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FR2791572A1 - Treating undesirable uterine bleeding, e.g. as side-effect of hormone therapy, by intranasal administration of estradiol - Google Patents

Treating undesirable uterine bleeding, e.g. as side-effect of hormone therapy, by intranasal administration of estradiol Download PDF

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Publication number
FR2791572A1
FR2791572A1 FR9904022A FR9904022A FR2791572A1 FR 2791572 A1 FR2791572 A1 FR 2791572A1 FR 9904022 A FR9904022 A FR 9904022A FR 9904022 A FR9904022 A FR 9904022A FR 2791572 A1 FR2791572 A1 FR 2791572A1
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Prior art keywords
estradiol
use according
nasal
cyclodextrin
composition
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Withdrawn
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FR9904022A
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French (fr)
Inventor
Yannis Tsouderos
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ADIR SARL
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ADIR SARL
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Priority to FR9904022A priority Critical patent/FR2791572A1/en
Priority to EP00915247A priority patent/EP1143978A2/en
Priority to PL00356767A priority patent/PL356767A1/en
Priority to NZ513672A priority patent/NZ513672A/en
Priority to KR1020017011124A priority patent/KR20010102464A/en
Priority to JP2000609012A priority patent/JP2002541076A/en
Priority to EA200100801A priority patent/EA200100801A1/en
Priority to HU0200244A priority patent/HUP0200244A3/en
Priority to CA002361885A priority patent/CA2361885A1/en
Priority to PCT/FR2000/000790 priority patent/WO2000059447A2/en
Priority to AU36623/00A priority patent/AU3662300A/en
Priority to CN00804471A priority patent/CN1346273A/en
Priority to BR0008577-4A priority patent/BR0008577A/en
Publication of FR2791572A1 publication Critical patent/FR2791572A1/en
Priority to ZA200106689A priority patent/ZA200106689B/en
Priority to NO20014022A priority patent/NO20014022D0/en
Priority to HK02106208.3A priority patent/HK1044486A1/en
Withdrawn legal-status Critical Current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
    • A61K31/568—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61K31/565—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
    • A61K31/568—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Otolaryngology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (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)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)

Abstract

The use of estradiol (I) is claimed for the preparation of an intranasally administered pharmaceutical composition for treating undesirable uterine bleeding. An Independent claim is included for a composition for use as above, in the form of an aqueous solution containing (I) (optionally as a mixture with a progestogen) and a partially and randomly methylated cyclodextrin.

Description

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La présente invention concerne l'utilisation d'hormones sexuelles pour l'obtention d'une composition pharmaceutique convenant pour l'administration par voie nasale utile au  The present invention relates to the use of sex hormones for obtaining a pharmaceutical composition suitable for nasal administration useful for

traitement des phénomènes de saignements utérins indésirables chez la femme.  treatment of undesirable uterine bleeding phenomena in women.

Lors des thérapies nécessitant l'administration d'hormones sexuelles, il est très fréquemment observé des saignements utérins en dehors des périodes normales prévues. Les hormones sexuelles peuvent être administrées dans le traitement des maladies dues à des carences oestrogéniques et à des symptômes de déficit en oestrogènes notamment liés à la ménopause artificielle ou naturelle. Ces carences oestrogéniques sont également impliquées dans la survenue de l'ostéoporose post-ménopausique ainsi que lors de  During therapies requiring the administration of sex hormones, uterine bleeding is very frequently observed outside of the normal scheduled periods. Sex hormones can be administered in the treatment of diseases due to estrogen deficiencies and to symptoms of estrogen deficiency, notably linked to artificial or natural menopause. These estrogen deficiencies are also implicated in the occurrence of postmenopausal osteoporosis as well as during

phénomènes de vieillissement cérébral et de maladies cardiovasculaires.  phenomena of cerebral aging and cardiovascular diseases.

D'autre part, les hormones sexuelles sont également administrées, à des doses différentes, à  On the other hand, sex hormones are also administered, in different doses, to

des fins contraceptives ou dans le traitement des aménorrhées non liées à la ménopause.  for contraceptive purposes or in the treatment of amenorrhea not related to menopause.

Les compositions pharmaceutiques contenant des hormones sexuelles actuellement à la disposition du corps médical sont des compositions convenant pour l'administration par voie orale (comprimés), transcutanée (gels, systèmes transdermiques), parenterale  The pharmaceutical compositions containing sex hormones currently available to the medical profession are compositions suitable for oral administration (tablets), transcutaneous administration (gels, transdermal systems), parenteral

(injections intramusculaires, implants) ou par voie vaginale (crèmes, gels,...).  (intramuscular injections, implants) or vaginally (creams, gels, ...).

Ces différents types de thérapies provoquent dans un certain nombre de cas des saignements utérins, de manière épisodique ou systématique en dehors des périodes de menstruations prévues. La gêne occasionnée par ces phénomènes de saignements est telle qu'elle provoque des inquiétudes chez les patientes qui ne peuvent faire elles-mêmes la  These different types of therapies provoke in a certain number of cases uterine bleeding, in an episodic or systematic way outside the periods of menstruation planned. The discomfort caused by these bleeding phenomena is such that it causes concern in patients who cannot do the work themselves.

différence entre un effet secondaire lié au traitement et la survenue d'une affection utérine.  difference between a treatment-related side effect and the occurrence of a uterine condition.

De tels phénomènes conduisent, le médecin traitant à demander des examens  Such phenomena lead, the attending physician to request examinations

complémentaires de plusieurs types afin de déterminer la cause de ces saignements.  of several types to determine the cause of this bleeding.

Lorsque ceux-ci sont simplement liés au traitement, les patientes souhaitent alors se  When these are simply linked to the treatment, the patients then wish to

tourner vers d'autres types de thérapies ou préfèrent arrêter le traitement.  turn to other types of therapies or prefer to stop treatment.

Les saignements apparaissent ainsi comme l'une des causes principales d'abandon des traitements.  Bleeding thus appears to be one of the main causes of treatment dropout.

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Actuellement, tous les types de traitements disponibles conduisent à des difficultés de compliance qui n'ont jusqu'à présent été qu'en parties améliorées par les formes  Currently, all types of treatment available lead to compliance difficulties which have so far only been partially improved by the forms

pharmaceutiques actuellement disponibles.  pharmaceutical products currently available.

La demanderesse a présentement découvert que l'utilisation des hormones sexuelles pour l'obtention d'une composition pharmaceutique convenant pour l'administration par voie nasale permettait de façon surprenante de traiter les saignements utérins observés en dehors des périodes menstruelles. Cet effet surprenant obtenu par voie nasale n'a jamais été  The Applicant has now discovered that the use of sex hormones to obtain a pharmaceutical composition suitable for administration by the nasal route surprisingly makes it possible to treat uterine bleeding observed outside of menstrual periods. This surprising effect obtained by nasal route has never been

observé avec les autres formulations actuellement à la disposition du corps médical.  observed with the other formulations currently available to the medical profession.

Cette amélioration est d'autant plus importante et intéressante qu'elle montre son efficacité  This improvement is all the more important and interesting as it shows its effectiveness

à long terme. Les traitements pouvant, en effet, se prolonger pendant plusieurs années.  long-term. The treatments can, in fact, be prolonged for several years.

Parmi les hormones sexuelles utilisables dans les compositions pharmaceutiques selon l'invention, on peut citer à titre non limitatif les oestrogènes stéroidiens naturels comme le 1 7-3-oestradiol (estradiol), l'oestrone et leurs dérivés, les estrogènes stéroïdiens de synthèse comme l'éthinylestradiol, les progestatifs comme la progestérone, les pregnanes dérivés de la progestérone ou de la 17- ca-OH-progestérone comme la dydrogestérone, l'acétate de chlormadinone, la médrogestérone, l'acétate de médroxyprogestérone, les norpregnanes  Among the sex hormones which can be used in the pharmaceutical compositions according to the invention, mention may be made, without limitation, of natural steroidal estrogens such as 1-7-3-estradiol (estradiol), estrone and their derivatives, synthetic steroidal estrogens such as ethinylestradiol, progestins like progesterone, pregnanes derived from progesterone or 17-ca-OH-progesterone like dydrogesterone, chlormadinone acetate, medrogesterone, medroxyprogesterone acetate, norpregnanes

comme la démégestone, la promégestone, l'acétate de nomégestrol ou les dérivés de la 19-  such as demegestone, promegestone, nomegestrol acetate or 19- derivatives

nortestostérone, comme la noréthistérone, la diacétate d'éthynodiol, le norgestrel, le lévonorgestrel, le désogestrel, le gestodène ou le norgestimate, ou les antrogènes comme la  nortestosterone, such as norethisterone, ethynodiol diacetate, norgestrel, levonorgestrel, desogestrel, gestodene or norgestimate, or antrogens such as

testostérone ou la dihydrotestostérone.  testosterone or dihydrotestosterone.

Les hormones sexuelles préférées selon l'invention sont l'estradiol ou les mélanges estradiol/progestatif Plus spécifiquement, les compositions pharmaceutiques convenant pour l'administration par voie nasale d'hormones sexuelles sont celles qui contiennent une ou plusieurs hormones sexuelles à des doses variant en fonction des besoins de la patiente et une cyclodextrine.  The preferred sex hormones according to the invention are estradiol or estradiol / progestogen mixtures More specifically, the pharmaceutical compositions suitable for the nasal administration of sex hormones are those which contain one or more sex hormones at doses varying in according to the needs of the patient and a cyclodextrin.

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De manière préférentielle, les compositions pharmaceutiques selon l'invention sont  Preferably, the pharmaceutical compositions according to the invention are

caractérisées en ce que la cyclodextrine est une cyclodextrine partiellement méthylée.  characterized in that the cyclodextrin is a partially methylated cyclodextrin.

Une composition préférée selon l'invention est une composition contenant de l'estradiol ou un mélange estradiol/progestatif et une cyclodextrine méthylée partiellement et de manière randomisée.  A preferred composition according to the invention is a composition containing estradiol or an estradiol / progestin mixture and a partially and randomly methylated cyclodextrin.

Lorsque la composition contient un progestatif, le progestatif préféré est la noréthistérone.  When the composition contains a progestin, the preferred progestin is norethisterone.

L'utilisation, selon l'invention, des compositions pharmaceutiques est préférée pour traiter  The use, according to the invention, of pharmaceutical compositions is preferred for treating

les saignements utérins indésirables au cours de la ménopause.  unwanted uterine bleeding during menopause.

A titre d'exemple, non limitatif, une composition pharmaceutique convenant pour l'administration par voie nasale d'estradiol a été préparée et testée en clinique dans le but d'observer le traitement des phénomènes de saignements utérins chez des femmes ménopausées. Cette composition est une solution contenant 0,21 g d'hémihydrate d'estradiol, 2,10 g de cyclodextrine méthylée partiellement et randomisée, 0,9 g de chlorure de sodium et de  By way of non-limiting example, a pharmaceutical composition suitable for nasal administration of estradiol has been prepared and clinically tested with the aim of observing the treatment of phenomena of uterine bleeding in postmenopausal women. This composition is a solution containing 0.21 g of estradiol hemihydrate, 2.10 g of partially randomized methylated cyclodextrin, 0.9 g of sodium chloride and

l'eau purifiée (q.s.p. 100 ml) après ajustage du pH de la solution à 6.  purified water (q.s.p. 100 ml) after adjusting the pH of the solution to 6.

Cette solution a été conditionnée dans un flacon muni d'une pompe doseuse permettant d'obtenir des pulvérisations nasales de 0,07 ml. Chaque pulvérisation délivre alors une  This solution was packaged in a bottle fitted with a dosing pump to obtain 0.07 ml nasal sprays. Each spray then delivers a

dose de 150 pig d'hémihydrate d'estradiol.  dose of 150 pig of estradiol hemihydrate.

Etudes cliniques: Des études cliniques ont été réalisées sur une population de patientes post-ménopausées  Clinical studies: Clinical studies have been performed on a population of post-menopausal patients

depuis moins de 10 ans.for less than 10 years.

Ces patientes ont été réparties en groupes recevant, durant un cycle de 28 jours soit - soit, une composition nasale d'estradiol du type de celle décrite plus haut (spray d'estradiol) et une composition orale placebo  These patients were divided into groups receiving, during a 28-day cycle either - or, a nasal composition of estradiol of the type described above (estradiol spray) and an oral placebo composition

-4 - 2791572-4 - 2791572

- soit, une formulation orale d'estradiol et une composition nasale placebo (spray placebo). Dans chaque groupe, les malades ont reçu un progestatif, au moins pendant 10 à 14 jours  - either, an oral formulation of estradiol and a placebo nasal composition (placebo spray). In each group, patients received progestin, at least for 10-14 days

par cycle aux doses recommandées pour chaque produit.  per cycle at the doses recommended for each product.

Les traitements ont été attribués selon un code de randomisation, et ont duré 3, 6 ou  Treatments were allocated according to a randomization code, and lasted 3, 6 or

12 mois.12 months.

La dose quotidienne administrée pour la forme spray nasal est de 300 pg d'estradiol (2 pulvérisations par jour) correspondant à une dose de 2 mg lorsque l'administration est  The daily dose administered for the nasal spray form is 300 pg of estradiol (2 sprays per day) corresponding to a dose of 2 mg when the administration is

effectuée par voie orale.performed orally.

l0 Résultats Il a été observé, lors de ces études cliniques, que chez les patientes du groupe traitées par le spray nasal d'estradiol les saignements utérins étaient environ 30 % moins fréquents que  10 Results In these clinical studies, it was observed that in patients in the group treated with estradiol nasal spray uterine bleeding was about 30% less frequent than

chez les patientes traitées par une forme orale d'estradiol.  in patients treated with an oral form of estradiol.

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Claims (7)

RevendicationsClaims 1/ Utilisation d'hormones sexuelles pour l'obtention d'une composition pharmaceutique convenant pour l'administration par voie nasale pour traiter les phénomènes de  1 / Use of sex hormones to obtain a pharmaceutical composition suitable for administration by the nasal route to treat the phenomena of saignements utérins indésirables chez la femme.  Unwanted uterine bleeding in women. 2/ Utilisation selon la revendication I caractérisée en ce que les hormones sexuelles sont l'estradiol ou un mélange estradiol/progestatif 3/ Utilisation selon la revendication I caractérisée en ce que l'hormone sexuelle est l'oestradiol. 4/ Utilisation selon la revendication I caractérisée en ce que les hormones sexuelles sont un mélange oestradiol/progestatif / Utilisation selon la revendication 4 caractérisée en ce que le progestatif est un dérivé  2 / Use according to claim I characterized in that the sex hormones are estradiol or a mixture of estradiol / progestogen 3 / Use according to claim I characterized in that the sex hormone is estradiol. 4 / Use according to Claim I, characterized in that the sex hormones are an estradiol / progestin mixture / Use according to Claim 4, characterized in that the progestogen is a derivative de la I 9-nortestostérone.of I 9-nortestosterone. 6/ Utilisation selon la revendication 5 caractérisée en ce que le progestatif est la noréthistérone. 7/ Utilisation selon la revendication 1 caractérisée en ce que la composition convenant  6 / Use according to claim 5 characterized in that the progestogen is norethisterone. 7 / Use according to claim 1 characterized in that the composition suitable pour l'administration nasale contient une hormone sexuelle et une cyclodextrine.  for nasal administration contains a sex hormone and a cyclodextrin. 8/ Utilisation selon la revendication 7 caractérisée en ce que la cyclodextrine contenue  8 / Use according to claim 7 characterized in that the cyclodextrin contained dans la composition nasale est une cyclodextrine méthylée partiellement.  in the nasal composition is a partially methylated cyclodextrin. 9/ Utilisation selon la revendication 8 caractérisée en ce que la cyclodextrine méthylée partiellement contenue dans la composition nasale est méthylée de manière randomisee.  9 / Use according to claim 8 characterized in that the methylated cyclodextrin partially contained in the nasal composition is methylated randomly. -6 - 2791572-6 - 2791572 / Utilisation selon l'une quelconque des revendications 7, 8 ou 9 caractérisée en ce que  / Use according to any one of claims 7, 8 or 9 characterized in that l'hormone sexuelle contenue dans la composition nasale est de l'estradiol.  the sex hormone contained in the nasal composition is estradiol. 11/ Utilisation selon l'une quelconque des revendications 7, 8, 9 ou 10 caractérisée en ce  11 / Use according to any one of claims 7, 8, 9 or 10 characterized in that que la composition nasale contient également un progestatif 12/ Composition pharmaceutique convenant pour l'administration par voie nasale selon  that the nasal composition also contains a progestogen 12 / Pharmaceutical composition suitable for administration by the nasal route according to l'une quelconque des revendications 1, 2, 3 ou 4 caractérisée en ce qu'elle se présente  any one of claims 1, 2, 3 or 4 characterized in that it is sous la forme d'une solution aqueuse contenant de l'estradiol ou un mélange  in the form of an aqueous solution containing estradiol or a mixture estradiol/progestatif et une cyclodextrine méthylée partiellement et randomisée.  estradiol / progestin and a partially randomized methylated cyclodextrin. 13/ Composition pharmaceutique selon la revendication 12 caractérisée en ce qu'elle contient 0,21 g d'estradiol, 2,10 g de cyclodextrine méthylée partiellement et randomisée, 0,9 g de chlorure de sodium pour une quantité d'eau purifiée suffisante pour obtenir un volume total de solution de 100 ml, le pH de ladite solution ayant été  13 / A pharmaceutical composition according to claim 12 characterized in that it contains 0.21 g of estradiol, 2.10 g of partially randomized methylated cyclodextrin, 0.9 g of sodium chloride for a sufficient quantity of purified water to obtain a total volume of solution of 100 ml, the pH of said solution having been ajusté à 6.adjusted to 6.
FR9904022A 1999-03-31 1999-03-31 Treating undesirable uterine bleeding, e.g. as side-effect of hormone therapy, by intranasal administration of estradiol Withdrawn FR2791572A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
FR9904022A FR2791572A1 (en) 1999-03-31 1999-03-31 Treating undesirable uterine bleeding, e.g. as side-effect of hormone therapy, by intranasal administration of estradiol
HU0200244A HUP0200244A3 (en) 1999-03-31 2000-03-30 Use of sex hormones for producing nasal pharmaceutical compositions useful in the treatment of undesirable uterine bleeding
AU36623/00A AU3662300A (en) 1999-03-31 2000-03-30 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding
NZ513672A NZ513672A (en) 1999-03-31 2000-03-30 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding
KR1020017011124A KR20010102464A (en) 1999-03-31 2000-03-30 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding
JP2000609012A JP2002541076A (en) 1999-03-31 2000-03-30 Use of Sex Hormones to Obtain Nasal Pharmaceutical Compositions Useful for the Treatment of Undesired Uterine Bleeding
EA200100801A EA200100801A1 (en) 1999-03-31 2000-03-30 THE APPLICATION OF SEXUAL HORMONES IN THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR NAZAL INTRODUCTION INTENDED FOR THE TREATMENT OF UNDESIRABLE Uterine BLEEDING
EP00915247A EP1143978A2 (en) 1999-03-31 2000-03-30 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding
CA002361885A CA2361885A1 (en) 1999-03-31 2000-03-30 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding
PCT/FR2000/000790 WO2000059447A2 (en) 1999-03-31 2000-03-30 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding
PL00356767A PL356767A1 (en) 1999-03-31 2000-03-30 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding
CN00804471A CN1346273A (en) 1999-03-31 2000-03-30 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding
BR0008577-4A BR0008577A (en) 1999-03-31 2000-03-30 Use of sex hormones to obtain a nasal pharmaceutical composition useful for treating unwanted uterine bleeding
ZA200106689A ZA200106689B (en) 1999-03-31 2001-08-14 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding.
NO20014022A NO20014022D0 (en) 1999-03-31 2001-08-17 Use of sex hormones to obtain a nasal pharmaceutical composition useful in the treatment of undesired uterine bleeding
HK02106208.3A HK1044486A1 (en) 1999-03-31 2002-08-23 Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR9904022A FR2791572A1 (en) 1999-03-31 1999-03-31 Treating undesirable uterine bleeding, e.g. as side-effect of hormone therapy, by intranasal administration of estradiol

Publications (1)

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FR2791572A1 true FR2791572A1 (en) 2000-10-06

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FR9904022A Withdrawn FR2791572A1 (en) 1999-03-31 1999-03-31 Treating undesirable uterine bleeding, e.g. as side-effect of hormone therapy, by intranasal administration of estradiol

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EP0349091A1 (en) * 1988-07-01 1990-01-03 Walter Adrianus Josephus Johannes Hermens Pharmaceutical composition
WO1997046574A1 (en) * 1996-06-07 1997-12-11 Pherin Corporation 19-nor-cholane steroids as neurochemical initiators of change in human hypothalamic function
WO1998003207A1 (en) * 1996-07-23 1998-01-29 Pherin Pharmaceuticals, Inc. Steroids as neurochemical stimulators of the vno to alleviate symptoms of pms and anxiety

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US4383993A (en) * 1980-05-30 1983-05-17 University Of Kentucky Research Foundation Nasal dosage forms containing natural female sex hormones

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EP0349091A1 (en) * 1988-07-01 1990-01-03 Walter Adrianus Josephus Johannes Hermens Pharmaceutical composition
WO1997046574A1 (en) * 1996-06-07 1997-12-11 Pherin Corporation 19-nor-cholane steroids as neurochemical initiators of change in human hypothalamic function
WO1998003207A1 (en) * 1996-07-23 1998-01-29 Pherin Pharmaceuticals, Inc. Steroids as neurochemical stimulators of the vno to alleviate symptoms of pms and anxiety

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BAYER S.R. ET AL: "Clinical manifestations and treatment of dysfunctional uterine bleeding.", JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, (1993) 269/14 (1823-1828)., XP000856624 *
BRENNER, PAUL F. ET AL: "Ovulation inhibition with nafarelin acetate nasal administration for six months", CONTRACEPTION (1985), 32(6), 531-51, XP000856801 *
BRUN J.L.: "[Management of uterine bleeding in 1994]. LE POINT SUR LE TRAITEMENT DES MENOMETRORRAGIES EN 1994.", CONTRACEPTION FERTILITE SEXUALITE, (1994) 22/3 (147-151)., XP000856625 *
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NO20014022L (en) 2001-08-17
EP1143978A2 (en) 2001-10-17
KR20010102464A (en) 2001-11-15
EA200100801A1 (en) 2002-04-25
HK1044486A1 (en) 2002-10-25
CA2361885A1 (en) 2000-10-12
WO2000059447A2 (en) 2000-10-12
WO2000059447A3 (en) 2001-04-26
CN1346273A (en) 2002-04-24
HUP0200244A3 (en) 2003-05-28
JP2002541076A (en) 2002-12-03
NO20014022D0 (en) 2001-08-17
AU3662300A (en) 2000-10-23
PL356767A1 (en) 2004-07-12
BR0008577A (en) 2002-10-01
HUP0200244A2 (en) 2002-07-29
ZA200106689B (en) 2002-11-14

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