US20110124612A1 - Multi-phase contraceptive preparation based on a natural estrogen - Google Patents

Multi-phase contraceptive preparation based on a natural estrogen Download PDF

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Publication number
US20110124612A1
US20110124612A1 US13020913 US201113020913A US2011124612A1 US 20110124612 A1 US20110124612 A1 US 20110124612A1 US 13020913 US13020913 US 13020913 US 201113020913 A US201113020913 A US 201113020913A US 2011124612 A1 US2011124612 A1 US 2011124612A1
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Prior art keywords
daily dose
mg
dose units
oestradiol valerate
ovulation
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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.)
Abandoned
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US13020913
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Jan Endrikat
Bernd Duesterberg
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Jan Endrikat
Bernd Duesterberg
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids

Abstract

The multiphase preparation having higher contraceptive safety and reduced side effects is based on a combination of a natural oestrogen with dienogest or drospirenon. The multiphase prepration is characterized by a first phase consisting of 2 daily dose dose units of 3 mg of oestradiol valerate, a second phase consisting of 2 groups of daily dose units, wherein a first group is formed by 5 daily dose units each containing a combination of 2 mg of oestradiol valerate and at least two or three times an ovulation-inhibitory dose of dienogest or drospirenon and a second group is formed by 17 daily dose units each containing a combination of 2 mg of oestradiol valerate and at least three or four times the ovulation-inhibitory dose of dienogest or drospirenon, a third phase consisting of 2 daily dose units of 1 mg of oestradiol valerate, and a further phase consisting of 2 daily dose units of pharmaceutically acceptable placebo.

Description

    TECHNICAL FIELD
  • The invention relates to a multiphase product for contraception based on a natural oestrogen with a synthetic progestogen.
  • Compared with the generic conventional ovulation-inhibiting products which have proved to be reliable and safe on wide use for a long time, this multiphase product achieves a greater contraceptive reliability over the entire duration of the cycle, improves the cyclic bleeding behaviour and minimizes or eliminates side effects such as breast tenderness, headaches, depressive moods and libido changes and the like.
  • PRIOR ART
  • The patent literature discloses multiphase products based on natural oestrogens in combination with progestogens.
  • The patent EP 0 770 388 B1 describes a multiphase product for contraception whose first phase consists of to 4 daily dose units, and each daily dose unit contains as active ingredient exclusively natural oestrogens. The second phase of the multiphase product consists of 2 groups of daily dose units with a combination of at least one natural oestrogen and at least one synthetic or natural progestogen. In this case, the first group is formed by 5 to 3 daily dose units and the second group is formed by 17 to 13 daily dose units. A third phase consists of 2 to 4 daily dose units, and each daily dose unit contains as active ingredient exclusively natural oestrogens. The daily dose unit of natural oestrogen remains constant within the phases, but falls from phase 1 to phase 3. The proportion of synthetic or natural progestogen in the second group of the second phase exceeds the proportion in the first group. A final phase consists of 2 to 4 daily dose units, and each daily dose unit contains as active ingredient a pharmaceutically acceptable placebo.
  • Use example 5 indicates a combination of oestradiol valerate with dienogest. In this case, in the first phase 3 daily dose units of 3 mg of oestradiol valerate, in the second phase, in the first group, 4 daily dose units of 2 mg of oestradiol valerate plus 1 mg of dienogest, in the second group of this second phase 16 daily dose units of 2 mg of oestradiol valerate plus 2 mg of dienogest and in the third phase 2 daily dose units of 1 mg of oestradiol valerate are administered. The last phase contains 3 daily dose units of pharmaceutically acceptable placebo.
  • For information on contraceptive reliability, the progesterone serum concentration was measured radio-immunologically. A limit of 4.0 ng/ml progesterone has been stated. The average rate of irregular bleeding (breakthrough bleeding and spotting) fell by 45 to 53% from the first intake cycle to the last intake cycle.
  • It is additionally known that the contraceptive reliability of combination products derives from the effect of both components, of the oestrogen and of the progestogen.
  • It is also known that the ovulation-inhibitory dose requires 1.0 mg a day for dienogest—Dienogest: Präklinik and Klinik eines neuen Gestagens, edited by A. T. Teichmann, Walter de Gruyter Berlin/New York (1995), p. 101) and 2.0-3.0 mg for drospirenone (Rosenbaum P, Schmidt W, Helmerhorst F M et al., Inhibition of ovulation by a novel progestogen (drospirenone) . . . , Eur contracept. Reprod. Health Care 5: 16-24 (2000)).
  • Moreover, TAUBERT, H.-D. and KUHL, H. (Kontrazeption mit Hormonen, editors Taubert, H.-D. et al., Georg Thieme Verlag Stuttgart/New York (1995), p. 160) show that there is no connection whatsoever between the occurrence of irregular bleeding and low serum concentrations of the oestrogen, in this case ethinyl-oestradiol, or of the particular progestogen.
  • FIELD OF THE INVENTION
  • It is consequently an object of the invention to indicate a composition for hormonal contraception based on a natural oestrogen which, compared with the generic conventional ovulation-inhibiting compositions based on natural oestrogens, achieves a greater contraceptive reliability over the entire duration of the cycle, improves the cyclic bleeding behaviour, and controls side effects such as breast tenderness, headaches, depressive moods and libido changes and the like. This object is achieved according to the invention by a multiphase product for contraception, whose first phase consists of 2 daily dose units of 3 mg of the natural oestrogen oestradiol valerate. A second phase consists of 2 groups of daily dose units, where a the first group contains 5 daily dose units of a combination of 2 mg of oestradiol valerate and at least twice or three times the ovulation-inhibitory dose of a synthetic progestogen. The second group of the second phase consists of 17 daily dose units of a combination of 2 mg of oestradiol valerate and at least three times or four times the ovulation inhibitory does of a synthetic progestogen. A third phase contains 2 daily dose units with 1 mg of oestradiol valerate and a further phase 2 daily dose units of pharmaceutically acceptable placebo.
  • As synthetic progestational active ingredient, use may advantageously be made of dienogest, drospirenone or a progestogen at at least twice its known ovulation-inhibitory dose.
  • The multiphase product according to the invention is particularly suitable for oral administration, but intravaginal, parenteral, including topical, rectal, intranasal, intrabuccal or sublingual administrations are also conceivable as dosage forms.
  • The multiphase product is produced with the conventional solid or liquid carriers or diluents and the excipients conventionally used in pharmaceutical technology appropriate for the desired mode of administration with a suitable dosage in a known manner.
  • Tablets, film-coated tablets, sugar-coated tablets or hard gelatin capsules are preferably used for oral administration.
  • EXEMPLARY EMBODIMENTS
  • The invention is to be demonstrated by some examples of use. In this connection, in particular the contraceptive reliability, the cyclic bleeding behaviour of the woman, and the tolerability of the administration regimen is demonstrated.
  • Contraceptive Reliability
  • The contraceptive reliability was demonstrated in principle by determining the Hoogland score which uses the follicle size, the oestradiol level and progesterone values. In the present case, the progesterone serum concentration was measured radio-immunologically on selected days of the cycle, and the number of ovulations (Hoogland score 6) and of luteinized, non-ruptured follicles (Hoogland score 5) was determined.
  • Cycle Stability
  • The cycle stability was assessed on the basis of a bleeding pattern recorded for each cycle. Of particular interest in this connection was the occurrence of irregular bleeding (spotting or breakthrough bleeding). The mode of recording was standardized. The data were analysed descriptively.
  • Tolerability
  • The tolerability was tested on the basis of subjective feelings such as headaches, depressive moods, breast tenderness, gastric upsets (nausea/vomiting), oedemas and libido changes.
  • Use Example 1
  • The following regimen was used:
  • days 1 to 2 3 mg of oestradiol valerate/d
    days 3 to 7 2 mg of oestradiol valerate/d + 2 mg of
    dienogest/d
    days 8 to 24 2 mg of oestradiol valerate/d + 3 mg of
    dienogest/d
    days 25 to 26 1 mg of oestradiol valerate/d
    days 27 to 28 placebo
  • The study was carried out on 93 female subjects 18 to 35 years old. The duration of intake amounted to 3 cycles in each case, with only cycles 2 and 3 being observed.
  • In the 2nd cycle (primary target variable), 3 of 93 women (3.23%) ovulated, and 2 of 92 women in the 3rd cycle.
  • It was thus possible to record reliable inhibition of ovulation in 96.77% on use of the administration regimen according to the invention.
  • At the same time, good tolerability is found on intake of the administration regimen according to the invention.
  • Use Example 2
  • days 1 to 2 3 mg of oestradiol valerate/d
    days 3 to 7 2 mg of oestradiol valerate/d + 3 mg of
    dienogest/d
    days 8 to 24 2 mg of oestradiol valerate/d + 4 mg of
    dienogest/d
    days 25 to 26 1 mg of oestradiol valerate/d
    days 27 to 28 placebo
  • The study was carried out on 93 female subjects 18 to years old. The duration of intake amounted to 3 cycles in each case, with only cycles 2 and 3 being observed.
  • In the 2nd cycle (primary target variable), 2 of 93 women (2.15%) ovulated, and 2 of 92 women in the 3rd cycle.
  • It was thus possible to record reliable inhibition of ovulation in 97.85% on use of the administration regimen according to the invention.
  • At the same time, good tolerability is found on intake of the administration regimen according to the invention.
  • It is possible with the two use examples to record an adequate inhibition of ovulation of respectively 97.85% and 96.77%. Very recent investigations with conventional ovulation inhibitors by Pierson R A et al., “Ortho Evra/Evra versus oral contraceptives: follicular development . . . ”, Fertil. Steril. 80(1), pp. 34-42 (2003) demonstrate ovulation in a certain percentage even with products which have proved to be reliable and safe on wide use for a long time. In the second treatment cycle it was possible to observe ovulations for example with a three-phase levonorgestrel-containing oral contraceptive in 14% (3 of 22), with a monophasic levonorgestrel-containing oral contraceptive (6 of 25) and with a triphasic norgestimate-containing oral contraceptive in 16% (4 of 25). These values are distinctly above those for the products according to the invention, so that a higher reliability can be expected with these compared with Pierson et al.

Claims (2)

  1. 1. Multiphase product for contraception based on a natural oestrogen with a synthetic progestogen characterized in that the first phase consists of 2 daily dose units of 3 mg of the natural oestrogen oestradiol valerate,
    a second phase consists of 2 groups of daily dose units, where the first group is formed by 5 daily dose units of a combination of 2 mg of oestradiol valerate and at least twice or three times the ovulation-inhibitory dose of a synthetic progestogen,
    and the second group is formed by 17 daily dose units of a combination of 2 mg of oestradiol valerate and at least three times or four times the ovulation-inhibitory dose of a synthetic progestogen,
    a third phase consists of 2 daily dose units with 1 mg of oestradiol valerate,
    and a further phase consists of 2 daily dose units of pharmaceutically acceptable placebo.
  2. 2. Multiphase product according to claim 1, characterized in that the synthetic progestational active ingredient is dienogest, drospirenone or a progestogen at at least twice its known ovulation-inhibitory dose.
US13020913 2004-04-20 2011-02-04 Multi-phase contraceptive preparation based on a natural estrogen Abandoned US20110124612A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
DE102004019743.1 2004-04-20
DE200410019743 DE102004019743B4 (en) 2004-04-20 2004-04-20 Multiphase product for contraception based on a natural estrogen
PCT/EP2005/004022 WO2005102247A3 (en) 2004-04-20 2005-04-15 Multi-phase contraceptive preparation based on a natural estrogen
US57877107 true 2007-06-27 2007-06-27
US12726799 US20100173877A1 (en) 2004-04-20 2010-03-18 Multi-phase contraceptive preparation based on a natural estrogen
US13020913 US20110124612A1 (en) 2004-04-20 2011-02-04 Multi-phase contraceptive preparation based on a natural estrogen

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US13020913 US20110124612A1 (en) 2004-04-20 2011-02-04 Multi-phase contraceptive preparation based on a natural estrogen

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US12726799 Continuation US20100173877A1 (en) 2004-04-20 2010-03-18 Multi-phase contraceptive preparation based on a natural estrogen

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US20110124612A1 true true US20110124612A1 (en) 2011-05-26

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US11578771 Active 2026-05-13 US8071577B2 (en) 2004-04-20 2005-04-15 Multi-phase contraceptive preparation based on a natural estrogen
US12726799 Abandoned US20100173877A1 (en) 2004-04-20 2010-03-18 Multi-phase contraceptive preparation based on a natural estrogen
US13020913 Abandoned US20110124612A1 (en) 2004-04-20 2011-02-04 Multi-phase contraceptive preparation based on a natural estrogen

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US12726799 Abandoned US20100173877A1 (en) 2004-04-20 2010-03-18 Multi-phase contraceptive preparation based on a natural estrogen

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US (3) US8071577B2 (en)
EP (1) EP1740163B1 (en)
JP (1) JP4908399B2 (en)
KR (1) KR20060134168A (en)
CN (1) CN1946383B (en)
CA (1) CA2561839C (en)
DE (2) DE102004019743B4 (en)
DK (1) DK1740163T3 (en)
ES (1) ES2348038T3 (en)
WO (1) WO2005102247A3 (en)

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DE102004019743B4 (en) 2004-04-20 2008-11-27 Bayer Schering Pharma Aktiengesellschaft Multiphase product for contraception based on a natural estrogen
ES2322479T3 (en) * 2005-10-13 2009-06-22 Bayer Schering Pharma Aktiengesellschaft Use of estradiol valerate in combination with dienogest for oral therapy of dysfunctional uterine bleeding, in conjunction with an oral contraception.
US8153616B2 (en) 2005-10-17 2012-04-10 Bayer Pharma Aktiengesellschaft Combination preparation for oral contraception and oral therapy of dysfunctional uterine bleeding containing estradiol valerate and dienogest and method of using same
EP1993531B1 (en) 2006-03-02 2015-10-14 Warner Chilcott Company, LLC Extended cycle multiphasic oral contraceptive method
DE102006010329A1 (en) * 2006-03-06 2007-09-13 Höltge, Michael, Dipl.-Med. Hormonal contraceptive, comprises combination preparation of testosterone, gestogen, and esterogen, in the form of single, double or multi-phase preparation
EP1930010A1 (en) * 2006-10-20 2008-06-11 Bayer Schering Pharma Aktiengesellschaft Application of estradiol valerate or 17ß-estradiol in combination with dienogest for oral therapy to maintain and/or increase the female libido
US20090117183A1 (en) * 2007-11-05 2009-05-07 Sabine Fricke Oral contraceptive containing a gestagen and an estrogen combined with pharmaceutically acceptable auxiliary agents and/or excipients, but not containing lactose, and method of making same

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ES2348038T3 (en) 2010-11-29 grant
WO2005102247A3 (en) 2006-01-12 application
EP1740163A2 (en) 2007-01-10 application
WO2005102247A2 (en) 2005-11-03 application
DE502005009904D1 (en) 2010-08-26 grant
DK1740163T3 (en) 2010-10-18 grant
CN1946383A (en) 2007-04-11 application
KR20060134168A (en) 2006-12-27 application
DE102004019743B4 (en) 2008-11-27 grant
EP1740163B1 (en) 2010-07-14 grant
CA2561839C (en) 2009-09-29 grant
JP2007533681A (en) 2007-11-22 application
US20100173877A1 (en) 2010-07-08 application
CN1946383B (en) 2010-06-09 grant
JP4908399B2 (en) 2012-04-04 grant
DE102004019743A1 (en) 2005-11-24 application
CA2561839A1 (en) 2005-11-03 application
US8071577B2 (en) 2011-12-06 grant
US20070259840A1 (en) 2007-11-08 application

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