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WO2006013464A1 - Thérapie de remplacement hormonal comprenant une combinaison de 17bêta-estradiol et d’acétate de chlormadinone - Google Patents

Thérapie de remplacement hormonal comprenant une combinaison de 17bêta-estradiol et d’acétate de chlormadinone Download PDF

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Publication number
WO2006013464A1
WO2006013464A1 PCT/IB2005/002506 IB2005002506W WO2006013464A1 WO 2006013464 A1 WO2006013464 A1 WO 2006013464A1 IB 2005002506 W IB2005002506 W IB 2005002506W WO 2006013464 A1 WO2006013464 A1 WO 2006013464A1
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WO
WIPO (PCT)
Prior art keywords
oestradiol
chlormadinone acetate
composition according
composition
combination
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/IB2005/002506
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English (en)
Inventor
Alain Munoz
Anthony Munoz
Jack Auzerie
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.)
AMISTAD PHARMA Sas
Original Assignee
AMISTAD PHARMA Sas
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
Application filed by AMISTAD PHARMA Sas filed Critical AMISTAD PHARMA Sas
Publication of WO2006013464A1 publication Critical patent/WO2006013464A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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 present invention relates to a hormone replacement therapy and in particular relates to a composition for limiting the effects induced during the menopause and subsequently.
  • the invention also relates to the treatment of menopausal women using this composition.
  • the majority of the current treatments are recommended as therapy for symptomatic disorders rather than being recommended as a long-term treatment to improve the quality of the ageing process.
  • the majority of women would prefer a hormone treatment that does not result in the return of their periods. In particular this is critical if the treatment is envisaged as a long-term therapy of greater than 3 years duration.
  • Prior art treatments suffer from numerous disadvantages, including low efficacy in 20 controlling unwanted bleeding, the irregularity of these bleeding episodes, undesirable side-effects such as weight gain, endometrial hyperplasia and proliferation and inability to take account of variability between patients and variability within the same patient over time. As a result, patient tolerability is not high, making the therapy ineffective, particularly when assessed in a population. 25
  • progestative agents by their nature as norsteroids, pose problems of carbohydrate tolerance, virilization and even involvement in carcinogenesis. The induced effects are also problematic in certain cases: weight gain, drowsiness or digestive disorders. Moreover high doses of progestative agents block the uterine mucosal hyperplasia.
  • WO 96/10991 discloses a pharmaceutical composition for transmucal administration, the composition being an oil-in-water emulsion containing, dissolved in the dispersed oil phase, 17B-estradiol together with a progestin.
  • EP 968 717 discloses a preparation directed towards limiting the effects induced during the menopause and subsequently, without periods, characterised in that it comprises, in combination, 17B-oestradiol and chlormadinone acetate.
  • the present invention provides a composition for limiting the effects induced during the menopause and subsequently, without the onset of periods, characterised in that it comprises, in combination, from about 0.5 to about 1 mg of 17 ⁇ -oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.
  • the present invention also provides a method of treating menopausal women and post- menopausal women, without the onset of periods, with a composition comprising, in combination, from about 0.5 to about 1 mg of 17 ⁇ -oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.
  • the present invention also provides a use of a composition comprising, in combination, from about 0.5 to about 1 mg of 17B-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate for the manufacture of a medicament for treating menopausal women and post-menopausal women, without the onset of periods.
  • the present invention also provides a kit adapted for use during one month for limiting the effects induced during the menopause and subsequently, without the onset of periods, characterised in that it consists of from 21 to 31 sequential daily doses, wherein each daily dose comprises, in combination, from about 0.5 to about 1 mg of 17B-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.
  • the present invention provides a composition for limiting the effects induced during the menopause and subsequently, without the onset of periods, characterised in that it comprises, in combination, from about 0.5 to about 1 mg of 17 ⁇ -oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.
  • the composition comprises, in combination, from about 0.5 to about 0.9 mg of 17 ⁇ -oestradiol and from about 0.5 to about 0.9 mg chlormadinone acetate.
  • Suitable preferred compositions comprise about 0.5 mg 17 ⁇ -oestradiol and about 0.5 mg chlormadinone acetate, or comprise about 1 mg 17B-oestradiol and about 1 mg chlormadinone acetate, or comprise about 0.5 mg 17 ⁇ -oestradiol and from about 0.5 mg to about 1 mg chlormadinone acetate, most preferably about 0.5 mg 17 ⁇ -oestradiol and about 0.9 mg chlormadinone acetate.
  • the dosage comprises equal parts of the two products and more particularly 0.5 mg 17 ⁇ -oestradiol and 0.5 mg chlormadinone acetate, or 1 mg 17 ⁇ - oestradiol and 1 mg chlormadinone acetate, or 0.9 mg 17 ⁇ -oestradiol and 0.9 mg chlormadinone acetate.
  • the dosage comprises less 17 ⁇ -oestradiol compared to chlormadinone acetate.
  • the 17 ⁇ -oestradiol is preferably in micronized form.
  • the composition is provided in the form of a tablet.
  • the tablet may optionally be splittable to allow a half dosage.
  • AU that is needed is to split the tablet in two and take only half. It is an advantage that it is possible to check immediately whether the dose taken is a whole or half dose.
  • the present invention also provides a method of treating menopausal women and post ⁇ menopausal women, without the onset of periods, with a composition comprising, in combination, from about 0.5 to about 1 mg of 17 ⁇ -oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.
  • the present invention also provides a use of a composition comprising, in combination, from about 0.5 to about 1 mg of 17 ⁇ -oestradiol and from about 0.5 to about 1 mg chlormadinone acetate for the manufacture of a medicament for treating menopausal women and post-menopausal women, without the onset of periods.
  • the treatment comprises use of a composition comprising, in combination, from about 0.5 to about 0.9 mg of 17 ⁇ -oestradiol and from about 0.5 to about 0.9 mg chlormadinone acetate.
  • the treatment of menopausal and post-menopausal women consists in administering to a patient half to one tablet per day for from 21 to 31 days of a month, preferably from 23 to 27 days of the month, most preferably 25 days, followed by a break of from 3 to 7 days, preferably from 5 to 7 days.
  • the product is preferably packaged in a presentation box that contains from 21 to 31 tablets, preferably 25 tablets, providing treatment for 1 month. This very simple presentation is easy to use, even for the elderly.
  • the product provided is suitable for long-term treatment.
  • the doses are lower compared to existing therapies.
  • a single daily dose is required. This has many advantages including the fact that the need to manage a pill box is avoided.
  • the claimed invention possesses significant advantages over these prior art compositions. Principal among these are as follows.
  • the patient's metabolic profile is good; specifically no change in glucose blood levels occurred during a one year clinical trial. 6) There is no change in body weight;
  • Bleeding profiles are very satisfying — there is a low abundance of bleeding episodes and any bleeding that does occur is cyclic and thus predictable;
  • the splittable aspect of one preferred embodiment of the invention allows modulation of the estradiol intake and in rum the estrogenic effect, which can not only vary from patient to patient, but can vary with time in the same patient. This flexibility contributes to the product's acceptability.
  • composition of the present invention by menopausal and post-menopausal women results in cyclic bleeding pattern and low abundance of bleeding episodes before the state of amenorrhea. This makes the preparation extremely desirable to women who would, in the absence of hormone replacement therapy, be experiencing anarchic bleedings.
  • existing combined continuous hormone replacement therapy treatments have the problem that bleeding episodes are quite frequent and irregular. The irregularity of bleeding in the treatments of the prior art is particularly unacceptable to women.
  • any bleeding that occurs when taking the composition of the present invention prior to the onset of amenorrhea is cyclical and, therefore, may be easily predicted by the patient, which makes the treatment far more acceptable compared to the treatments of the prior art.
  • a Phase III clinical trial was conducted in post-menopausal women for the orally administered Continuelle® product. All participants in the trial signed a confidentiality agreement. All unused tablets were returned. A whole tablet of the product contained 2mg of 17 ⁇ -oestradiol and 2 mg chlormadinone acetate.
  • the trial was conducted over the course of 1 year.
  • the therapeutic regimen followed was either 1 or 0.5 tablet per day from day 1 to day 25 followed by a 5 to 6 day therapeutic window during each calendar month for a twelve month period.
  • the tablet being breakable, the patients were allowed to decrease from 1 tablet daily to half a tablet daily according to their climacteric symptoms under the investigators' supervision. Whenever a half tablet dosage was adopted, this had to be maintained until the end of the trial.
  • a mammography was done at selection if none had been performed or was fully documented in the patient's file within the previous year. Estrogen impregnation was measured at enrolment from vaginal smears. This was repeated under treatment at month 6 and/or month 12.
  • Transvaginal ultrasound measurement of endrometrial thickness was done at inclusion and at month 6 (optional) and 12. A biopsy was performed on inclusion visit and last visit under treatment (between the 20th and 25th day of the therapeutic month).
  • the trial had a very low drop out rate with a total of 336 patients completing the trial. 72.6% of the patients were treated with 1 tablet a day and 27.4% treated with half a tablet a day. The switch to the half tablet a day was motivated by mastodynia and bleeding.
  • Table 1 shows the histological results on the final visit for all patients treated (336 women).
  • Atropic Endometrium 173 ( 70.9%) 64 ( 69.6%) 237 ( 70.5%)

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L’invention décrit une composition permettant de limiter les effets induits pendant et après la ménopause, sans délai d’action, caractérisée en ce qu’elle comprend, en combinaison, d’environ 0,5 à environ 1 mg de 17β-estradiol et d’environ 0,5 à environ 1 mg d’acétate de chlormadinone, de préférence d’environ 0,5 à environ 0,9 mg de 17β-estradiol et d’environ 0,5 à environ 0,9 mg d’acétate de chlormadinone. Est également décrit un procédé de traitement des femmes en période de ménopause et post-ménaupose par l’administration d’une composition selon l’invention. De plus, l’utilisation de la composition selon l’invention dans le traitement des effets induits pendant et après la ménopause, sans délai d’action, est prévue.
PCT/IB2005/002506 2004-07-27 2005-07-26 Thérapie de remplacement hormonal comprenant une combinaison de 17bêta-estradiol et d’acétate de chlormadinone Ceased WO2006013464A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US59129104P 2004-07-27 2004-07-27
US60/591,291 2004-07-27

Publications (1)

Publication Number Publication Date
WO2006013464A1 true WO2006013464A1 (fr) 2006-02-09

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/002506 Ceased WO2006013464A1 (fr) 2004-07-27 2005-07-26 Thérapie de remplacement hormonal comprenant une combinaison de 17bêta-estradiol et d’acétate de chlormadinone

Country Status (1)

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WO (1) WO2006013464A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008107099A1 (fr) * 2007-03-07 2008-09-12 Grünenthal GmbH Médicament contenant au moins un gestagène

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3409721A (en) * 1967-09-15 1968-11-05 Neomed Lab Inc Oral dosage system effective to control the reproduction cycle
US5633242A (en) * 1994-08-12 1997-05-27 Oettel; Michael Pharmaceuticals for contraception/hormone substitution containing a biogenous estrogen component
EP0968717A1 (fr) * 1998-06-02 2000-01-05 Investigations therapeutiques essais cliniques services société à Responsabilité Limitée Préparation sous forme galénique simple visant à limiter les effects induits durant la ménopause et postérieurement et traitement avec cette préparation
WO2000059577A1 (fr) * 1999-03-30 2000-10-12 Jencap Research Ltd. Hormonotherapie substitutive intermittente a base d'oestrogenes faiblement doses
US6500814B1 (en) * 1997-09-11 2002-12-31 Wyeth Pharmaceuticals Hormonal contraceptive

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3409721A (en) * 1967-09-15 1968-11-05 Neomed Lab Inc Oral dosage system effective to control the reproduction cycle
US5633242A (en) * 1994-08-12 1997-05-27 Oettel; Michael Pharmaceuticals for contraception/hormone substitution containing a biogenous estrogen component
US6500814B1 (en) * 1997-09-11 2002-12-31 Wyeth Pharmaceuticals Hormonal contraceptive
EP0968717A1 (fr) * 1998-06-02 2000-01-05 Investigations therapeutiques essais cliniques services société à Responsabilité Limitée Préparation sous forme galénique simple visant à limiter les effects induits durant la ménopause et postérieurement et traitement avec cette préparation
WO2000059577A1 (fr) * 1999-03-30 2000-10-12 Jencap Research Ltd. Hormonotherapie substitutive intermittente a base d'oestrogenes faiblement doses

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008107099A1 (fr) * 2007-03-07 2008-09-12 Grünenthal GmbH Médicament contenant au moins un gestagène
US8361995B2 (en) 2007-03-07 2013-01-29 Richter Gedeon Nyrt. Drug comprising at least one gestagen

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