US20100173877A1 - 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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US20100173877A1
US20100173877A1 US12/726,799 US72679910A US2010173877A1 US 20100173877 A1 US20100173877 A1 US 20100173877A1 US 72679910 A US72679910 A US 72679910A US 2010173877 A1 US2010173877 A1 US 2010173877A1
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daily dose
dose units
ovulation
oestradiol valerate
dienogest
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US12/726,799
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Jan Endrikat
Bernd Duesterberg
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Priority to US12/726,799 priority Critical patent/US20100173877A1/en
Publication of US20100173877A1 publication Critical patent/US20100173877A1/en
Priority to US13/020,913 priority patent/US20110124612A1/en
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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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P15/18—Feminine contraceptives
    • 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

Definitions

  • the invention relates to a multiphase product for contraception based on a natural oestrogen with a synthetic progestogen.
  • 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.
  • 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 2 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.
  • 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.
  • 3 daily dose units of 3 mg of oestradiol valerate 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the invention is to be demonstrated by some examples of use.
  • the contraceptive reliability in particular the cyclic bleeding behaviour of the woman, and the tolerability of the administration regimen is demonstrated.
  • the contraceptive reliability was demonstrated in principle by determining the Hoogland score which uses the follicle size, the oestradiol level and progesterone values.
  • 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.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Orthopedics, Nursing, And Contraception (AREA)
  • Steroid Compounds (AREA)
  • Compositions Of Macromolecular Compounds (AREA)

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 2 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 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), 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. 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. 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.
US12/726,799 2004-04-20 2010-03-18 Multi-phase contraceptive preparation based on a natural estrogen Abandoned US20100173877A1 (en)

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US12/726,799 US20100173877A1 (en) 2004-04-20 2010-03-18 Multi-phase contraceptive preparation based on a natural estrogen
US13/020,913 US20110124612A1 (en) 2004-04-20 2011-02-04 Multi-phase contraceptive preparation based on a natural estrogen

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE102004019743.1 2004-04-20
DE102004019743A DE102004019743B4 (en) 2004-04-20 2004-04-20 Multiphase preparation for contraception based on natural estrogen
PCT/EP2005/004022 WO2005102247A2 (en) 2004-04-20 2005-04-15 Multi-phase contraceptive preparation based on a natural estrogen
US57877107A 2007-06-27 2007-06-27
US12/726,799 US20100173877A1 (en) 2004-04-20 2010-03-18 Multi-phase contraceptive preparation based on a natural estrogen

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PCT/EP2005/004022 Continuation WO2005102247A2 (en) 2004-04-20 2005-04-15 Multi-phase contraceptive preparation based on a natural estrogen
US57877107A Continuation 2004-04-20 2007-06-27

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US11/578,771 Active 2026-05-13 US8071577B2 (en) 2004-04-20 2005-04-15 Multi-phase contraceptive preparation based on a natural estrogen
US12/726,799 Abandoned US20100173877A1 (en) 2004-04-20 2010-03-18 Multi-phase contraceptive preparation based on a natural estrogen
US13/020,913 Abandoned US20110124612A1 (en) 2004-04-20 2011-02-04 Multi-phase contraceptive preparation based on a natural estrogen

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US13/020,913 Abandoned US20110124612A1 (en) 2004-04-20 2011-02-04 Multi-phase contraceptive preparation based on a natural estrogen

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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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DE102004019743B4 (en) * 2004-04-20 2008-11-27 Bayer Schering Pharma Aktiengesellschaft Multiphase preparation for contraception based on natural estrogen
PT1787649E (en) * 2005-10-13 2009-05-08 Bayer Schering Pharma Ag Use of estradiolvalerate and dienogest for oral treatment of dysfunctional uterine bleeding in a contraceptive method
EP1937274B1 (en) * 2005-10-13 2012-02-22 Bayer Pharma Aktiengesellschaft Use of estradiol valerate combined with dienogest for oral therapy of dysfunctional uterine bleeding in the form of oral contraceptives
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
SG172654A1 (en) 2006-03-02 2011-07-28 Warner Chilcott Co 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
WO2012155091A1 (en) * 2011-05-11 2012-11-15 Kirax Corporation Package for improved treatment of conditions

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