WO2001034126A2 - Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt) - Google Patents

Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt)

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Publication number
WO2001034126A2
WO2001034126A2 PCT/US2000/023771 US0023771W WO0134126A2 WO 2001034126 A2 WO2001034126 A2 WO 2001034126A2 US 0023771 W US0023771 W US 0023771W WO 0134126 A2 WO0134126 A2 WO 0134126A2
Authority
WO
WIPO (PCT)
Prior art keywords
estrogen
mesoprogestin
mesoprogestins
hrt
replacement therapy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2000/023771
Other languages
French (fr)
Other versions
WO2001034126A9 (en
WO2001034126A3 (en
Inventor
Walter Elger
Kristof Chwalisz
Gerd Schubert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jenapharm GmbH and Co KG
Original Assignee
Jenapharm GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US10/433,984 priority Critical patent/US7629334B1/en
Priority to JP2001536126A priority patent/JP2003513908A/en
Priority to EEP200200102A priority patent/EE200200102A/en
Priority to CA002383659A priority patent/CA2383659C/en
Priority to UA2002032428A priority patent/UA75339C2/en
Priority to EP00991840A priority patent/EP1605924B1/en
Priority to BR0013710-3A priority patent/BR0013710A/en
Priority to SK297-2002A priority patent/SK287121B6/en
Priority to HR20020266A priority patent/HRP20020266A2/en
Priority to NZ517469A priority patent/NZ517469A/en
Priority to EA200200285A priority patent/EA007840B1/en
Application filed by Jenapharm GmbH and Co KG filed Critical Jenapharm GmbH and Co KG
Priority to PL353931A priority patent/PL198798B1/en
Priority to IL14841700A priority patent/IL148417A0/en
Priority to DE60040764T priority patent/DE60040764D1/en
Priority to AU36332/01A priority patent/AU781836B2/en
Priority to HU0202460A priority patent/HUP0202460A3/en
Priority to ROA200200230A priority patent/RO122180B1/en
Priority to SI200020041A priority patent/SI20851B/en
Publication of WO2001034126A2 publication Critical patent/WO2001034126A2/en
Publication of WO2001034126A3 publication Critical patent/WO2001034126A3/en
Priority to BG106443A priority patent/BG65846B1/en
Priority to IL148417A priority patent/IL148417A/en
Priority to NO20021000A priority patent/NO20021000L/en
Anticipated expiration legal-status Critical
Publication of WO2001034126A9 publication Critical patent/WO2001034126A9/en
Ceased legal-status Critical Current

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens

Definitions

  • the present invention relates to the field of hormone replacement therapy (HRT).
  • HRT hormone replacement therapy
  • menopausal symptoms occur owing to altered hormone production.
  • estrogen production the risk of osteoporosis increases at the same time (reduction of bone tissue while retaining the same bone structure, due to increased bone degradation and/or reduced bone growth); likewise in postmenopausal women, a myocardial infarction rate that is significantly increased compared to premenopausal women and an increased incidence of other cardiovascular diseases are observed, which also can be attributed to reduced estrogen production.
  • HRT Hormone replacement therapy
  • Estrogen exerts a protective action on the cardiovascular system, on the bones (reduction of the risk of osteoporosis), and on the central nervous system (avoidance of so-called "hot flashes").
  • the chronic use of estrogens in hormone replacement therapy leads to an increased risk of endometrial carcinoma (Ernster, V. L. et al. (1988): Benefits and Risks of Menopausal Estrogen and/or Progestin Hormone Use; Prev. Med. 17:201-223).
  • True antiestrogens refer, according to EP-A-0 178 862, for example, to tamoxifen, nafoxidine, MER-25, as well as those antiestrogens which act in a receptor-mediated manner and which at the same time also have an estrogenic (agonistic) partial action This estrogenic partial action occurs in the uterus and in bone
  • a disadvantage to such a pharmaceutical agent that contains a "true” antiestrogen with a partial estrogenic action is that, owing to the chronically estrogenic stimulation of the endometrium, such as occurs with use of estrogens, an increased risk of the development of an endometrial carcinoma exists (Fomander, T et al (1989) Adjuvant Tamoxifen in Early Breast Cancer Occurrence of New Primary Cancers Lancet 21 117-119)
  • antiestrogens such as raloxifen for inhibiting bone degradation and for treating penmenopausal syndrome have become known (US Patent 5,393,763 or 5,391 ,557)
  • Antiestrogens of this type show a clearly reduced agonistic (estrogenic) action on the endometrium, but exert a significantly estrogenic action on the bone Since these substances are also not completely dissociated, however (i e , they always have a residual estrogenic action on the endometrium), they can also result in a proliferation of the endometrium after long-term treatment
  • WO-EP 94/03408 proposes to avoid this permanent stimulation of the endometrium by simultaneously using a compound with a progesterone-antagonistic action as well as a compound with an antiestrogenic action while at the same time there is a partial agonistic action for the production of a pharmaceutical agent for hormone replacement therapy
  • the component with a progesterone- antagonistic action inhibits the changes that are caused by the partial estrogenic action of the antiestrogen (stimulation of the myomet ⁇ um and endometrium) only in the uterus, while, however, the other estrogenic effects, which are highly desired in hormone replacement therapy, for example on bone and on the cardiovascular system, remain unchanged
  • an estrogen optionally together with a gestagen, both at very low dosages, which by themselves do not ensure stable bleeding behavior, combined with a periodic, one-time administration of an antiprogestin (progesterone antagonist) for contraception and for hormone replacement therapy, is described in WO-A 93/17686
  • the progesterone antagonist ensures a reduction in breakthrough bleeding
  • WO-A 94/18983 The joint, and preferably simultaneous use of a competitive progesterone antagonist with an estrogen without gestagen is described in WO-A 94/18983
  • the use of the estrogen according to this publication is done entirely according to the conventional principles of estrogen replacement therapy
  • the progesterone antagonist is used in an amount that inhibits the endometrial proliferation that is induced by estrogen
  • WO-A 97/33589 discloses a pharmaceutical agent that contains in combination individual dosage units of an estrogen and individual dosage units of a competitive progesterone antagonist for separate, sequential administration of the competitive progesterone antagonist, which can be used for hormone replacement therapy, as well as packaging that contains this pharmaceutical agent
  • HRT hormone replacement therapy
  • a further object of this invention is to provide application regimens for this pharmaceutical for HRT
  • This invention discloses the use of mesoprogestins as pharmaceutical components for the manufacture of a medicament for hormone replacement therapy (HRT)
  • HRT hormone replacement therapy
  • Another aspect is the combined use of an estrogen together with a mesoprogestin for the manufacture of a medicament for HRT
  • a further aspect of the invention is the use of the mesoprogestin in a daily amount of 1 0 to 50 0 mg, more preferred is a daily dose of 5 0 to 25 0 mg mesoprogestin and most preferred is a daily dose of 10 0 to 25 0 mg of a mesoprogestin
  • Yet another preferred aspect of the invention is to administer the mesoprogestin in a daily dose to achieve and maintain substantial amenorrhoea due to inhibition of the estrogen- induced endometrial proliferation
  • the pharmaceutical agents according to the invention are suitable both for preventive use and for curative use in hormone replacement therapy (HRT), since degradation of bone mass is prevented by the estrogen and simultaneously the estrogen exerts a protective effect on the cardiovascular system and the undesirable stimulating effect on the endometrium is prevented by the antiprohferative action of the mesoprogestin
  • mesoprogestins i a compounds disclosed in DE 43 32 283 and in DE 43 32 284 are suitable for the purposes of the invention, i e as pharmaceutical components for the manufacture of a medicament for hormone replacement therapy (HRT) and as component for the combined use together with an estrogen for the manufacture of a medicament for HRT as well as in respective HRT-methods and methods of treating hormone deficiency and hormone irregularity symptoms in the pen-menopause, the menopause and post- menopause
  • HRT hormone replacement therapy
  • J 867 [4-[17 ⁇ -Methoxy-17 ⁇ -(methoxymethyl)-3-oxoestra-4,9-d ⁇ en-1 1 ⁇ -yl]benzaldehyd-(1 E)-ox ⁇ m] and J 912 [4-[17 ⁇ -Hydroxy-17 ⁇ -(methoxymethyl)-3-oxoestra-4,9-d ⁇ en-11 ⁇ -yl]benzaldehyd- (1 E)-ox ⁇ m] ( both DE 43 32 283) and J 900 [4-[17 ⁇ -Methoxy-17 ⁇ -(methoxymethyl)-3- oxoestra-4,9-d ⁇ en-11 ⁇ -yl]benzaldehyd-(1 E)-[0-(ethoxy)carbonyl]ox ⁇ m], J 914 [4-[17 ⁇ - Methoxy-17 ⁇ -(methoxymethyl
  • J 867 is described in DE 43 32 283 and J 900 and 914 are described in DE 43 32 284 as well as in corresponding patent applications as compounds having strong antiprogestagenic and compared to RU 486 having markedly reduced antiglucocorticoid activity Moreover these compounds are mentioned to have (indirect) antiestrogenic properties reflected by reduced uterine weights in cyclic guinea pigs
  • mesoprogestins are defined as compounds possessing both agonistic and antagonistic activities at the progesterone receptor (PR) in vivo
  • PR progesterone receptor
  • mesoprogestins show high binding affinity to PR
  • mesoprogestins exhibit different pharmacodynamic properties compared to either progestins or antiprogestins
  • progesterone agonistic activity in mesoprogestins measured in commonly used biological tests in vivo represents the key property of this novel class of PRMs This activity remains, however, below that of progesterone in the plateau of the dose response curve
  • Mesoprogestins fail to maintain pregnancy in ovariectomized pregnant rodents as mice and rats
  • mesoprogestins to antagonize progesterone function is also tested in the McPhail test using a progesterone dose which induces a McPhail score ranging between 3 and 4
  • a mesoprogestin inhibits the effect of progesterone to a significant degree, but the maximum inhibition is below that which is inducible with RU 486 or other pure antiprogestins (e g onapnstone)
  • the mesoprogestins stabilize, therefore, the function of PR at an intermediate activity level providing the rationale for the novel clinical applications in gynecological therapy
  • Corresponding functional states cannot be achieved with progestins or antiprogestins
  • the progestagenic activity of J867, J956, J1042 and RU 486 was evaluated in estradiol-p ⁇ med juvenile rabbits after 4 days of subcutaneous (s c ) treatment in the absence of progesterone)
  • the progestagenic effect of the mesoprogestins was observed at doses equal to or higher that 0 03 mg/rabbit Progesterone induced endometrial transformation at doses equal to or higher that 0 1 mg reaching a maximum effect at 1 mg/rabbit (approximately McPhail score 4)
  • Neither mesoprogestin tested (J1042, J867, J956) reached the maximum effect of progesterone J956 showed a biphasic response in this test with a maximum effect of McPhail score 1 5 at 0 3-1 mg/rabbit
  • the antiprogestagenic activity of J867, J956, J1042 and RU 486 was evaluated in estradiol-p ⁇ med juvenile rabbits after 4 days of subcutaneous (s c ) treatment in the presence of progesterone (1 mg/rabbit s c )
  • the antiprogestagenic activity of mesoprogestins at higher clinically relevant doses doses i e 3- 30 mg/rabbit was lower that that of RU 486
  • the guinea pig is considered as relevant model of human gestation and parturition (Elger W, Fahnnch M, Beier S, Quing SS, Chwalisz K (1987). Endometrial and myomet ⁇ al effects of progesterone antagonists in pregnant guinea pigs Am J Obstet Gynecol 157 1065-1074, Elger W, Neef G, Beier S, Fahnnch M, Grundel M, Heermann J, Malmendier A, Laurent D, Pun CP, Singh MM, Hasan SH, Becker H (1992) Evaluation of antifertility activities of antigestagens in animal model In Pun CP and Van Look PFA (eds), Current Concepts in Fertility Regulation and Reproduction Wiley Eastern Limited, New Delhi, pp 303-328, Elger W, Faehn ch M, Beier S, Qing SS, Chwalisz K (1986) Mechanism of action of progesterone antagonists in pregnant guinea pigs Contraception 6
  • Table 1 Studies of relative binding activity (RBA) and ED 50 of abortifacient activity in pregnant rats and guinea pigs.
  • estrogenic aspect of this invention is analogous to conventional estrogen replacement therapy Consequently, any compound that is effective as estrogen can be used in the known doses and according to the methods that are known for estrogen replacement therapy
  • estrogens all estrogenically active compounds are suitable for the purposes of this invention.
  • Estrogens that can be used within the scope of this invention are, for example, ethinylestradiol, 17 ⁇ -estrad ⁇ ol as well as its esters such as estrad ⁇ ol-3-benzoate, estrad ⁇ ol-17-valerate, -cypionate, -undecylate, -enanthate and/or other estradiol esters (US-PS 2,611 ,773, US-PS 2,990,414, US-PS 2,054,271 , US-PS 2,225,419 and US-PS 2,156,599) and conjugated estrogens
  • Estradiol-, ethinylestradiol- and estrone-3-sulfamates for example estrone-N,N- dimethylsulfamate, estrone-N,N-d ⁇ ethylsulfamate, eth ⁇ nylestrad ⁇ ol-3-N,N- dimethylsulfamate, eth ⁇ nylestrad ⁇ ol-3-N,N-d ⁇ ethylsulfamate, eth ⁇ nylestrad ⁇ ol-3-N,N- tetramethylenesulfamate, estrone sulfamate, estrad ⁇ ol-3-sulfamate, estrad ⁇ ol-3-N,N- dimethylsulfamate, estrad ⁇ ol-3-N,N-d ⁇ ethylsulfamate, eth ⁇ nylestrad ⁇ ol-3-sulfamate, which all represent prodrugs for the corresponding 3-hydroxy compounds (W El
  • the mesoprogestins can be used analogously as antiprogestins in the HRT-regimes together with an estrogen as is already otherwise disclosed
  • the dosage units of the estrogen are intended for administration preferably over a period of 28 to 112 days
  • the dosage units of the mesoprogestin are provided for administration over a period of at least 4 days and at most 30 days
  • a special embodiment contains the dosage units of the mesoprogestin for administration over a period of 7 days
  • the pharmaceutical agent is preferably designed in such a way that the dosage units of estrogen and the dosage units of the mesoprogestin are present together in the pharmaceutical agent in such a number that the sum of the number of daily dosage units of the estrogen and the dosage units of the mesoprogestin is 28 or 28 plus 7 or 28 plus a multiple of 7
  • compositions can be used.
  • compositions of the pharmaceutical agent which are preferred as well are also possible, however, in which the number of the daily dosage units of estrogen and the number of dosage units of the mesoprogestin are not in each case 7 or a multiple of 7 it is important only that the sum of these daily units can be divided by 7, i e , the taking of the pharmaceutical agent leads to an exactly 4-week or multiple-week administration cycle
  • a mesoprogestin can be used after the menopause alone, i e without an estrogen due to its tissue-specific effects on bones (prevention of osteoporosis) and mammary gland (inhibition of proliferation) Such a regimen may be beneficial for women who do not tolerate estrogens
  • Penmenopausal women show an increased rate of breakthrough bleeding This is mainly due to corpus luteum deficiency an inadequate progesterone production
  • the estrogen production is generally maintained in penmenopausal women
  • the mesoprogestin is, therefore, administered prior to the menopause in order to stabilize the endometrium After the menopause, which can be assessed by the measurement of estrogen levels as it is well known to those skilled in the art, the mesoprogestin will be given in combination with an estrogen or a mixture of estrogens
  • mesoprogestin cares for the endometnal protection required under the estrogen substitution therapy by suppressing endometrial proliferation
  • This combination of mesoprogestin and estrogen according to the invention assures induction and maintenance of amenorrhoea during penmenopause
  • the administration can be on a daily basis or in longer regular intervals depending on the release rate of the active substance from its pharmaceutical formulation or depending on the kinetic of the bioavailiabihty of the respective active compound itself
  • the mesoprogestin is administered in a dose being sufficient to achieve effective amenorrhoea from the beginning of the treatment
  • doses of mesoprogestins being able to induce and maintain amenorrhoea can be determined by routine and conventional methods for instance by determining effectiveness in clinical trials Striking advantages of the herein disclosed HRT-methods compared to the classical estrogen/gestagen-HRT-preparations are amenorrhoea from the beginning of the treatment (estrogen/gestagen-preparations are leading to breakthrough bleedings in the first administration cycles and reduced effects on lipid metabolism and mood
  • the mesoprogestins provide a much more balanced endometnal protection due to the inhered partial progestagenic activity
  • the presence of agonistic activity at the progesterone receptor is beneficial with respect to endometnal protection, i e prevention of endometnal hyperplasia due to unopposed estrogen effect on endometrium
  • Signs of endometrial hyperstimulation were previously described after prolonged treatment of endomet ⁇ osis with RU 486 (Murphy AA, Kettel LM, Morales AJ, et al , (1995) Endometrial effects of long-term, low-dose administration of RU 486, Fertil Steril 63 761 -766)
  • estrogen can be present in dosage units that are intended for daily administration
  • the mesoprogestin can also be present in daily oral dosage units
  • these dosage units can advantageously be present in the form of a dosage unit that can be administered once a week
  • the mesoprogestin should preferably be prepared in a formulation that results in a delayed release of the active ingredient
  • a delayed release of the mesoprogestin can be achieved, for example, by formulating the dosage unit that is to be administered orally as a composite tablet or by providing the dosage unit that is to be administered orally with a timed-disintegration coating, as is readily known to one skilled in the art
  • the mesoprogestin that is used for the production of the pharmaceutical agent according to the invention can also have a longer half-life than this precursor As a result, a longer-lasting action is also achieved
  • the mesoprogestin is preferably selected for this invention from the group of the compounds J867, J912, J956, J1042
  • the formulation of the estrogen mesoprogestin is done in a completely conventional manner, as is already known for the formulation of these compounds for their individual use in hormone replacement therapy for estrogen, for example Cyclo-Progynova, or as described for J867 in DE 43 32 283
  • administration can be done using an intrautenne release system (c f Mirena), but this variant is not preferred within the scope of this invention
  • the estrogen can be administered transdermally with a skin patch
  • the progesterone antagonist can be administered daily orally or one or more times as a depot formulation
  • the estrogen is contained per daily dosage unit according to the invention in an amount of 1 to 2 mg of 17 ⁇ -estrad ⁇ ol or a bioequivalent amount of another estrogen
  • the transdermal administration system should release daily approximately 50 ⁇ g of 17 ⁇ -estrad ⁇ ol or a bioequivalent amount of another estrogen
  • the administration of the estrogen using a vaginal cream or vaginal ring is also possible
  • the daily amounts are about 1 25 mg or 0 2 mg in the case of 17 ⁇ -estrad ⁇ ol In this case, these are only approximate values
  • the mesoprogestin is contained in each dosage unit preferably in an amount such that, when used over the intended length of time, it is sufficient for amenorrhea to occur
  • the mesoprogestin is contained in each daily dosage unit in an amount that is equivalent to 0 5 mg to 50 mg, preferably 1 mg to 25 mg of J867
  • the bioequivalent doses of a mesoprogestin can be assessed in the McPhail test
  • the packaging that contains the pharmaceutical agent according to the invention is prepared in such a way that, in addition to the component(s) mesoprogestin (and estrogen) in the respectively intended form of administration (orally in the form of pills, coated tablets, etc in a blister pack, as may be appropriate for estrogen and/or progesterone antagonists, or the estrogen as a skin patch and the progesterone antagonist in the form of pills, coated tablets, etc in a blister or in a capsule as a depot that is to be administered once), said packaging also contains instructions for the use of the pharmaceutical agent (package insert)
  • the entire disclosure of all applications, patents and publications, cited above or below, and of corresponding provisional application filed as U S Serial No 09/386,140 on August 31 , 1999, and converted to provisional by petition of August 29, 2000 is hereby incorporated by reference

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Abstract

The present invention refers to the use of mesoprogestins as pharmaceutical components for the manufacture of a medicament for hormone replacement therapy (HRT) and as component for the combined use together with an estrogen for the manufacture of a medicament for HRT as well as in respective HRT-methods and methods of treating hormone deficiency and hormone irregularity symptoms. Mesoprogestins are defined as compounds possessing both agonistic and antagonistic activities at the progesterone receptor (PR) in vivo. They stabilize the function of PR at an intermediate level of agonistic and antagonistic. Corresponding functional states cannot be achieved with progestins or antiprogestins. J867, J912, J956 and J1042 are the mesoprogestins preferred according to the invention.

Description

Mesoprogestins (progesterone receptor modulators) as a component of compositions for Hormone Replacement Therapy (HRT)
The present invention relates to the field of hormone replacement therapy (HRT).
With the onset of menopause in women, so-called menopausal symptoms occur owing to altered hormone production. Because of reduced estrogen production, the risk of osteoporosis increases at the same time (reduction of bone tissue while retaining the same bone structure, due to increased bone degradation and/or reduced bone growth); likewise in postmenopausal women, a myocardial infarction rate that is significantly increased compared to premenopausal women and an increased incidence of other cardiovascular diseases are observed, which also can be attributed to reduced estrogen production.
Hormone replacement therapy (= HRT) with estrogens or with an estrogen/gestagen combination is currently the standard method for treating the symptoms that are associated with menopause (Ernster, V. L. et al. (1988): Benefits and Risks of Menopausal Estrogen and/or Progestin Hormone Use; Prev. Med. 17:201-223).
Estrogen exerts a protective action on the cardiovascular system, on the bones (reduction of the risk of osteoporosis), and on the central nervous system (avoidance of so-called "hot flashes"). However, the chronic use of estrogens in hormone replacement therapy leads to an increased risk of endometrial carcinoma (Ernster, V. L. et al. (1988): Benefits and Risks of Menopausal Estrogen and/or Progestin Hormone Use; Prev. Med. 17:201-223).
By simultaneously using a gestagen for hormone replacement therapy, the stimulating effect of estrogen on the endometrium is suppressed (Gibbson, W. E., 1986, Biochemical and Histologic Effects of Sequential Estrogen/Progestin Therapy on the Endometrium of Postmenopausal Women; Am. J. Obstet. Gynecol: 154:46-61); in contrast, however, in the case of combined therapy with an estrogen and gestagen, the protective effects of the estrogenic components with respect to the plasma lipids can at least be attenuated (Lobo, R. (1992): The Role of Progestins in Hormone Replacement Therapy; Am. J. Obstet. Gynecol. 166: 1997-2004). In addition, with an estrogen/gestagen treatment based on a hormone dosage that is lower than with an oral contraceptive agent, undesirable intracyclic menstrual bleeding can occur (Hillard, T C et al (1992) Continuous Combined Conjugated Equine Estrogen-Progestagen Therapy Effects of Medroxyprogesterone Acetate and Norethindrone Acetate on Bleeding Patterns and Endometrial Histologic Diagnosis, Am J Obstet Gynecol 167 1-7)
Finally, recent findings show that many gestagens can increase the risk of breast cancer ( Staff a, J A et al (1992) Progestins and Breast Cancer An Epidemiologic Review, 57 473-491 ), King, R J B (1991 ) A Discussion of the Roles of Estrogen and Progestin in Human Mammary Carcinogenesis, J Ster Biochem Molec Bio 39 81 1 1-81 18)
In summary the picture that forms is that the known estrogen-mono- and estrogen/gestagen combination therapies do not represent any satisfactory options for treating the symptoms that are associated with menopause
Recently, the use of "true" antiestrogens for the production of pharmaceutical agents for hormone replacement therapy (HRT) has also been proposed (EP-A-0 178 862) "True" antiestrogens refer, according to EP-A-0 178 862, for example, to tamoxifen, nafoxidine, MER-25, as well as those antiestrogens which act in a receptor-mediated manner and which at the same time also have an estrogenic (agonistic) partial action This estrogenic partial action occurs in the uterus and in bone
A disadvantage to such a pharmaceutical agent that contains a "true" antiestrogen with a partial estrogenic action is that, owing to the chronically estrogenic stimulation of the endometrium, such as occurs with use of estrogens, an increased risk of the development of an endometrial carcinoma exists (Fomander, T et al (1989) Adjuvant Tamoxifen in Early Breast Cancer Occurrence of New Primary Cancers Lancet 21 117-119)
In contrast, positive effects on the bone are produced by the partial estrogenic action of tamoxifen, in women, tamoxifen seems to partially prevent the degradation of the bone mass (Love, R R et al (1992) Effects of Tamoxifen on Bone Mineral Density in Postmenopausal Women with Breast Cancer, N Engl J Med 26 852-856)
In addition, studies on tamoxifen have shown that its antiestrogenic component is responsible for growth inhibition when used in the treatment of breast cancer in postmenopausal women (Buckley, M M T et al (1989), Tamoxifen A Reappraisal of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use, Drugs 37 451 - 490)
In addition, antiestrogens such as raloxifen for inhibiting bone degradation and for treating penmenopausal syndrome have become known (US Patent 5,393,763 or 5,391 ,557) Antiestrogens of this type show a clearly reduced agonistic (estrogenic) action on the endometrium, but exert a significantly estrogenic action on the bone Since these substances are also not completely dissociated, however (i e , they always have a residual estrogenic action on the endometrium), they can also result in a proliferation of the endometrium after long-term treatment
Accordingly, the necessary chronic use of an antiestrogen with a partial agonistic action in hormone replacement therapy can be considered harmful since stimulation of the endometrium can promote the development of endometrial carcinoma
WO-EP 94/03408 proposes to avoid this permanent stimulation of the endometrium by simultaneously using a compound with a progesterone-antagonistic action as well as a compound with an antiestrogenic action while at the same time there is a partial agonistic action for the production of a pharmaceutical agent for hormone replacement therapy In the case of such a pharmaceutical agent, the component with a progesterone- antagonistic action inhibits the changes that are caused by the partial estrogenic action of the antiestrogen (stimulation of the myometπum and endometrium) only in the uterus, while, however, the other estrogenic effects, which are highly desired in hormone replacement therapy, for example on bone and on the cardiovascular system, remain unchanged
The administration of an estrogen, optionally together with a gestagen, both at very low dosages, which by themselves do not ensure stable bleeding behavior, combined with a periodic, one-time administration of an antiprogestin (progesterone antagonist) for contraception and for hormone replacement therapy, is described in WO-A 93/17686 The progesterone antagonist ensures a reduction in breakthrough bleeding
The joint, and preferably simultaneous use of a competitive progesterone antagonist with an estrogen without gestagen is described in WO-A 94/18983 The use of the estrogen according to this publication is done entirely according to the conventional principles of estrogen replacement therapy The progesterone antagonist is used in an amount that inhibits the endometrial proliferation that is induced by estrogen WO-A 97/33589 discloses a pharmaceutical agent that contains in combination individual dosage units of an estrogen and individual dosage units of a competitive progesterone antagonist for separate, sequential administration of the competitive progesterone antagonist, which can be used for hormone replacement therapy, as well as packaging that contains this pharmaceutical agent
In any case, chronic (e g , daily) treatment with a progesterone antagonist can lead to side- effects, for example in the liver, because of the daily burden of the organism Moreover, a potential drawback of antiprogestins is that their misuse for abortion cannot be ruled out completely
It is therefore the object of this invention to provide a pharmaceutical and a method for hormone replacement therapy (HRT) which avoids the aforementioned drawbacks and which provides further favorable features in HRT
A further object of this invention is to provide application regimens for this pharmaceutical for HRT
This invention discloses the use of mesoprogestins as pharmaceutical components for the manufacture of a medicament for hormone replacement therapy (HRT)
Another aspect is the combined use of an estrogen together with a mesoprogestin for the manufacture of a medicament for HRT
A further aspect of the invention is the use of the mesoprogestin in a daily amount of 1 0 to 50 0 mg, more preferred is a daily dose of 5 0 to 25 0 mg mesoprogestin and most preferred is a daily dose of 10 0 to 25 0 mg of a mesoprogestin
Yet another preferred aspect of the invention is to administer the mesoprogestin in a daily dose to achieve and maintain substantial amenorrhoea due to inhibition of the estrogen- induced endometrial proliferation
The pharmaceutical agents according to the invention are suitable both for preventive use and for curative use in hormone replacement therapy (HRT), since degradation of bone mass is prevented by the estrogen and simultaneously the estrogen exerts a protective effect on the cardiovascular system and the undesirable stimulating effect on the endometrium is prevented by the antiprohferative action of the mesoprogestin
These pharmaceutical agents are thus especially suitable for long-term use in HRT
As mesoprogestins i a compounds disclosed in DE 43 32 283 and in DE 43 32 284 are suitable for the purposes of the invention, i e as pharmaceutical components for the manufacture of a medicament for hormone replacement therapy (HRT) and as component for the combined use together with an estrogen for the manufacture of a medicament for HRT as well as in respective HRT-methods and methods of treating hormone deficiency and hormone irregularity symptoms in the pen-menopause, the menopause and post- menopause
As mesoprogestins are preferred the compounds J867, J912, J 900, J 914 and J 956 J 867 [4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dιen-1 1 β-yl]benzaldehyd-(1 E)-oxιm] and J 912 [4-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dιen-11 β-yl]benzaldehyd- (1 E)-oxιm] ( both DE 43 32 283) and J 900 [4-[17β-Methoxy-17α-(methoxymethyl)-3- oxoestra-4,9-dιen-11 β-yl]benzaldehyd-(1 E)-[0-(ethoxy)carbonyl]oxιm], J 914 [4-[17β- Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dιen-1 1 β-yl]benzaldehyd-(1 E)-(O-acetyl)oxιm] and J 956 [4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dιen-1 1 β-yl]benzaldehyd- (1 E)-[0-(ethylamιno)carbonyl]oxιm] (all DE 43 32 284) and J1042 [4-[17β-Methoxy-17α- (methoxymethyl)-3-oxoestra-4,9-dιen-11 β-yl]benzaldehyd-(1 E)-[0-(ethylthιo)carbonyl]oxιm (German Patent Application 198 09 845 6)]
Further preferred mesoprogestins are
4-[17β-Hydroxy-17α-(ethoxymethyl)-3-oxoestra-4,9-dιen-1 1 β-yl]benzaldehyd-(1 E)-oxιm,
4-[17β-Methoxy-17α-(ethoxymethyl)-3-oxoestra-4,9-dιen-11 β-yl]benzaldehyd-(1 E)-oxιm,
4-[17β-Hydroxy-17α-(chlormethyl)-3-oxoestra-4,9-dιen-1 1 β-yl]benzaldehyd-(1 E)-oxιm,
4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dιen-11 β-yl]benzaldehyd-(1 E)-(O- methyl)oxιm (all DE 43 32 283) and
4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dιen-11 β-yl]benzaldehyd-(1 E)-[0-
(phenylamιno)carbonyl]oxιm,
4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dιen-11 β-yl]benzaldehyd-(1 E)-
[propionyljoxim, 4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dιen-1 1 β-yl]benzaldehyd-(1 E)- [benzoyl]oxιm (all DE 43 32 284)
J 867 is described in DE 43 32 283 and J 900 and 914 are described in DE 43 32 284 as well as in corresponding patent applications as compounds having strong antiprogestagenic and compared to RU 486 having markedly reduced antiglucocorticoid activity Moreover these compounds are mentioned to have (indirect) antiestrogenic properties reflected by reduced uterine weights in cyclic guinea pigs
These effects should promise the exertion of a particularly favorable influence on pathologically modified tissues in which estrogens stimulate growth (endometπotic focuses, myomas, etc )
The disclosure of these applications does not pertain to the use of the new compounds for hormone replacement therapy
Also, a progestagenic activity of the compounds which is advantageous for the herein claimed indication HRT is not mentioned in these applications at all
Further, the mentioned applications are silent about any active dose to be used to treat any of the therein mentioned conditions
According to the invention mesoprogestins are defined as compounds possessing both agonistic and antagonistic activities at the progesterone receptor (PR) in vivo As progestins and antiprogestins, mesoprogestins show high binding affinity to PR However, mesoprogestins exhibit different pharmacodynamic properties compared to either progestins or antiprogestins The presence of progesterone agonistic activity in mesoprogestins measured in commonly used biological tests in vivo represents the key property of this novel class of PRMs This activity remains, however, below that of progesterone in the plateau of the dose response curve Mesoprogestins fail to maintain pregnancy in ovariectomized pregnant rodents as mice and rats
In the classical bioassay, the McPhail test, assessing progestagenic and antiprogestagenic effects in rabbits (Selye H , Textbook of Endocrinology, 1947, pp 345-346), progesterone produces a maximum McPhail score of 4 (by definition) Treatment with a mesoprogestin in the absence of progesterone leads, however, to a McPhail score which is higher than that under any dose of RU 486, i e above 0 5 - 1 0, preferentially 2 0 - 3 0, but to distinctly lower score than 4 at the plateau of the dose response curve at the clinically relevant doses for the claimed indications (i e 0 01 mg - 30 mg/rabbit)
The capacity of mesoprogestins to antagonize progesterone function is also tested in the McPhail test using a progesterone dose which induces a McPhail score ranging between 3 and 4 A mesoprogestin inhibits the effect of progesterone to a significant degree, but the maximum inhibition is below that which is inducible with RU 486 or other pure antiprogestins (e g onapnstone)
The mesoprogestins stabilize, therefore, the function of PR at an intermediate activity level providing the rationale for the novel clinical applications in gynecological therapy Corresponding functional states cannot be achieved with progestins or antiprogestins
Pharmacological results demonstrating the utility of the mesoproqestines in the claimed indications
The PR antagonistic and agonistic properties of mesoprogestins were assessed in estrogen- primed rabbits in the McPhail test according to Selye (Textbook of Endocrinology, 1947, pp 345-346)
A) Assessment of PR agonistic properties of mesoprogestins in rabbits (Figure 1 A)
The progestagenic activity of J867, J956, J1042 and RU 486 (dose range 0 003-100 mg/rabbit) was evaluated in estradiol-pπmed juvenile rabbits after 4 days of subcutaneous (s c ) treatment in the absence of progesterone) The progestagenic effect of the mesoprogestins was observed at doses equal to or higher that 0 03 mg/rabbit Progesterone induced endometrial transformation at doses equal to or higher that 0 1 mg reaching a maximum effect at 1 mg/rabbit (approximately McPhail score 4) Neither mesoprogestin tested (J1042, J867, J956) reached the maximum effect of progesterone J956 showed a biphasic response in this test with a maximum effect of McPhail score 1 5 at 0 3-1 mg/rabbit
B) Assessment of PR antagonistic properties of mesoprogestins in rabbits (Figure 1 B)
Similarly, the antiprogestagenic activity of J867, J956, J1042 and RU 486 (dose range 0 001-100 mg/rabbit) was evaluated in estradiol-pπmed juvenile rabbits after 4 days of subcutaneous (s c ) treatment in the presence of progesterone (1 mg/rabbit s c ) The first antiprogestagenic effect of the mesoprogestins and RU 486 was observed with a dose of 0 3-1 mg mg/rabbit (McPhail index 0 = no transformation, 4 = complete transformation) The antiprogestagenic activity of mesoprogestins at higher clinically relevant doses doses (i e 3- 30 mg/rabbit) was lower that that of RU 486
In the guinea pig model which allows a good prediction of the effects in humans with respect to the abortifacient activity (Elger W, Beier S , Chwalisz K, Fahnπch M, Hasan SH, Henderson D, Neef G, Rohde R (1986) Studies on the mechanism of action of progesterone antagonists J Steroid Biochem 25 835-845) the mesoprogestins J 867, J 912, J 956, J 1042 lead up to 100 mg/kg/day to a maximal abortion rate of 20%
C) Evaluation of abortifacient effects
Physiological background
The guinea pig is considered as relevant model of human gestation and parturition (Elger W, Fahnnch M, Beier S, Quing SS, Chwalisz K (1987). Endometrial and myometπal effects of progesterone antagonists in pregnant guinea pigs Am J Obstet Gynecol 157 1065-1074, Elger W, Neef G, Beier S, Fahnnch M, Grundel M, Heermann J, Malmendier A, Laurent D, Pun CP, Singh MM, Hasan SH, Becker H (1992) Evaluation of antifertility activities of antigestagens in animal model In Pun CP and Van Look PFA (eds), Current Concepts in Fertility Regulation and Reproduction Wiley Eastern Limited, New Delhi, pp 303-328, Elger W, Faehn ch M, Beier S, Qing SS, Chwalisz K (1986) Mechanism of action of progesterone antagonists in pregnant guinea pigs Contraception 6 47-62, Elger W, Chwalisz K, Faehnnch M, Hasan SH, Laurent D, Beier S, Ottow E, Neef G, Garfield RE (1990) Studies on labor-conditioning and labor-inducing effects of antiprogesterones in animal model In Garfield RE (eds), Norwell, pp 153-175 ) The mechanism of abortion of antiprogestins in this species is the initiation of labor and finally the expulsion of the conceptus Abortifacient effects in the rat during very early pregnancy reflect inhibitory effects on nidation rather than initiation of uterine contractions Studies in the rat model lead to "overestimation" of the potential of antiprogestins to terminate pregnancy in humans Conversely, in the guinea pig model, irrespective of the antiprogestin doses, there were high rates of ongoing pregnancies similar to the situation in humans (Elger et al , Current Concepts in Fertility Regulation and Reproduction cited above) Furthermore, in both humans and guinea pigs, there is a strong synergism between antiprogestins and prostaglandins with respect the induction of labor (see the articles cited above and Elger W, Beier S (1983) Prostaglandine und Antigestagene fur den Schwangerschaftsabbruch (Prostaglandins and antigestagens for pregnancy termination) German Patent DE 3337450 12, Van Look P, Bygdeman M (1989) Antiprogestational steroids a new dimension in human fertility regulation Oxford reviews of reproductive medicine 1 1 2-60)
Assessment of labor inducing activity Figure 2
Pregnant guinea pigs were treated on days 43 and 44 of pregnancy and observed until day 50 of gestation For the effects of various treatments see table 1 and figure 2 It is typical for this model that expulsions occur with a delay of several days after treatment It can be seen that Mesoprogestins have a much reduced abortifacient activity compared to RU486 The following ranking of abortifacient activity was found RU486>J956>J867, J912>J1042 The differences with respect to abortifacient activity seem qualitative ones It is not possible to overcome the low abortifacient activity of a Mesoprogestin by the use of a higher dose
Table 1 : Studies of relative binding activity (RBA) and ED50 of abortifacient activity in pregnant rats and guinea pigs.
Figure imgf000010_0001
# by Kaufmann, progesterone = 100%, 2dexamethasone = 100% treatment days 5 - 7 of pregnancy, autopsy day 9, treatment day 43 - 44 of pregnancy, autopsy day 50, *SAS, probit procedure
Application forms and regimes of the estrogens and mesoprogestins for the purposes of this invention The estrogenic aspect of this invention is analogous to conventional estrogen replacement therapy Consequently, any compound that is effective as estrogen can be used in the known doses and according to the methods that are known for estrogen replacement therapy
As estrogens, all estrogenically active compounds are suitable for the purposes of this invention
• Estrogens that can be used within the scope of this invention are, for example, ethinylestradiol, 17β-estradιol as well as its esters such as estradιol-3-benzoate, estradιol-17-valerate, -cypionate, -undecylate, -enanthate and/or other estradiol esters (US-PS 2,611 ,773, US-PS 2,990,414, US-PS 2,054,271 , US-PS 2,225,419 and US-PS 2,156,599) and conjugated estrogens
• Estradiol-, ethinylestradiol- and estrone-3-sulfamates, for example estrone-N,N- dimethylsulfamate, estrone-N,N-dιethylsulfamate, ethιnylestradιol-3-N,N- dimethylsulfamate, ethιnylestradιol-3-N,N-dιethylsulfamate, ethιnylestradιol-3-N,N- tetramethylenesulfamate, estrone sulfamate, estradιol-3-sulfamate, estradιol-3-N,N- dimethylsulfamate, estradιol-3-N,N-dιethylsulfamate, ethιnylestradιol-3-sulfamate, which all represent prodrugs for the corresponding 3-hydroxy compounds (W Elger et al , in J Steroid Biochem Molec Biol , Vol 55, No 3/4, 395-403, 1995, DE 44 29 398 A1 and DE 44 29 397 A1 ), can also be used in the pharmaceutical agent according to the invention
• Finally, the orally bioavailable derivatives of 17α- and 17β-estradιol with a modified D- nng of the steroid skeleton are also suitable
• The use of a natural estrogen (also conjugated estrogens) or a prodrug of a natural estrogen is preferred according to the invention
The mesoprogestins can be used analogously as antiprogestins in the HRT-regimes together with an estrogen as is already otherwise disclosed
Analogously to WO-A 94/18983 both active substances, estrogen and mesoprogestin, are administered simultaneously, either combined or separately, and continuously This administration can be on a daily basis or in longer regular intervals depending on the release rate of the active substance from its pharmaceutical formulation or depending on the kinetic of the bioavaihability of the respective active compound itself WO 01/34126 - π - PCT/US00/23771
Another possibility to combine estrogen substitution and mesoprogestin therapy effectively follows the sequential administration regime disclosed for an estrogen/competitive progesterone antagonist-combination in WO-A 97/33589
According to this regime the dosage units of the estrogen are intended for administration preferably over a period of 28 to 112 days
In another embodiment the dosage units of the mesoprogestin are provided for administration over a period of at least 4 days and at most 30 days
A special embodiment contains the dosage units of the mesoprogestin for administration over a period of 7 days
The pharmaceutical agent is preferably designed in such a way that the dosage units of estrogen and the dosage units of the mesoprogestin are present together in the pharmaceutical agent in such a number that the sum of the number of daily dosage units of the estrogen and the dosage units of the mesoprogestin is 28 or 28 plus 7 or 28 plus a multiple of 7
The taking of this embodiment of the pharmaceutical agent according to the invention thus leads to an administration cycle that lasts exactly a certain number of weeks, but at least four weeks
As examples, the following compositions can be used
• 28 daily units of estrogen + 7 daily units of mesoprogestin, 28 daily units of estrogen + 14 daily units of mesoprogestin, 28 daily units of estrogen + 21 daily units of mesoprogestin, 56 daily units of estrogen + 21 daily units of mesoprogestin, etc
Compositions of the pharmaceutical agent which are preferred as well are also possible, however, in which the number of the daily dosage units of estrogen and the number of dosage units of the mesoprogestin are not in each case 7 or a multiple of 7 it is important only that the sum of these daily units can be divided by 7, i e , the taking of the pharmaceutical agent leads to an exactly 4-week or multiple-week administration cycle
Yet another administration regime for HRT in which a mesoprogestin is used as component starts with the administration of the mesoprogestin alone in the penmenopause Around the expected occurrence of the menopause an estrogen is administered in addition to the mesoprogestin Thereafter both components are administered together until the end of the treatment
Alternatively, a mesoprogestin can be used after the menopause alone, i e without an estrogen due to its tissue-specific effects on bones (prevention of osteoporosis) and mammary gland (inhibition of proliferation) Such a regimen may be beneficial for women who do not tolerate estrogens
This leads to a reliable induction of amenorrhoea already during the peπmenopause and guarantees the still required contraception in this stage of life Otherwise alternative contraceptive measures would be necessary but these would achieve no amenorrhoea
Penmenopausal women show an increased rate of breakthrough bleeding This is mainly due to corpus luteum deficiency an inadequate progesterone production The estrogen production is generally maintained in penmenopausal women The mesoprogestin is, therefore, administered prior to the menopause in order to stabilize the endometrium After the menopause, which can be assessed by the measurement of estrogen levels as it is well known to those skilled in the art, the mesoprogestin will be given in combination with an estrogen or a mixture of estrogens
After the menopause the mesoprogestin cares for the endometnal protection required under the estrogen substitution therapy by suppressing endometrial proliferation This combination of mesoprogestin and estrogen according to the invention assures induction and maintenance of amenorrhoea during penmenopause
Again, the administration can be on a daily basis or in longer regular intervals depending on the release rate of the active substance from its pharmaceutical formulation or depending on the kinetic of the bioavailiabihty of the respective active compound itself
Advantageously in all administration regimes the mesoprogestin is administered in a dose being sufficient to achieve effective amenorrhoea from the beginning of the treatment Such doses of mesoprogestins being able to induce and maintain amenorrhoea can be determined by routine and conventional methods for instance by determining effectiveness in clinical trials Striking advantages of the herein disclosed HRT-methods compared to the classical estrogen/gestagen-HRT-preparations are amenorrhoea from the beginning of the treatment (estrogen/gestagen-preparations are leading to breakthrough bleedings in the first administration cycles and reduced effects on lipid metabolism and mood
Compared to the regimen containing progesterone antagonists, the mesoprogestins provide a much more balanced endometnal protection due to the inhered partial progestagenic activity The presence of agonistic activity at the progesterone receptor is beneficial with respect to endometnal protection, i e prevention of endometnal hyperplasia due to unopposed estrogen effect on endometrium Signs of endometrial hyperstimulation were previously described after prolonged treatment of endometπosis with RU 486 (Murphy AA, Kettel LM, Morales AJ, et al , (1995) Endometrial effects of long-term, low-dose administration of RU 486, Fertil Steril 63 761 -766)
On the other hand, the drawbacks of progestins, i e negative effects on lipid metabolism and mood and stimulatory effects on the mammary gland, are reduced or absent during mesoprogestin treatment
Further, there is no potential for misuse as an abortifacient because of the high doses of a mesoprogestin needed to induce abortion
According to all embodiments, estrogen can be present in dosage units that are intended for daily administration
The mesoprogestin can also be present in daily oral dosage units
If the dosage units of the mesoprogestin are provided for administration over a period of 7 days, these dosage units can advantageously be present in the form of a dosage unit that can be administered once a week
In such a dosage unit that is to be administered once a week, the mesoprogestin should preferably be prepared in a formulation that results in a delayed release of the active ingredient
Examples of the following sequential regimen administrations include the following
• 2-3 months estrogen followed by 1-30 days mesoprogestin WO 01/34126 14 - PCT/USOO/23771
• alternate E and mesoprogestin administration, so called 3 day on/off regimen 3 days estrogen followed by 3 days mesoprogestin, followed by 3 days estrogen, etc (comment this progestin/estrogenregimen is currently used in the USA to achieve amenorrhea)
A delayed release of the mesoprogestin can be achieved, for example, by formulating the dosage unit that is to be administered orally as a composite tablet or by providing the dosage unit that is to be administered orally with a timed-disintegration coating, as is readily known to one skilled in the art
By deπvatization, for example by este fication of a free hydroxy group in an effective precursor, the mesoprogestin that is used for the production of the pharmaceutical agent according to the invention can also have a longer half-life than this precursor As a result, a longer-lasting action is also achieved
The mesoprogestin is preferably selected for this invention from the group of the compounds J867, J912, J956, J1042
For the purposes of this invention, the formulation of the estrogen mesoprogestin is done in a completely conventional manner, as is already known for the formulation of these compounds for their individual use in hormone replacement therapy for estrogen, for example Cyclo-Progynova, or as described for J867 in DE 43 32 283
In particular, reference is also made to the information that is contained in WO-A 93/17686 and WO-A 94/18983
In addition to oral administration of the estrogen and the mesoprogestin, it is equally possible to administer one or both of the components transdermally, for example with a skin patch, which is best known for the administration of estrogen (Chmara Patch)
In addition, administration can be done using an intrautenne release system (c f Mirena), but this variant is not preferred within the scope of this invention
The administration of one or both components as a depot formulation is also possible WO 01/34126 - - PCT/U OO/23
Finally, all above-mentioned types of administration can be combined For example, the estrogen can be administered transdermally with a skin patch, and the progesterone antagonist can be administered daily orally or one or more times as a depot formulation
The estrogen is contained per daily dosage unit according to the invention in an amount of 1 to 2 mg of 17β-estradιol or a bioequivalent amount of another estrogen
As bioequivalent amounts of other estrogens for the purposes of this invention, the following amounts can be considered
• ethinylestradiol 5-35 μg
• conjugated estrogens 0 3- to 1 25 mg
• In the case of transdermal administration of the estrogen, the transdermal administration system should release daily approximately 50 μg of 17β-estradιol or a bioequivalent amount of another estrogen
• The administration of the estrogen using a vaginal cream or vaginal ring is also possible The daily amounts are about 1 25 mg or 0 2 mg in the case of 17β-estradιol In this case, these are only approximate values
In the pharmaceutical agent according to the invention, the mesoprogestin is contained in each dosage unit preferably in an amount such that, when used over the intended length of time, it is sufficient for amenorrhea to occur
In an especially preferred embodiment of the pharmaceutical agent according to the invention, the mesoprogestin is contained in each daily dosage unit in an amount that is equivalent to 0 5 mg to 50 mg, preferably 1 mg to 25 mg of J867 The bioequivalent doses of a mesoprogestin can be assessed in the McPhail test
The packaging that contains the pharmaceutical agent according to the invention is prepared in such a way that, in addition to the component(s) mesoprogestin (and estrogen) in the respectively intended form of administration (orally in the form of pills, coated tablets, etc in a blister pack, as may be appropriate for estrogen and/or progesterone antagonists, or the estrogen as a skin patch and the progesterone antagonist in the form of pills, coated tablets, etc in a blister or in a capsule as a depot that is to be administered once), said packaging also contains instructions for the use of the pharmaceutical agent (package insert) The entire disclosure of all applications, patents and publications, cited above or below, and of corresponding provisional application filed as U S Serial No 09/386,140 on August 31 , 1999, and converted to provisional by petition of August 29, 2000 is hereby incorporated by reference
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions

Claims

Claims:
1. Use of mesoprogestins as a pharmaceutical component for the manufacture of a medicament for hormone replacement therapy (HRT).
2. Use of a mesoprogestin according to claim 1 together with an estrogen for the manufacture of a medicament for HRT.
3. Use of a mesoprogestin according to claim 1 or 2 in a daily amount of 1.0 to 50.0 mg.
4. Use according to claim 3 wherein the daily dose of the mesoprogestin is 5.0 to 25.0 mg.
5. Use according to claim 4 wherein the daily dose is 10.0 to 25.0.
6. Use of J 867, J 912, J 856 and J 1042 as a mesoprogestin according to anyone of the preceding claims 1 to 5.
7. Use of ethinylestradiol, estradiol, an estradiol ester or a 3-sulfamat of 17β- ethinylestradiol or 17β-estradiol as an estrogen according to claim 2.
PCT/US2000/023771 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt) Ceased WO2001034126A2 (en)

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PL353931A PL198798B1 (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt)
EEP200200102A EE200200102A (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of hormone replacement therapy (HRT) compositions
CA002383659A CA2383659C (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt)
UA2002032428A UA75339C2 (en) 1999-08-31 2000-08-31 Use of mesoprogestins (progesterone receptor modulators) as pharmaceutical components for manufacture of medicament for hormone replacement therapy (hrt)
EP00991840A EP1605924B1 (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt)
BR0013710-3A BR0013710A (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt)
SK297-2002A SK287121B6 (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (HRT)
HR20020266A HRP20020266A2 (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt)
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EA200200285A EA007840B1 (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulator) as a component of compositions for hormone replacement therapy (hrt)
DE60040764T DE60040764D1 (en) 1999-08-31 2000-08-31 MESOPROGESTINES (PROGESTERONE RECEPTOR MODULATORS) AS A COMPONENT OF COMPOSITIONS FOR HORMONOUS SUB-THERAPY
US10/433,984 US7629334B1 (en) 1999-08-31 2000-08-31 Mesoprogrestins (progesterone receptor modulations) as a component of compositions for hormone replacement therapy (HRT)
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AU36332/01A AU781836B2 (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (HRT)
HU0202460A HUP0202460A3 (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt)
ROA200200230A RO122180B1 (en) 1999-08-31 2000-08-31 Use of mesoprogestins in hormone replacement therapy
SI200020041A SI20851B (en) 1999-08-31 2000-08-31 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy (hrt)
BG106443A BG65846B1 (en) 1999-08-31 2002-02-26 Mesoprogestins (progesterone receptor modulators) as a component of compositions for hormone replacement therapy
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014935A1 (en) * 2002-08-02 2004-02-19 Schering Aktiengesellschaft Progesterone receptor modulators having an increased antigonadotropic activity for use in female fertility testing and hormone replacement therapy
WO2004045620A1 (en) * 2002-11-18 2004-06-03 Tap Pharmaceutical Products Inc. Use of selective progesterone receptor modulators for the treatment of androgen deficiency
US7550451B2 (en) 2002-08-02 2009-06-23 Bayer Schering Pharma Ag Progesterone receptor modulators with increased antigonadotropic activity for female birth control and hormone replacement therapy

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2611370C1 (en) * 2016-01-12 2017-02-21 Общество с ограниченной ответственностью Медицинская Корпорация "РАНА" Application of preparation laennek for reduction or elimination of manifestation of menopausal symptoms (versions)

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2054271A (en) 1932-05-17 1936-09-15 Schering Kahlbaum Ag Production of crystallized hormone esters
DE699310C (en) 1936-11-20 1940-11-27 Chemische Ind Ges Process for the preparation of compounds of the estradiol type which are esterified in the 3-position
US2225419A (en) 1937-03-01 1940-12-17 Schering Corp Process for the conversion of 17-cisalcohols of the cyclopentanopolyhydrophenanthrene series into the corresponding 17-trans-alcohols
US2611773A (en) 1951-08-21 1952-09-23 Upjohn Co Estradiol 17-cyclopenetanepropionate
US2990414A (en) 1957-03-26 1961-06-27 Syntex Sa 17-undecenoate of estradiol
US4729999A (en) * 1984-10-12 1988-03-08 Bcm Technologies Antiestrogen therapy for symptoms of estrogen deficiency
MX9301121A (en) * 1992-03-02 1993-09-01 Schering Ag METHOD AND EQUIPMENT FOR ORAL CONTRACEPTION AND REGULATION OF MENSTRUATION WITH ESTROGEN / PROGESTIN / ANIPROGESTIN.
TW366342B (en) * 1992-07-28 1999-08-11 Lilly Co Eli The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss
DE4225623C2 (en) * 1992-08-03 1994-06-30 Karl Hehl Process for the production of a powdery injection molding compound for the production of porcelain and its use
US5468736A (en) * 1993-02-25 1995-11-21 The Medical College Of Hampton Road Hormone replacement therapy
DE4332284C2 (en) * 1993-09-20 1997-05-28 Jenapharm Gmbh 11-Benzaldoxime-17beta-methoxy-17alpha-methoxymethyl-estradiene derivatives, process for their preparation and medicaments containing these compounds
DE4332283A1 (en) * 1993-09-20 1995-04-13 Jenapharm Gmbh Novel 11-benzaldoximestradiene derivatives, processes for their preparation and medicaments containing these compounds
US5391557A (en) * 1993-10-15 1995-02-21 Eli Lilly And Company Methods for the treatment of peri-menopausal syndrome
PT787002E (en) * 1994-10-24 2007-03-30 Schering Ag COMPETITIVE PROGESTERONE ANTAGONISTS FOR NEED-ORIENTED FEMALE FERTILITY CONTROL
DE19610635A1 (en) * 1996-03-11 1997-09-18 Schering Ag Sequential estrogen / progesterone antagonist combination for hormone replacement therapy
ES2174265T3 (en) * 1996-06-25 2002-11-01 Akzo Nobel Nv PROGESTOGEN-ANTI-PROGESTOGEN REGIMES.
WO1998005679A2 (en) * 1996-08-05 1998-02-12 Duke University Mixed agonists of the progesterone receptor and assays therefor
DE19809845A1 (en) * 1998-03-03 1999-09-09 Jenapharm Gmbh S-substituted 11beta-benzaldoxime-estra-4,9-diene-carbonic acid thiol esters, processes for their preparation and pharmaceutical preparations containing these compounds
BR9916999A (en) * 1999-01-14 2001-10-30 Bayer Ag Substituted 2-arylimine heterocycles and compositions containing them, for use as progesterone receptor binding agents

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014935A1 (en) * 2002-08-02 2004-02-19 Schering Aktiengesellschaft Progesterone receptor modulators having an increased antigonadotropic activity for use in female fertility testing and hormone replacement therapy
JP2005539016A (en) * 2002-08-02 2005-12-22 シエーリング アクチエンゲゼルシャフト Progesterone receptor modulators with enhanced anti-gonadotropin activity for female fertility regulation and hormone replacement therapy
US7550451B2 (en) 2002-08-02 2009-06-23 Bayer Schering Pharma Ag Progesterone receptor modulators with increased antigonadotropic activity for female birth control and hormone replacement therapy
WO2004045620A1 (en) * 2002-11-18 2004-06-03 Tap Pharmaceutical Products Inc. Use of selective progesterone receptor modulators for the treatment of androgen deficiency

Also Published As

Publication number Publication date
RS50396B (en) 2009-12-31
HUP0202460A3 (en) 2004-04-28
ZA200201621B (en) 2004-08-25
CA2383659A1 (en) 2001-05-17
BG106443A (en) 2002-09-30
AU3633201A (en) 2001-06-06
CA2383659C (en) 2009-02-10
EP1605924B1 (en) 2008-11-05
UA75339C2 (en) 2006-04-17
HUP0202460A2 (en) 2002-12-28
LT2002037A (en) 2002-11-25
EA007840B1 (en) 2007-02-27
EE200200102A (en) 2003-04-15
WO2001034126A9 (en) 2002-09-12
NZ517469A (en) 2004-01-30
NO20021000D0 (en) 2002-02-28
SK287121B6 (en) 2009-12-07
LT5011B (en) 2003-04-25
KR20020027618A (en) 2002-04-13
SI20851A (en) 2002-10-31
NO20021000L (en) 2002-03-14
AU781836B2 (en) 2005-06-16
AR025456A1 (en) 2002-11-27
CO5200773A1 (en) 2002-09-27
ATE413168T1 (en) 2008-11-15
SI20851B (en) 2009-06-30
IL148417A0 (en) 2002-09-12
CZ2002706A3 (en) 2002-10-16
IL148417A (en) 2010-11-30
BG65846B1 (en) 2010-03-31
LV12942B (en) 2003-06-20
RO122180B1 (en) 2009-02-27
YU14102A (en) 2006-01-16
ES2316402T3 (en) 2009-04-16
JP2003513908A (en) 2003-04-15
EA200200285A1 (en) 2002-08-29
CZ301412B6 (en) 2010-02-24
PL198798B1 (en) 2008-07-31
BR0013710A (en) 2002-05-07
DE60040764D1 (en) 2008-12-18
WO2001034126A3 (en) 2001-11-22
HRP20020266A2 (en) 2004-08-31
CN1454088A (en) 2003-11-05
KR100729311B1 (en) 2007-06-19
EP1605924A2 (en) 2005-12-21
MXPA02002190A (en) 2002-09-30
PE20010581A1 (en) 2001-06-04
PL353931A1 (en) 2003-12-15
SK2972002A3 (en) 2002-07-02

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