WO2003041719A1 - Procede de contraception chez des femelles de mammiferes, et kit pharmaceutique correspondant - Google Patents

Procede de contraception chez des femelles de mammiferes, et kit pharmaceutique correspondant Download PDF

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Publication number
WO2003041719A1
WO2003041719A1 PCT/NL2002/000740 NL0200740W WO03041719A1 WO 2003041719 A1 WO2003041719 A1 WO 2003041719A1 NL 0200740 W NL0200740 W NL 0200740W WO 03041719 A1 WO03041719 A1 WO 03041719A1
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androgen
progestogen
estrogen
dosage units
days
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PCT/NL2002/000740
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English (en)
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Herman Jan Tijmen Coelingh-Bennink
Agatha Antonia Magdalena Van Beek
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Pantarhei Bioscience B.V.
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Publication of WO2003041719A1 publication Critical patent/WO2003041719A1/fr

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    • 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

Definitions

  • the present invention is concerned with a new method of contraception in mammalian females. More particularly the present invention relates to a contraceptive method comprising the administration to a female of one or more dosage units containing a combination of steroids including at least an androgen, in a therapeutically effective amount to inhibit ovulation. Generally the inhibition of ovulation is achieved by suppressing the pituitary release of follicle stimulating hormone (FSH), which gonadotrophin stimulates the ovarian follicular development that precedes ovulation and/or by the prevention of the occurrence of a luteinising hormone (LH) surge that induces actual ovulation.
  • FSH follicle stimulating hormone
  • LH luteinising hormone
  • the invention also relates to a pharmaceutical kit containing a plurality of oral dosage units for use in the aforementioned contraceptive method.
  • the first are known as monophasic preparations. These contain a constant amount of an estrogen and a progestogen. Newer preparations known as bi- or triphasic preparations have varying levels of estrogen and progestogen; in most cases consisting of relatively constant levels of estrogen with a step- wise increase in progestogen throughout the cycle. This pattern of estrogen and progestogen administration results in a relatively dominant estrogenic formulation at the beginning of the package with increasing progestogenic activity toward the end of the package. Mono-, bi- and triphasic contraceptives are commonly referred to as combined contraceptives.
  • Virtually all combined contraceptives have in common that they are based on a regimen which involves an administration-free interval of about 7 days whereby withdrawal bleeding, simulating the natural menses, occurs. Thus 21 day intervals of hormone administration alternate with 7 days during which no hormones are administered.
  • the so called sequential method has been proposed. Typical of the sequential contraceptive method is that it comprises two consecutive phases, i.e. one phase during which estrogen and no progestogen is administered and another phase during which a combination of estrogen and progestogen is aolministered.
  • the first sequential methods like the aforementioned combined contraceptives, made use of an administration free interval of about 7 days.
  • US 5,770,226 (Hughes et al.) describes oral contraceptives which comprise dosage units that contain a combination of estrogen, androgen and progestogen. The additional inclusion of an androgen is said to mitigate a decrease in bone accrual in younger users of oral contraceptives.
  • the contraceptives disclosed make use of a 7 day placebo interval, followed . by 21 days, during which a combination of estrogen, androgen and progestogen is administered.
  • the examples of the US-application describe the use of buccal dosage units containing a combination of testosterone, progesterone and either estradiol or ethinyl estradiol in a method of hormone replacment and in the treatment of female sexual dysfunction.
  • the buccal dosage units described in the US-application are not suitable for use in a method of female contraception as the bioavailability of bucally administered steroids, especially the bioavailablity of progesteron, is too low to inhibit ovulation during the complete menstrual cycle.
  • a contraceptive method that employs the administration of at least two different steroids in a manner known per se to inhibit ovulation, which method additionally employs the continuous administration of an androgen during a prolonged period of time (i.e. 28 days or more).
  • the continuous aoministration of the androgen helps to avoid androgen deficiency and/or the occurrence of fluctuations in serum androgen levels, both of which phenomena are often observed when steroids are administered in accordance with the regimens commonly used to inhibit ovulation.
  • serum androgen concentrations are maintained at a fairly constant physiological level, which is sufficiently high to prevent mood changes and feelings of discomfort.
  • the androgen may exert this effect through activation of androgen receptors. It is known that androgen receptors are present in endometrial tissue. Horie et al., "Immunohistochemical localisation of androgen receptor in the human endometrium, decidua, placenta and pathological conditions of the endometrium", Hum. Reprod. vol. 7, No. 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.
  • the proliferative effect of estrogens on the endometrium in female contraceptive users may also be suppressed by co-administration of an androgen only, i.e. without progestogen.
  • Such co-administration can be effective in suppressing the proliferative effect of estrogen in contraceptive regimens which use periods of estrogen only administration (e.g. a sequential method).
  • the present method also offers the advantage that the continuous co-administration of androgen in known contraceptive regimens produces less vaginal breakthrough spotting and bleeding.
  • one aspect of the invention is concerned with a method of contraception in mammalian females, said method comprising the administration to the female of dosage units containing at least two different steroids, including an androgen, in a therapeutically effective amount to inhibit ovulation, wherein the androgen is administered continuously during a period of at least 28 days, preferably of at least 60 days.
  • 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.
  • androgen is co-administered in an amount which is therapeutically effective to suppress symptoms of hypoandrogenism.
  • the androgen is administered in an amount sufficient to maintain the serum androgen concentration of the female mammal at a level equivalent to between 0.5 and 5.0, preferably between 0.7 and 4.0 and most preferably between 1.0 and 3.0 nanomoles testosterone per litre.
  • the testosterone concentrations relate to the total testosterone present in the serum, i.e.including both free testosterone and bound testosterone.
  • the present method preferably employs, in addition to the androgen, at least one estrogen and optionally at least one progestogen in a therapeutically effective amount to inhibit ovulation during a period of at least 28 days, preferably at least 60 days.
  • a contraceptive method that comprises the administration of dosage units containing at least one progestogen in a therapeutically effective amount to inhibit ovulation during a period of at least 28 days, preferably at least 60 days.
  • a method which comprises uninterrupted administration of at least one progestogen is meant that out of the sequence of dosage units that are being ⁇ administered at regular (i.e. essentially constant) intervals, not more than 1 dosage unit is skipped. In case of e.g. an uninterrupted daily oral administration regimen this means that the maximum administration-free interval is 2 days.
  • uninterrupted regimens wherein no skips occur at all.
  • the contraceptive method comprising uninterrupted administration of at least one progestogen encompasses a method that comprises the continuous combined administration of progestogen and androgen in an amount that is effective to inhibit ovulation. Said method also encompasses a contraceptive method which employs continuous uninterrupted administration of progestogen and at least one estrogen as described in WO 99/12531.
  • these so called continuous combined methods employ continuous co- administration of androgen, progestogen and optionally estrogen during a prolonged period of time (e.g. several months).
  • no regular menses occur as the continuous administration of progestogen in the indicated amounts induces amenorrhoea.
  • female whenever referred to in here, relates to female mammals.
  • the female mammal is a homo sapiens.
  • females are usually biologically capable of child bearing between the age of 12 and 55.
  • the dosage units according to the invention may be administered orally, parenterally, transdermally, intravaginally or intranasally.
  • Dosage units to be administered on a daily basis can suitably be selected from oral, transdermal and intravaginal dosage units.
  • Methods for transdermal administration including the associated methods for manufacturing such systems are well known in the art. In this connection, reference may be made to U.S. Pat. Nos. 4,752,478, 4,685,911, 4,438,139 and 4,291,014, which are included herein by reference.
  • the dosage units are administered orally, transdermally or intravaginally.
  • the dosage units are administered orally.
  • the dosage units may be administered at intervals which may range from 6 hours to 2 weeks.
  • the dosage units are administered at least once daily as this helps to n inimise fluctuations in blood serum levels of the active principles.
  • the present contraceptive method encompasses three main embodiments, i.e.: i. a continuous combined method which comprises continuous co-administration of progestogen, androgen and optionally estrogen during a period of a least 28 days, preferably of at least 60 days. ii. an uninterrupted sequential method which comprises continuous co-administration of estrogen and androgen during a period of a least 28 days, preferably of at least 60 days, and co-administration of progestogen during at least a part of said period. iii. a method comprising continuous administration of androgen, intervals during which progestogen and optionally estrogen are co-administered, separated by estrogen and progestogen-free intervals of at least 2 days (e.g. an interrupted sequential method or a combined method).
  • the period during which estrogen, androgen and progestogen are co-administered spans at least 10 days. More preferably estrogen, androgen and progestogen are co-administered during a period of at least 14 days.
  • the estrogen, androgen and progestogen are suitably co-administered during a period of at least 20 days.
  • An important advantage of the present method resides in the fact that androgen levels are maintained at a stable physiological level.
  • serum estrogen levels are maintained at a relatively constant level through the continuous administration of an effective amount of estrogen during a period of at least 28 days, preferably of at least 60 days.
  • a preferred embodiment of the invention relates to a continuous combined method that comprises continuous co-administration during a period of at least 28 days, preferably of at least 60 days, of at least one estrogen, at least one progestogen and at least one androgen in an amount effective to inhibit ovulation.
  • the main advantages of such a method reside in the prevention of withdrawal bleedings, a decrease of break through bleeding/spotting, less subjective complaints such as the symptoms caused by hormone fluctuations and a lower risk of VTE. It is also believed that the avoidance of chronic fluctuations in blood serum steroid levels may have a positive impact on the occurrence of premenstrual syndrome and the risk of breast cancer.
  • the present invention relates to an uninterrupted sequential method consisting of two alternating consecutive phases, an estrogenic and a progestogenic phase, wherein during the estrogenic phase one or more dosage units are administered to provide a therapeutically effective amount of a combination of estrogen and androgen to inhibit ovulation and during the progestogenic phase one or more dosage units are administered to provide a combination of estrogen, progestogen and androgen in a therapeutically effective amount to inhibit ovulation and to transform the endometrium from a proliferative into a secretory state.
  • dosage units containing an estrogen, an androgen and no progestogen are administered at least once daily during a period of 3-18 consecutive days, preferably during a period of 5-14 consecutive days.
  • the advantages of the present invention are particularly appreciated in contraceptive methods wherein unopposed estrogen is administered during a significant part of the 4-weekly cycle.
  • an androgen can suitably be applied to reduce the proliferative effect of the estrogen.
  • the present invention also encompasses a combined contraceptive method comprising the combined administration of estrogen, androgen and progestogen, wherein the method comprises an interval of at least 2 days during which no progestogen and no estrogen is administered and wherein the resulting decrease in serum progestogen and estrogen level induces menses.
  • estrogens synthetic and biogenic
  • examples of estrogens which may suitably be used in the present invention include ethinyl estradiol, mestranol, quinestranol, estradiol, estrone, estran, estriol, estetrol, conjugated equine estrogens, precursors capable of liberating such an estrogen when used in the present method and mixtures thereof.
  • the present method comprises the administration of a biogenic estrogen, such as estradiol, during a period of at least 3 days, preferably of at least 5 days.
  • a biogenic estrogen such as estradiol
  • the estrogen containing dosage units employed in the present method preferably contain one or more estrogens in an amount which is equivalent to a daily oral dosage of 3-40 ⁇ g, preferably 10-30 ⁇ g ethinyl estradiol.
  • the phrase "equivalent to a daily dosage" should not be interpreted restrictedly.
  • the above mentioned requirement that the administration of the present medicament is to provide the equivalent of a daily dosage of 3- 40 ⁇ g ethinyl estradiol encompasses a protocol wherein ethinyl estradiol is administered once a week, provided the weekly dosage is between 21 and 280 ⁇ g, i.e. such that the average daily dose is between 3 and 40 ⁇ g ethinyl estradiol.
  • the androgen used in the present method is preferably selected from the group consisting of dehydroepiandrosterone (DHEA); DHEA-sulphate; 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; 7 ⁇ -methyl-19-nortestosterone (MENT); precursors capable of liberating these androgens when used in the present method and mixtures thereof.
  • DHEA dehydroepiandrosterone
  • DHEA-sulphate testosterone
  • testosterone esters such as testosterone undecanoate
  • the androgen is selected from the group consisting of DHEA, danazol, gestrinone, testosterone esters, 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 androgens used in the present method are DHEA and/or testosterone undecanoate. These androgens offer the advantage that they can effectively be used in oral dosage units.
  • DHEA testosterone undecanoate and androstenedione are precursors of testosterone and that said precursors per se exhibit virtually no affinity for androgen receptors in the female body.
  • the effectiveness of the 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 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 which is equivalent to a daily oral dosage of 10-120 mg DHEA. Most preferably the androgen is administered in an amount which is equivalent to a daily oral dosage of 20-60 mg DHEA.
  • DHEA and its sulphate ester are the major secretory products of the human adrenal gland and collectively circulate at levels far exceeding any other steroid in the body.
  • DHEA is weakly active as a sex hormone but is a precursor for the androgen testosterone and for the estrogenic hormones estrone and estradiol.
  • DHEA-S Once DHEA is released into the body from the adrenal gland it is partly converted into the sulphate ester DHEA-S by the liver.
  • Many tissues are able to convert DHEAS back to DHEA, which in turn can act as a precursor for testosterone, estrone and estradiol.
  • the liver and the kidney are the principal organs involved in clearing steroid hormones from the circulation. Hepatic metabolism accomplishes two functions for DHEA: a decrease in the biologic activity of the hormone, and an increase in its water solubility, because of conversion to the hydrophilic sulphate form that can be excreted in urine.
  • the dosage units in an amount which leads to an increase in blood serum androgen level of no more than 5 nmole testosterone equivalent per litre, preferably less than 3 nmole testosterone equivalent per litre and most preferably less than 1.5 nmole testosterone equivalent per litre.
  • progestogen precursors which may be employed in accordance with the present invention include: anagestone acetate, chlormadinone acetate, cyproterone , acetate, gestodene acetate, hydroxymethylprogesterone acetate, hydroxyprogesterone acetate, hydroxyprogesterone hexanoate, hydroxyprogesterone caproate, hydroxyprogesterone enanthate, medroxyprogesterone acetate, megestrol acetate, melengestrol acetate, nomegestrol acetate, norethindrone acetate, norethisterone acetate, norethisterone enanthate, quingestanol acetate, (17alpha)-17-hydroxy-l l-methylene-19-norpregna-4,15-diene-20-yn-3-one, tibolone, algestone acetophenide, nestorone, promegestone, 17-hydroxyprogesterone
  • Progestogen containing dosage units employed in accordance with the present method preferably contain progestogen in an amount which is equivalent to a daily oral dosage of 30- 750 ⁇ g, preferably of 75-150 ⁇ g levonorgestrel.
  • precursors of an active ingredient are meant components capable of liberating the active ingredient when used in the present contraceptive method, particularly after administration e.g. as a result of metabolic conversion of the precursor substance.
  • Particularly useful precursors of the hormones present in the kit according to the invention are substances that differ from these hormones in that the hydrogen in at least one of the hydroxyl groups in the hormone-molecule has been substituted by -CO-R, wherein R is a hydrocarbon radical comprising from 1-25 carbons.
  • the present invention not only encompasses the use of estrogens, androgens and progestogens specifically mentioned in this application, but also metabolites of these hormones that display comparable functionality.
  • levonorgestrel is a metabolite of norgestimate
  • estriol is a metabolite of 17beta-estradiol. Both these progestogens and estrogens have found application in contraceptive formulations and/or preparations for hormone replacement therapy.
  • Another aspect of the invention relates to a pharmaceutical kit that can suitably be used in the sequential contraceptive method described above.
  • the pharmaceutical kit for use in such a method comprises 10-28 oral dosage units containing estrogen in an amount which is equivalent to 3-40 ⁇ g ethinyl estradiol, progestogen in an amount which is equivalent to 30- 750 ⁇ g levonorgestrel and androgen in an amount which is equivalent to 5-250 mg dehydroepiandrosterone and 3-18 dosage units containing estrogen in an amount which is equivalent to 3-40 ⁇ g ethinyl estradiol, androgen in an amount which is equivalent to 5-250 mg dehydroepiandrosterone and essentially no progestogen.
  • the natural interval between menses is somewhere between 20 and 35 days.
  • the kit consists of 20 to 35 daily dosage units.
  • Most preferably the kit consists of 28 daily dosage units.
  • kits that can suitably be used in the aforementioned continuous combined method.
  • a kit typically comprises at least 28 oral dosage units containing estrogen in an amount which is equivalent to 3-40 ⁇ g ethinyl estradiol, progestogen in an amount which is equivalent to 30-750 ⁇ g levonorgestrel and androgen in an amount which is equivalent to 5-250 mg dehydroepiandrosterone.
  • An advantage of such a kit is that all dosage units are identical, meaning that, unlike similar kits for use in sequential and combined contraceptive methods, the reliability of the method cannot be affected by administering the wrong dosage unit.
  • the dosage units in the aforementioned kits preferably contain estrogen in an amount equivalent to 10-30 ⁇ g ethinyl estradiol and/or progestogen in an amount equivalent to 75-150 ⁇ g levonorgestrel and/or androgen in an amount equivalent to 10-120 mg dehydroepiandrosterone. Most preferably said dosage units contain one or more androgens in an amount equivalent to 20-60 mg dehydroepiandrosterone.
  • the dosage units are preferably arranged in a fixed sequence corresponding to the intended order of administration, e.g. in a tablet strip.
  • dosage units to be used in different phases e.g. estrogenic or progestogenic phase are easily distinguishable, e.g.
  • Data indications may be provided on the packaging.
  • the packaging may be a tube or box or a strip.
  • the box may be circular, square, or otherwise shaped with the dosage units being accommodated separately therein for ease of administration.
  • Date indications may appear adjacent to each dosage unit corresponding with the days on which each dosage unit is to be taken. Some indication of the sequence in which the dosage units are to be taken preferably appears on the packaging regardless of its form.
  • the dosage units in the present kit are prepared according to conventionally known procedures in accordance with the method of administration.
  • the active ingredients are prepared according to known methods in a pharmaceutically acceptable form for administration. These ingredients, in their required quantities are combined with the appropriate pharmaceutical carriers such as additives, vehicles and/or flavour ameliorating substances.
  • diluents these substances may be referred to as diluents, binders and lubricants. Gums, starches and sugars are also common terms. Typical of these types of substances or excipients are pharmaceutical grades of mannitol, lactose starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like.
  • the active ingredient(s) may comprise from about 0.01% by weight to about 99.99% by weight of the total formulation and the remainder comprises the pharmaceutically acceptable carrier. The percentage of active ingredient(s) may vary according to the delivery system or method of administration and is chosen in accordance with conventional methods known in the art.
  • the active ingredients are compounded with the chosen carrier and in for example the case of a tablet form, placed in a tablet moulding apparatus to form the tablets which are subsequently packaged in accordance with the chosen regimen.
  • a clinical study is conducted in 200 healthy young women.
  • Four groups of 50 women who use a combined oral contraceptive containing 30 microgram ethinyl estradiol for at least 21 days before the start of the study, receive a daily oral dose of 20 microgram ethinyl estradiol and 100 microgram levonorgestrel, or 30 microgram ethinyl estradiol and 150 microgram levonorgestrel, either with or without 50 mg DHEA for 104 days (15 weeks) without pauses.
  • Vaginal spotting and bleeding is scored daily by the participants in a diary and the effects on general well being are scored at baseline and at the end of the study on a psychometric rating scale.
  • the psychometric rating scale used is especially suited for identifying differences in a population of healthy young women.
  • the scale is a 24-item (placid, sleepy, jittery, intense, lacking confidence, energetic, sensitive, tired, well-balanced, at-rest, drowsy, fearful, lively, sickly, in a good mood, irritable, clutched-up, quiet, full-of- pep, optimistic, moody, active, tense, sad), 4-point (yes, definitely; yes, a bit; no, in fact not; no, definitely not) scale to be scored by the woman herself.
  • endocrine measurements are performed in a subgroup of the participants (17 ⁇ -estradiol, progesterone, total testosterone, LH, FSH and SHBG).
  • Ovulation inhibition is investigated by analysing pregnanediol samples twice a week during 4 weeks between week 7 and 14.
  • endocrine measurements are performed in a subgroup of the participants (17 ⁇ -estradiol, progesterone, total testosterone, LH, FSH and SHBG).
  • a clinical study is conducted in 100 healthy young women. Two groups of 50 women, who use a combined oral contraceptive containing 30 microgram ethinyl estradiol for at least 21 days before the start of the study, receive a daily oral dose of 3 mg 17 ⁇ -estradiol and 1.5 mg norethisterone acetate either with or without 50 mg DHEA for 104 days (15 weeks) without pauses. Ovulation inhibition is investigated as described in Example 1. Vaginal spotting and bleeding is scored daily by the participants in a diary. The effects on general well being are scored at baseline and at the end of the study using the psychometric rating scale described in example 1. Again consistent inhibition of ovulation is observed in both groups.
  • Example 1 who receive an oral dose of 20 mg dydrogesterone daily, without interruption for 104 days; 15 weeks), Of these 100 women, 50 receive an additional daily oral dose of 50 mg dehydroepiandrosterone, while 50 others do not.
  • Ovulation inhibition, vaginal spotting and bleeding are assessed using the methods described in Example 1. Also the effects on general well being are scored using the method described in example 1. Both groups showed consistent inhibition of ovulation throughout the period of 104 days.
  • a clinical study is conducted in 40 healthy young women with regular cycles. Blood samples are taken for the state of the art haemostatic variables during the late follicular phase of the normal cycle and at the end of the luteal phase of that cycle. These two measurements serve as baseline control. Twenty women receive 30 microgram of ethinyl estradiol starting on Day 1 of the spontaneous menses, for 14 days (days 1-14). On day 12, 13 or 14, another blood sample is taken for haemostasis parameter testing. Subsequently the women receive 30 microgram ethinyl estradiol combined with 20 mg dydrogesterone on days 15-28. On day 26, 27 or 28 another blood sample is taken for haemostasis parameter testing. On day 29 the women continue with 30 microgram EE for 14 days again followed by the combination regimen. Total period of hormonal exposure will be 3x28 days.
  • the comparator is a group of 20 women who continuously receive 50 mg of DHEA in addition to the regimens mentioned above.
  • samples are taken during the spontaneous cycle (2x baseline) at the end of the first period of EE administration and at the end of the first combined administration. Furthermore, samples are taken at similar timepoints during the last cycle of 28 days.
  • Results show that the addition of DHEA resulted in better anticoagulant and fibrinolytic activity when compared to the group of women not using the additional DHEA.
  • a clinical study is conducted in 100 healthy young women. Fifty women receive the monophasic contraceptive pill containing 30 microgram EE plus 150 microgram desogestrel for 21 days, followed by a pause of 7 days. Another 50 women receive the same pill with the addition of 50 mg DHEA daily, continuing in the contraceptive pill pause of 7 days. Both regimens are followed for 112 days (16 weeks).
  • 8 groups receive one or two of the study compounds for 5 days.
  • One group receives the positive control levonorgestrel at an oral dose of 0,8 ⁇ g per day for 5 days, and one group is used as the negative control.
  • the following study compounds are given to the rabbits for 5 days: three groups receive DHEA, each group in a different dose (25 mg, 100 mg or 500 mg per day orally).
  • Three other groups receive levonorgestrel (0.8 ⁇ g/day) together with DHEA in the aforementioned doses and two groups receive either testosterone undecanoate in an oral dose of 80 mg per day, or an infra muscular dose of 30 mg per day.
  • Autopsy is performed after the treatment period and the uterus is weighed and histological sections are prepared from each uterine horn and these are microscopically evaluated according to the McPhail Index.
  • the pre-treatment phase induces proliferation of the endometrium.
  • the degree of endometrial differentiation is investigated. More differentiation of the endometrium is observed when levonorgestrel and DHEA are given together compared to the groups only receiving levonorgestrel or DHEA. This differentiation is particularly pronounced in the group that has received the highest dosage of DHEA together with levonorgestrel.
  • no further proliferation of the endometrium is observed in any of the treatment groups. In this setting it is presumed that the effect of the study compounds on the endometrial tissue is indicative of the effect on endometriotic tissue. This is a reasonable presumption because this latter tissue is essentially identical to endometrial tissue.

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Abstract

L'invention concerne un procédé de contraception chez des femelles de mammifères, qui consiste à administrer des unités posologiques contenant au moins deux stéroïdes différents, y compris un androgène, selon une quantité efficace du point de vue thérapeutique, pour inhiber l'ovulation. L'androgène est administré en continu durant une période d'au moins 28 jours, de préférence pendant au moins 60 jours. Selon un autre aspect, l'invention concerne un kit pharmaceutique, destiné à être utilisé en liaison avec ce procédé, qui comprend entre 10 et 28 unités posologiques par voie orale à base d'oestrogène, de progestogène et d'androgène, et entre 3 et 18 unités posologiques à base d'oestrogène et d'androgène mais essentiellement dépourvues de progestogène. Selon un autre aspect, l'invention concerne un kit comprenant au moins 28 unités posologiques à base d'oestrogène, de progestogène et d'androgène.
PCT/NL2002/000740 2001-11-15 2002-11-15 Procede de contraception chez des femelles de mammiferes, et kit pharmaceutique correspondant WO2003041719A1 (fr)

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EP01204377 2001-11-15
EP01204377.4 2001-11-15

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1462107A1 (fr) * 2003-03-28 2004-09-29 Pantarhei Bioscience B.V. Weibliches Empfängnisverhutungmethode und pharmazeutische Zuberaitungen die für eine solche Methode geeignet sind
WO2006036055A2 (fr) * 2004-09-27 2006-04-06 Pantarhei Bioscience B. V. Methode de contraception destinee a des mammiferes femelles et trousse d'utilisation associe
WO2013012326A1 (fr) 2011-07-19 2013-01-24 Pantarhei Bioscience B.V. Comprimé contenant de la déhydroépiandrostérone (dhea)

Citations (5)

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EP1462107A1 (fr) * 2003-03-28 2004-09-29 Pantarhei Bioscience B.V. Weibliches Empfängnisverhutungmethode und pharmazeutische Zuberaitungen die für eine solche Methode geeignet sind
WO2006036055A2 (fr) * 2004-09-27 2006-04-06 Pantarhei Bioscience B. V. Methode de contraception destinee a des mammiferes femelles et trousse d'utilisation associe
WO2006036055A3 (fr) * 2004-09-27 2008-01-10 Pantarhei Bioscience Bv Methode de contraception destinee a des mammiferes femelles et trousse d'utilisation associe
WO2013012326A1 (fr) 2011-07-19 2013-01-24 Pantarhei Bioscience B.V. Comprimé contenant de la déhydroépiandrostérone (dhea)
US10179107B2 (en) 2011-07-19 2019-01-15 Pantarhei Bioscience B.V. Tablet containing dehydroepiandrosterone (DHEA)

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