive.
  • Estrone sulphate can be reconverted into esfrone by sulphatase. Inhibition of the latter enzyme will result in a general lowering of blood serum estrone levels and accumulation of estrone sulphate. As will be evident from the biosynthesis diagram, such a lowering of the estrone level will be accompanied by a similar lowering of the 17 ⁇ -estradiol level. Consequently, the co- administration of a sulphatase inhibitor will improve the efficacy of the present method as it enhances the action of the SEEM.
  • the sulphatase inhibitor is co-administered intravaginally as such a mode of administration allows the inhibitor to exert a localised effect on the tissue to be treated rather than a systemic effect throughout the body.
  • sulphatase inhibitors include: estrone-3-O-sulfamate (EMATE), 4- methyl-coumarin-7-O-sulfamate (COUMATE), 665-COUMATE, 666-COUMATE, 667- COUMATE, 668-COUMATE, 669-COUMATE, 4-sulfamated phenyl ketone derivatives, 4- sulfamated phenyl alkyl ketone derivatives, 4'-O-sulfarnoyl-4-biphenyl derivatives.
  • EMATE estrone-3-O-sulfamate
  • COUMATE 4- methyl-coumarin-7-O-sulfamate
  • 665-COUMATE 666-COUMATE
  • 667- COUMATE 668-COUMATE
  • 669-COUMATE 4-sulfamated phenyl ketone derivatives
  • 4- sulfamated phenyl alkyl ketone derivatives 4-'-O-
  • the present method comprises continuous intravaginal administration of the SEEM 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.
  • continuous 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.
  • an administration regimen is deemed to be continuous 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.
  • 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.
  • the method employs between once weekly and once monthly intravaginal administration of the drug delivery vehicle. In case the administration intervals exceed one day, 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.
  • the present method of treating the benign gynaecological disorders comprises co-administration of an estrogen in a therapeutically effective amount to reduce possible symptoms of hypoestrogenism resulting from the intravaginal administration of the SEEM.
  • the present method offers the advantage that, due to the non-systemic and relatively low intravaginal dosage of the SEEM, it will produce significantly less symptoms of hypoestrogenism than known methods for treating estrogen sensitive gynaecological disorders.
  • 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 SEEM.
  • a mode of administration for applying the estrogen which is different from intravaginal or infra-uterine administration.
  • the blood serum estrogen level may be restored to its usual level, without the administered estrogen having a significant effect on the proliferation of the leiomyomas, endometriotic and/or adenomyotic tissue.
  • estrogen is co-administered with the SEEM so as to maintain the estrogen blood serum level of the female at a level which is equivalent to at least 30 pg 17 ⁇ - estradiol/ml.
  • the 17 ⁇ -estradiol blood serum level of the female is maintained at a level of at least 30 pg/ml.
  • the esfrogen used in the present method is preferably selected from the group consisting of ethinyl esfradiol, mestranol, quinesfranol, esfradiol, estrone, estran, estriol, conjugated equine estrogens, precursors capable of liberating such an estrogen when used in the present method and mixtures thereof.
  • the estrogen is selected from the group consisting of ethinyl esfradiol, esfradiol, precursors of these estrogens and mixtures thereof, and administered in an amount equivalent to a daily oral dose of 1-40 ⁇ g ethinyl esfradiol (e.g.
  • the amount of SEEM or estrogen that is effective to achieve the desired results may be determined empirically with respect to any given SEEM or estrogen and for any given mammal.
  • the effective dose ranges, as well as being compound specific, may also depend upon patient characteristics, such as age and weight.
  • the method comprises the intravaginal co-administration of an anti-estrogen in an amount effective to prevent the interaction between (endogenous) estrogens, especially 17 ⁇ -estradiol, and estrogen receptors in the myomas, endometriotic, adenomyotic or endometrial tissue.
  • 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.
  • anti-estrogens can suitably be used to reduce or inhibit the impact of estrogens, hence the term "anti-estrogens".
  • anti-estrogens 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 anti-estrogen receptor response.
  • An example of anti-estrogens capable of triggering a selective estrogen receptor response are so called selective esfrogen receptor modulators (SERM's).
  • Examples of 'true' anti-esfrogens that may be used in the present method include ICI 164384, ICI 182780, ZM 189154, EM-800, RU 58668, precursors of these anti-esfrogens, and mixtures thereof.
  • anti-estrogens that exert SERM-like activity as well as their precursors may suitably be used in the present method.
  • 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
  • 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.
  • the anti-estrogen is selected from the group consisting of ICI 164384, ICI 182789, precursors of these substances and mixtures thereof.
  • the anti-estrogen is suitably co-administered in an amount equivalent to a daily dosage of less than 600 mg raloxifene, preferably of more than 250 ⁇ g raloxifene and more preferably in an amount equivalent to a daily dosage of 600 ⁇ g to 60 mg raloxifene.
  • 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 combined administration of anti-estrogen and SEEM 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 SEEM 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 esfradiol can interact with estrogen receptors in the aforementioned tissues.
  • Another embodiment of the present method comprises co-administration of an androgen.
  • the androgen enhances the action of the SEEM, in particular the SEEM'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 SEEM, particularly those side-effects associated with hypo-estrogenism.
  • 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.
  • 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.
  • DHEA dehydroepiandrosterone
  • DHEAS DHEA-sulphate
  • testosterone testosterone esters such as testosterone undecanoate, testosterone propionate,
  • 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.
  • 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.
  • the androgen used in the present method is DHEA and/or testosterone undecanoate.
  • 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.
  • 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.
  • the medicament 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.
  • the androgen is administered in a systemic fashion. Most preferably the androgen is administered orally, hi a particularly preferred embodiment, the present method comprises the combined systemic co- administration of an androgen and an estrogen.
  • the present method comprises co-administration of an anti-progestogen in an effective amount to boost the atrophic effect of the SEEM on the leiomyomas, endometriotic, adenomyotic and endometrial tissue.
  • an anti-progestogen in an effective amount to boost the atrophic effect of the SEEM on the leiomyomas, endometriotic, adenomyotic and endometrial tissue.
  • these tissues next to estrogen receptors, also express progestogen receptors.
  • Anti-progestogens have been shown to inhibit endometrial proliferation.
  • the combined use of a SEEM and an anti-progestogen is very effective in suppressing such proliferation, but more importantly also in achieving atrophy of the target tissues.
  • the anti-progestogen is administered intravaginally.
  • the intravaginal administration offers the advantage that, in comparison to systemic administration, the same local clinical 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 1.beta., 17.
  • the anti-progestogen used in the present method is mifepristone and/or a precursor thereof.
  • the anti-progestogen is suitably administered in a daily amount of at least 10 ⁇ g. More preferably the minimum daily dosage is equivalent to an intravaginal daily dosage of at least 200 ⁇ g, most preferably at least 500 ⁇ g 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 recto vaginal endometriosis.
  • precursors of an active ingredient are meant components capable of liberating the active ingredient when used in the present method after intravaginal and/or, in the case of estrogen, following oral administration, e.g. as a result of metabolic conversion of the precursor substance.
  • estriol is a metabolite of 17beta-estradiol.
  • the present method is particularly useful when used in the treatment of pre- or peri-menopausal females. Most preferably the present method is used to treat premenopausal females.
  • a drug delivery vehicle for intravaginal use comprising at least 10 ⁇ g of a SEEM selected from the group consisting of aromatase inhibitors, 17 ⁇ -hydroxysteroid dehydrogenase type 1 inhibitors and combinations thereof; and pharmaceutically acceptable excipient.
  • a SEEM selected from the group consisting of aromatase inhibitors, 17 ⁇ -hydroxysteroid dehydrogenase type 1 inhibitors and combinations thereof; and pharmaceutically acceptable excipient.
  • the amount of SEEM exceeds 20 ⁇ g, more preferably said amount exceeds 100 ⁇ g.
  • the amount of SEEM will not exceed 600 mg, preferably it will not exceed 400 mg, more preferably it will not exceed 200 mg.
  • the drug delivery device contains SEEM in an amount equivalent to at least 250 ⁇ g exemestane.
  • the drug delivery vehicle according to the invention may be a tablet, capsule, gel, cream, film, suppository, tampon, pessary, vaginal sponge, lotion, foam, ointment, paste, solution or a vaginal ring.
  • the drug delivery vehicle additionally contains anti- estrogen in an amount exceeding 50 ⁇ g, more preferably in an amount exceeding 100 ⁇ g.
  • anti-estogen will not exceed 600 mg, preferably it will not exceed 400 mg, more preferably it will not exceed 200 mg.
  • the drug delivery vehicle contains anti-estrogen in an amount equivalent to at least 600 ⁇ g raloxifene.
  • COX-2 inhibitors and/or sulphatase inhibitors include COX-2 inhibitors and/or sulphatase inhibitors.
  • COX-2 inhibitor or sulphatase inhibitor is incorporated in an amount of at least 10 ⁇ g. More preferably the COX-2 inhibitor is present in an amount equivalent to at least 100 ⁇ g rofecoxib. The amount of COX-2 inhibitor will normally not exceed the equivalent of 250 mg rofecoxib.
  • the drug delivery vehicle additionally contains at least 10 ⁇ g of anti-progestogen.
  • the delivery vehicle contains anti-progestogen in an amount equivalent to at least 200 ⁇ g, more preferably at least 500 ⁇ g mifepristone. Usually the amount of anti-progestogen will not exceed 500 mg, preferably it will not exceed 300 mg, more 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.
  • the invention provides a tampon device for delivering the SEEM to the vaginal epithelium, said tampon comprising an absorbent material which has been soaked with a pharmaceutically acceptable solution of the aromatase inhibitor.
  • 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.
  • the delivery vehicle may be a vaginal ring.
  • Vaginal rings are torus 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.
  • 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.
  • release rate 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 drug load near the surface is depleted.
  • Yet another aspect of the present invention relates to a pharmaceutical kit comprising a drug delivery vehicle as defined herein before and a plurality of oral dosage units comprising estrogen in an amount equivalent to at least 1 ⁇ g ethinyl esfradiol and/or androgen in an amount equivalent to 5-250 mg DHEA.
  • a pharmaceutical kit comprising a drug delivery vehicle as defined herein before and a plurality of oral dosage units comprising estrogen in an amount equivalent to at least 1 ⁇ g ethinyl esfradiol and/or androgen in an amount equivalent to 5-250 mg DHEA.
  • the estrogen and or androgen containing medicament is designed for once daily oral administration. Accordingly, the preferred amount of estrogen and/or androgen included in the oral dosage units corresponds to the daily dosages that have been advocated herein before.
  • the dosage units in the aforementioned kit may advantageously contain an anti- estrogen and/or an anti-progestogen.
  • the anti-estrogen is incorporated in the intravaginal drug delivery device in an amount of at least 10 ⁇ g.
  • the anti-progestogen is also suitably incorporated in the intravaginal drug delivery device, typically in an amount of at least 10 ⁇ g.
  • 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 25 mg exemestane 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 8-10 weeks of vaginally administered exemestane, 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 hypoestrogenism.
  • Example 2 Example 1 is repeated. However, instead of exemestane the participants receive a daily intravaginal dosage of 25 mg rofecoxib. The participants show significant fibroid atrophy after 8-10 weeks of treatment.
  • Example 3 A clinical study is conducted in 10 women with stage 3 or 4 rectovaginal endometriosis, complaining from severe dyspareunia and/or low pelvic pain and/or painful defecation.
  • the women receive a daily intravaginal dosage of 25 mg exemestane for 8-10 weeks.
  • the size of the endometriotic lesions is assessed by ultrasonography and rectovaginal examination by palpation. Every week the women fill out a questionnaire assessing the level and occurrence of dyspareunia, low pelvic pain and painful defecation.
  • the study participants are recording symptoms of hypoestrogenism in a diary.
  • Example 3 is repeated.
  • the participants additionally receive a intravaginal dosage of 25 mg rofecoxib.
  • the participants receiving the combination of vaginal exemestane and rofecoxib show a larger reduction of pain and of the size of the endometriotic lesions during the treatment than the females described in example 3, who only receive exemestane and the females described in example 2, who only receive rofecoxib.
  • Example 1 is repeated.
  • the participants additionally receive a daily oral dosage of 1 mg 17- ⁇ esfradiol.
  • the participants receiving the combination of vaginal exemestane 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 exemestane.
  • Example 3 is repeated.
  • the participants additionally receive a daily oral dosage of 1 mg 17- ⁇ esfradiol.
  • the participants receiving the combination of vaginal exemestane and oral estrogen show significant reduction of pain and of the size of the endometriotic lesions during the treatment and record less symptoms of hypoestrogenism than the females described in example 1, who only receive exemestane.
  • Example 1 is repeated.
  • the participants who receive exemestane additionally receive a daily intravaginal dosage of 30 mg raloxifene.
  • the participants receiving the combination of exemestane and raloxifene show a larger reduction of fibroid size than the participants of example 1 who receive only exemestane.
  • a clinical study is conducted in 20 women with stage 3 or 4 endometriosis, complaining from severe dysmenorrhoea and/or abdominal pain.
  • Ten women are randomised to a treatment group receiving a daily intravaginal dosage of 25 mg exemestane.
  • the other ten women receive a daily intravaginal dosage of 25 mg exemestane together with a oral dosage of 50 mg dehydroepiandrosterone (DHEA). Both groups are treated for 6 months.
  • DHEA dehydroepiandrosterone
  • 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 receiving exemestane with or without DHEA. The women receiving DHEA report a larger reduction in pain and also 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. A trend can be seen that the women receiving DHEA experience less subjective side-effects than the women not receiving DHEA.
  • Example 1 is repeated with the exception that the participants who receive exemestane additionally receive a daily intravaginal dosage of 10 mg mifepristone.
  • the participants receiving the combination of exemestane and mifepristone show a larger reduction of fibroid size than the participant of example 1 who receive only exemestane.

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Abstract

Un aspect de la présente invention concerne un procédé à base de vecteur de transport de médicament, s'appliquant au traitement d'un trouble gynécologique bénin affectant les mammifères du sexe féminin. Les troubles gynécologiques bénins concernés sont essentiellement les léiomyomes utérins, endométrioses, adénomyoses, ménorragies et métrorragies fonctionnelles. Le procédé implique d'administrer par voie intravaginale au mammifère de sexe du féminin atteint de trouble gynécologique bénin un tel vecteur de transport de médicament contenant un modulateur SEEM (Selective Estrogen Enzyme Modulator). En l'occurrence, le procédé permet d'apporter une dose thérapeutiquement efficace du modulateur SEEM prévenant ou réduisant les symptômes dudit trouble gynécologique bénin. Ce modulateur SEEM est choisi dans le groupe constitué des inhibiteurs d'aromatase, des inhibiteurs de cyclo-oxygénase 2 (COX-2), des inhibiteurs de 17ß-hydroxystéroïde déshydrogénase de type 1, et de certaines de leurs combinaisons. Le procédé de l'invention convient aux traitements de longue durée des troubles gynécologiques bénins réagissant aux oestrogènes, particulièrement dans le cas de patientes préménopausées et périménopausées, sans effets secondaires. Un autre aspect de l'invention concerne un vecteur de transport de médicament pour l'utilisation intravaginale. Il comprend au moins 10 µg d'un modulateur SEEM appartenant au groupe des inhibiteurs d'aromatase, des inhibiteurs de 17ß-hydroxystéroïde déshydrogénase de type 1 et certaines de leurs combinaisons ainsi qu'un excipient pharmaceutiquement admis.
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US7910570B2 (en) 2003-02-05 2011-03-22 Astrazeneca Ab Composition comprising a combination of an aromatase inhibitor, a progestin and an oestrogen and its use for the treatment of endometriosis
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US7754709B2 (en) 2003-06-10 2010-07-13 Solvay Pharmaceuticals Bv Tetracyclic thiophenepyrimidinone compounds as inhibitors of 17β hydroxysteroid dehydrogenase compounds
EP1638573A4 (fr) * 2003-06-20 2009-12-02 Merck & Co Inc Utilisation d'inhibiteurs selectifs de la cyclooxygenase de type 2 pour le traitement de l'endometriose
US8088758B2 (en) 2003-11-12 2012-01-03 Abbott Products Gmbh 17β-hydroxysteroid dehydrogenase type I inhibitors
US7435757B2 (en) 2004-07-02 2008-10-14 Schering Ag 2-substituted D-homo-estra-1,3,5(10)-trienes as inhibitors of 17β-hydroxy steroid dehydrogenase type 1
EA011455B1 (ru) * 2004-07-02 2009-04-28 Шеринг Акциенгезельшафт НОВЫЕ 2-ЗАМЕЩЁННЫЕ D-ГОМО-ЭСТРА-1,3,5(10)-ТРИЕНЫ В КАЧЕСТВЕ ИНГИБИТОРОВ 17β-ГИДРОКСИСТЕРОИДДЕГИДРОГЕНАЗЫ ТИПА 1
WO2006003012A1 (fr) * 2004-07-02 2006-01-12 Schering Aktiengesellschaft NOUVEAUX D-HOMO-ESTRA-1,3,5(10)-TRIENES 2-SUBSTITUES SERVANT D'INHIBITEURS DE LA 17ß-HYDROXYSTEROIDE-DESHYDROGENASE DE TYPE 1
CN1980949B (zh) * 2004-07-02 2010-05-05 舍林股份公司 作为17β-羟基甾体脱氢酶1抑制剂的新型2-取代D-加碳-雌甾-1,3,5(10)-三烯
US7732493B2 (en) 2004-07-02 2010-06-08 Bayer Schering Pharma Aktiengesellschaft 2-substituted D-homo-estra-1,3,5(10)-trienes as inhibitors of 17β-hydroxy steroid dehydrogenase type 1
JP4871274B2 (ja) * 2004-07-02 2012-02-08 バイエル ファーマ アクチエンゲゼルシャフト １７β−ヒドロキシステロイドデヒドロゲナーゼタイプ１の阻害剤としての新規な二置換Ｄ−ホモ−エストラ−１，３，５（１０）−トリエン類
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WO2006114702A3 (fr) * 2005-04-25 2007-01-04 Pfizer Prod Inc Compositions pharmaceutiques et methodes comprenant une combinaison d'un modulateur selectif du recepteur de l'oestrogene et d'un inhibiteur de l'aromatase
US8030298B2 (en) 2005-05-26 2011-10-04 Abbott Products Gmbh 17β-HSD1 and STS inhibitors
US8435973B2 (en) 2005-05-26 2013-05-07 Abbott Products Gmbh 17-beta HSD1 and STS inhibitors
US8080540B2 (en) 2006-09-19 2011-12-20 Abbott Products Gmbh Therapeutically active triazoles and their use
US8288367B2 (en) 2006-11-30 2012-10-16 Solvay Pharmaceuticals Gmbh Substituted estratriene derivatives as 17BETA HSD inhibitors
WO2011120925A1 (fr) 2010-03-31 2011-10-06 Bayer Pharma Aktiengesellschaft Forme galénique parentérale libérant des inhibiteurs de l'aromatase et des gestagènes, pour le traitement de l'endométriose
DE102010003494A1 (de) 2010-03-31 2011-10-06 Bayer Schering Pharma Aktiengesellschaft Parenterales Abgabesystem, das Aromatasehemmer und Gestagene freisetzt, für die Behandlung von Endometriose
EP2552404B1 (fr) 2010-03-31 2015-01-21 Bayer Intellectual Property GmbH Forme galénique parentérale libérant des inhibiteurs de l'aromatase et des gestagènes, pour le traitement de l'endométriose
CN107693794A (zh) * 2010-06-16 2018-02-16 恩多研究公司 治疗或预防雌激素相关疾病的方法
US11576891B2 (en) 2010-06-16 2023-02-14 Endorecherche, Inc. Methods of treating or preventing estrogen-related diseases
CN104168902A (zh) * 2011-08-26 2014-11-26 智利圣地亚哥大学 阴道内给药非类固醇抗炎药物美洛昔康和吡罗昔康用于中断女性排卵过程的用途
WO2024197239A1 (fr) * 2023-03-23 2024-09-26 William Bologna Compositions bioadhésives et procédé de traitement de l'endométriose avec des inhibiteurs d'aromatase sans augmentation de la production de gonadatropine

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