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WO1996010991A1 - Composition pharmaceutique contenant des hormones sexuelles - Google Patents

Composition pharmaceutique contenant des hormones sexuelles Download PDF

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Publication number
WO1996010991A1
WO1996010991A1 PCT/SE1995/001102 SE9501102W WO9610991A1 WO 1996010991 A1 WO1996010991 A1 WO 1996010991A1 SE 9501102 W SE9501102 W SE 9501102W WO 9610991 A1 WO9610991 A1 WO 9610991A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
treatment
administration
estradiol
Prior art date
Application number
PCT/SE1995/001102
Other languages
English (en)
Inventor
Stefan Friess
Harald Heckenmüller
Heike Kublik
Original Assignee
Astra Aktiebolag
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 Astra Aktiebolag filed Critical Astra Aktiebolag
Priority to AU36904/95A priority Critical patent/AU3690495A/en
Publication of WO1996010991A1 publication Critical patent/WO1996010991A1/fr

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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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to a pharmaceutical composition having a form suitable for transmucosal administration and containing a combination of two lipophilic drugs which are one sex hormone and one derivative of a sex hormone.
  • the present invention also relates to the use of this pharmaceutical composition in the treatment of postmenopausal disorders and osteoporosis.
  • estrogens are common medical treatment for postmenopausal disorders and osteoporosis.
  • Unopposed estrogen therapy is known to increase the risk of endometrial carcinoma and hyperplasia and to increase the incidence of irregular bleedings as negative side-effects. Therefore, in addition to estradiol and its derivatives, progestin has been strongly recommended in therapy to protect against an estrogen-mediated increased risk of such negative side- effects.
  • the dose of progestin should result in a sufficient plasma level to provoke the changes of the endometrium.
  • Sex hormones and derivatives of sex hormones are substances which are very potent with respect to their biological activity.
  • One major problem in the use of such substances as drugs is to administer very small amounts of the drug to the patient at metered doses. This problem is particularly pronounced in cases where the first pass mechanism via the intestinal mucosa must be circumvented.
  • compositions for oral administration of estradiolvalerate and medroxyproge- sterone acetate have been disclosed in EP 461290.
  • the doses of sex hormone and sex hormone derivatives in this composition are very high and the first pass mechanism of the estradiol valerate is not circumvented.
  • Parenteral administration circumvents the undesired first pass effect.
  • parenteral for example intravenous or intramuscular drug administration such as the need for sterile delivery devices, pain and irritation caused by reiterated injections and the potential risk for infections.
  • Another disadvantage is that the patient normally needs medical assistance in administering.
  • Transdermal drug delivery as another parenteral route implicates the risk of skin irritations. It also leaves very limited possibilities to adjust the dose and frequency of application to all therapeutic goals and individual needs.
  • Another alternative is drug administration via the transmucosal route.
  • drug administration via the transmucosal route is drug administration via the transmucosal route.
  • bioavailability of a drug after transmucosal administration is largely unpredictable, depending inter alia on the chemical nature of the drug and the drug delivery system.
  • transmucosal, preferably nasal drug delivery systems of natural sex hormones for example:
  • EP 272097 The use of an emulsion for nasal application is known from EP 272097.
  • This patent refers to nasal administration of pharmacologically active polypeptides together with a phospholipid such as a phosphatidylcholine, which is a lecithin, preferably admixed with a vegetable oil.
  • a phospholipid such as a phosphatidylcholine, which is a lecithin, preferably admixed with a vegetable oil.
  • the resulting system is characterized in that the water soluble active drug is located in the coherent, hydrophilic outer phase of a two phase system consisting of oil in water.
  • a lecithin which is described in detail in this patent is used as an adjuvant which is effective in promoting the polypeptide uptake.
  • the addition of a vegetable oil is useful for stabilizing the emulsion.
  • Synthetic derivatives of sex hormones orally administered can be utilized as a way of obtaining a higher bioavailability than by oral administration of the natural sex hormones.
  • many synthetic derivatives of progesterone which are less susceptible to hepatic metabolism, show better efficacy upon oral administration than does the natural hormone itself.
  • negative side-effects have been observed upon administration of synthetic derivatives of sex hormones. Such side-effects depend both on the dose and the structure of the molecule of the sex hormone derivative.
  • Progestins have very different specific individual activities even if administered in the same way. This is illustrated in Table 1 where the therapeutic oral doses for some progesterone derivatives in combination treatment with estrogens are presented. These figures are doses generally recommended for therapeutic purposes.
  • the progestins are classified as follows:
  • progesterone and 17 ⁇ -hydroxy progesterone and (9 ⁇ ,10 ⁇ )-6,7- didehydroprogesterone Representatives of this group are medroxyprogesterone acetate, dydrogesterone, medrogestone, chlormadinone acetate and megestrol acetate.
  • medroxyprogesterone acetate Representatives of this group are medroxyprogesterone acetate, dydrogesterone, medrogestone, chlormadinone acetate and megestrol acetate.
  • 19-nortestosterone Representatives of this group are norethindrone, norgestrel, levonorgestrel, desogestrel, 3-keto-desogestrel, gestodene.
  • the derivatives of 19-nortestosterone exert higher specific activities than the derivatives of progesterone and 17 ⁇ -hydroxyprogesterone.
  • combination drugs one major problem resides in the different chemical character of the drugs to be administered. Different solubility properties contribute to making the preparation of the combined drug difficult and to limiting the number of combinations of drugs and solvents. Yet another difficulty in combination drugs is the respective specific activity of the different drugs sometimes making it necessary to distribute very different amounts of two or more drugs.
  • Two-phase liquid systems suitable to solve this problem often require additives such as emulsifyers and /or preservatives in order to retain their physical and microbial stability.
  • emulsifyers are often not well tolerated by mucosa and their use can result in damages of the mucosal membranes. The amount of such additives therefore, needs to be kept low.
  • DE 4019670 discloses a drug which is a mixture of estrogen with chlormadinone acetate for the treatment of the postmenopause of woman ("Besch dernic Weinjahre der Frau"). There is, however, in DE 4019670 neither any indication as to how to solve the problem of administering the combination of drugs nor as to how to prepare such a pharmaceutical preparation nor how such a preparation is constructed.
  • WO 93/21924 claims a pharmaceutical composition containing at least one precursor of testosterone which is applied nasally as a dosing spray. There is, however, no indication as to how such a pharmaceutical composition is constructed nor manufactured.
  • WO 93/24107 discloses the use of a metered dose spray for nasal application of sex hormones and their derivatives according to this publication.
  • the aim of the metered spray of WO 93/24107 is to keep the dose of active substance low and to facilitate the penetration of the hormone through the blood-brain barrier in order to treat central nervous system diseases. There is, however, no indication as to the composition of the formulation or as to how to prepare the formulation.
  • emulsions as drug carriers are known from several patents.
  • EP 391369 emulsion systems are used as vehicles of delivery of lipophilic drugs. Only by combining three different groups of surfactants comprising phospholipids, a non- ionic surfactant and a cholic acid derivative a very small particle size and an outstanding long term stability was obtained.
  • the emulsions are for topical, parenteral and oral administration.
  • surfactants, especially ionic surfactants are irritant to mucosa and are, therefore, less suitable for transmucosal administration of drugs and there is nowhere any indication as to how these emulsions can be administered transmucosally.
  • EP 215313 an emulsion system for a certain hydrophobic drug comprising a combination of a surfactant, a co-surfactant and benzyl alcohol as a co-solvent is disclosed. There is, however, no indication of the use of this emulsion for transmucosal or nasal application of the drug. Also, the emulsion system of EP 215 313 requires both a co-surfactant and, as a co-solvent, benzyl alcohol. Detailed description of the invention
  • the present invention provides a pharmaceutical composition for transmucosal administration characterized in comprising a pharmaceutical composition for transmucosal administration, which composition is an oil-in-water emulsion containing, dissolved in the dispersed oil phase, the natural sex hormone 17 ⁇ - estradiol together with a progestin which is selected from the group consisting of progesterone derivatives, 17 ⁇ -hydroxy progesterone and its derivatives, (9 ⁇ , 10 ⁇ )- 6,7-didehydroprogesterone and its derivatives, and 19-nortestosterone and its derivatives.
  • a pharmaceutical composition for transmucosal administration which composition is an oil-in-water emulsion containing, dissolved in the dispersed oil phase, the natural sex hormone 17 ⁇ - estradiol together with a progestin which is selected from the group consisting of progesterone derivatives, 17 ⁇ -hydroxy progesterone and its derivatives, (9 ⁇ , 10 ⁇ )- 6,7-didehydroprogester
  • the present invention provides a dosage form which is flexible with respect to the need of different concentration levels of the two active ingredients of the pharmaceutical composition.
  • the present invention provides a pharmaceutical composition for the effective treatment of postmenopausal problems and osteoporosis while minimizing negative side-effects otherwise provoked by too high doses of the progesterone derivative part of said composition.
  • compositions of the present invention avoids irritation of the mucosa otherwise provoked by solubilizers and/or preservatives thereby minimizing damage to mucosal membranes caused by long-term use of said compositions.
  • compositions of the present invention avoids degradation of the hormone and the hormone derivative component of the pharmaceutical composition by first pass metabolism in the liver as far as this is considered relevant for the particular hormone or hormone derivative.
  • administration of compositions of the present invention improves the uptake of the hormone and the hormone derivative component of the pharmaceutical composition in the blood of patients.
  • the present invention provides pharmaceutical compositions which contain no solubilizers and which are low in or devoid of preservatives thereby avoiding irritation of the mucosa and minimizing damage to mucosal membranes caused by long-term use of said compositions.
  • the present invention provides a method of prophylaxis or treatment of postmenopausal disorders or osteoporosis by using a transmucosal and in particular a nasal formulation of a drugs at a sufficient extent of adsorption.
  • the present invention provides a pharmaceutical composition for transmucosal administration characterized in comprising an active ingredient being the natural sex hormone 17 ⁇ -estradiol combined with a progestin which is selected from the group consisting of progesterone derivatives, (9 ⁇ ,10 ⁇ )-6,7-didehydroproge- sterone derivatives, 17 ⁇ -hydroxy-progesterone and its derivatives, and 19- nortestosterone and its derivatives, dissolved in an oil constituting the incoherent inner phase of an oil-water two-phase system, an emulsifying agent and, optionally, stabilizers.
  • a progestin which is selected from the group consisting of progesterone derivatives, (9 ⁇ ,10 ⁇ )-6,7-didehydroproge- sterone derivatives, 17 ⁇ -hydroxy-progesterone and its derivatives, and 19- nortestosterone and its derivatives, dissolved in an oil constituting the incoherent inner phase of an oil-water two-phase system, an emul
  • the progestins are 17 ⁇ -hydroxyprogesterone, dydrogesterone, medroxy-progesterone and its acetate, medrogestone, chlormadinone and its acetate, norethindrone and its acetate, megestrol and its acetate, norgestrel, levonorgestrel, desogestrel, 3-keto-desogestrel, gestodene.
  • the pharmaceutical composition Due to its ability to contain in a two-phase system, sufficient amounts although in very small volumes to be administered, strongly lipophilic derivatives of both 17 ⁇ -estradiol and derivatives of progesterone the pharmaceutical composition is particularly suitable for nasal administration, which is a convenient way of administrating drugs for therapy and treatment over extended periods of time.
  • compositions of the present invention solve the problem of avoiding degradation of 17 ⁇ -estrogen by first-pass mechanism by administering the hormone via mucous membrane. It solves, in the same way, the problem of minimizing the dose of sex hormone derivative.
  • Effective doses of the emulsion of the present invention will result in serum levels of 17 ⁇ -estradiol of 20-200 pg/ml.
  • progestin or progestin hormone/estrogen will generally be between 0.1 /1 and 100/1 by weight.
  • the data below are examples of the proportions of hormones and hormone derivatives in pharmaceutical compositions of the present invention. Percentage figures are, all, by weight of the total emulsion.
  • compositions of the present invention should contain 5-50%, preferably 10-30% of the oleaginous vehicle constituting the oil phase and 0.7-6%, preferably 1-3% of the emulsifying agents.
  • Antioxidants such as tocopherol can be added to 0.01-0.2%, preferably 0.02-0.1%.
  • Tonicity modifyers such as sorbitol can be added to 270-320 mOsmol/kg, preferably 280-300 mOsmol/kg.
  • a pH regulator such as NaOH can be added to pH 6-8, preferably to about 7.4 depending on the emulsifying agent and oil. Preservatives can be added if necessary.
  • Preservatives can be added if necessary.
  • As one embodiment of the present invention can be mentioned: 1.
  • the active ingredient which is a combination of estradiol and progestins as described above, namely dydrogesterone, medroxyprogesterone, medroxy ⁇ progesterone acetate, chlormadinone acetate, norethindrone acetate, levonogestrel and desogestrel. Most preferred is dydrogesterone.
  • natural oils can be mentioned vegetable oils such as cottonseed oil, soy bean oil, castor oil, olive oil, almond oil or safflower oil.
  • a semisynthetic oil component can be selected from the group consisting of middle chain triglycerides and mono acid triglycerides.
  • Artificial oils can be polyoxyethylene ester of caprylic and capric acid and polyoxyethylated triglycerides.
  • a natural surfactant being a phospholipid such as egg lecithin or soy lecithin.
  • stabilizers can be added such as:
  • An atonicity modifier such as glycerol, mannitol, xylitol, sorbitol, lactose or glucose.
  • a pH regulative agent such as sodium hydroxide or a salt of a long chain fatty acid such as sodium oleate.
  • An antioxidant such as DL-a tocopherol
  • compositions of the present invention can be manufactured by dissolving the active ingredients in an oil phase, adding the emulsifyer, optionally with the addition of a stabilizer (i.e. antioxidant), adding the water, optionally with the addition of a stabilizer (osmolarity regulator) and, thereafter, homogenizing the two solutions to an emulsion.
  • a stabilizer i.e. antioxidant
  • a stabilizer i.e. antioxidant
  • osmolarity regulator osmolarity regulator
  • compositions for transmucosal administration are examples of pharmaceutical compositions for transmucosal administration.
  • Soy bean oil 2.0 g
  • compositions as described above can be administered by nasal application.
  • the amount of the liquid administered per unit dose and per nostril should be less than 0.2 ml.
  • the emulsion system according to Example 1 was prepared in the following way:
  • the active ingredients were dissolved in the oil phase.
  • Tonicity modifier and cosurfactant were dissolved in the water phase.
  • the phospholipid for example lecithin
  • the two phases were mixed and emulsified by a high speed shear mixer.
  • the resulting, coarse, emulsion was then homogenized using a high pressure homogenizer until a fine monodispersed emulsion with a small range of droplet size was formed.
  • the experiment described below serves to illustrate the uptake of active ingredients in vivo upon nasal administration of a pharmaceutical composition according to the present invention in sheep.
  • Mixed breed adult sheep were used for the animal experiments.
  • the emulsion formulation of Example 5 containing 17 ⁇ -estradiol and dydrogesterone was administered to six sheep by application of 0.14 ml of a nasal spray into each nostril.
  • the given dose was 108 ⁇ g of 17 ⁇ -estradiol and 910 ⁇ g of dydrogesterone.
  • Prior to administration blood samples were taken from all animals. After application blood samples were taken from the canulated external jugular vein at 0, 5, 10, 20, 30, 45, 60, and 120 minutes.
  • the nasal dose of about 100 ⁇ g 17 ⁇ - estradiol results in an estradiol plasma level equivalent to the luteal phase of the female menstrual cycle which is desired for the treatment of osteorporosis and postmenopausal disorders.
  • a pronounced absorption after nasal application can also be observed for dydrogesterone.
  • the plasma concentration of dydrogesterone decreases from lOllpg/ml to about 56 pg/ml after 120 minutes.
  • Table 2a Plasma concentration of estradiol after nasal application of 108mg 17 ⁇ -estradiol to 6 sheep
  • Table 2b Plasma concentration of dydrogesterone after nasal application of 910 ⁇ g to 6 sheep

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Une composition pharmaceutique présente une forme adaptée à une administration transmuqueuse et contient comme ingrédients actifs du 17β-÷stradiol et un composé choisi parmi les progestines.
PCT/SE1995/001102 1994-10-06 1995-09-27 Composition pharmaceutique contenant des hormones sexuelles WO1996010991A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU36904/95A AU3690495A (en) 1994-10-06 1995-09-27 Pharmaceutical composition containing derivatives of sex hormones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9403389-1 1994-10-06
SE9403389A SE9403389D0 (sv) 1994-10-06 1994-10-06 Pharmaceutical composition containing derivattves of sex hormones

Publications (1)

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WO1996010991A1 true WO1996010991A1 (fr) 1996-04-18

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SE (1) SE9403389D0 (fr)
WO (1) WO1996010991A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2779062A1 (fr) * 1998-06-02 1999-12-03 Investigations Therapeutiques Preparation sous forme galenique simple visant a limiter les effets induits durant la menopause et posterieurement et traitement avec cette preparation
WO2000024373A1 (fr) * 1998-10-24 2000-05-04 West Pharmaceutical Services Drug Delivery & Clinical Research Centre, Ltd. Emulsion huile dans eau comprenant une huile hydroxylee
WO2001064937A2 (fr) * 2000-03-02 2001-09-07 Mcgill University Facteur inhibiteur de caspase et utilisations correspondantes
EP1462107A1 (fr) * 2003-03-28 2004-09-29 Pantarhei Bioscience B.V. Weibliches Empfängnisverhutungmethode und pharmazeutische Zuberaitungen die für eine solche Methode geeignet sind
EP1462106A1 (fr) * 2003-03-28 2004-09-29 Pantarhei Bioscience B.V. Compositions pharmaceutiques et trousses comprenant 17-beta estradiol et progesteron pour le traitement des troubles gynecologiques
WO2006036055A2 (fr) * 2004-09-27 2006-04-06 Pantarhei Bioscience B. V. Methode de contraception destinee a des mammiferes femelles et trousse d'utilisation associe
US7749987B2 (en) 1996-10-08 2010-07-06 Laboratorie Theramek Contraception method
WO2011134937A2 (fr) 2010-04-26 2011-11-03 Besins Healthcare Luxembourg Sarl Compositions d'émulsion pharmaceutique comprenant du progestogène
US8168619B1 (en) 1999-10-25 2012-05-01 Laboratoire Theramex Hormonal composition based on a progestational agent and an oestrogen and use thereof
RU2582272C2 (ru) * 2009-12-15 2016-04-20 Течсфере, С.А.Де К.В. Фармацевтическая композиция для парентерального введения в форме суспензии с длительным высвобождением в низкой и очень низкой дозе при гормональной терапии климактерического синдрома

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0391369A2 (fr) * 1989-04-05 1990-10-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Emulsions pour médicaments
EP0461290A1 (fr) * 1990-06-14 1991-12-18 HENNING BERLIN GmbH CHEMIE- UND PHARMAWERK Capsules à couleur liquide
WO1994022426A1 (fr) * 1993-04-07 1994-10-13 Astra Aktiebolag Composition pharmaceutique contenant des medicaments lipophiles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0391369A2 (fr) * 1989-04-05 1990-10-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Emulsions pour médicaments
EP0461290A1 (fr) * 1990-06-14 1991-12-18 HENNING BERLIN GmbH CHEMIE- UND PHARMAWERK Capsules à couleur liquide
WO1994022426A1 (fr) * 1993-04-07 1994-10-13 Astra Aktiebolag Composition pharmaceutique contenant des medicaments lipophiles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STN INTERNATIONAL, DERWENT INFORMATION LTD., WPIDS Accession No. 89-064960, ASAHI CHEM. IND. CO. LTD., "Prepn. of Emulsion Formulations Enclosing Drugs - Which are Slightly Soluble in Water and Oil, by Kneading Drug With an Oil in Presence of Phospholipid Before Emulsifying"; & JP,A,01 016 716, 20-01-89, (8909). *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7749987B2 (en) 1996-10-08 2010-07-06 Laboratorie Theramek Contraception method
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
FR2779062A1 (fr) * 1998-06-02 1999-12-03 Investigations Therapeutiques Preparation sous forme galenique simple visant a limiter les effets induits durant la menopause et posterieurement et traitement avec cette preparation
WO2000024373A1 (fr) * 1998-10-24 2000-05-04 West Pharmaceutical Services Drug Delivery & Clinical Research Centre, Ltd. Emulsion huile dans eau comprenant une huile hydroxylee
AU765251B2 (en) * 1998-10-24 2003-09-11 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited O/W emulsion comprising an hydroxylated oil
US8168619B1 (en) 1999-10-25 2012-05-01 Laboratoire Theramex Hormonal composition based on a progestational agent and an oestrogen and use thereof
US9084796B2 (en) 1999-10-25 2015-07-21 Laboratoire Theramex Hormonal composition and its use
WO2001064937A2 (fr) * 2000-03-02 2001-09-07 Mcgill University Facteur inhibiteur de caspase et utilisations correspondantes
WO2001064937A3 (fr) * 2000-03-02 2002-02-07 Univ Mcgill Facteur inhibiteur de caspase et utilisations correspondantes
EP1462107A1 (fr) * 2003-03-28 2004-09-29 Pantarhei Bioscience B.V. Weibliches Empfängnisverhutungmethode und pharmazeutische Zuberaitungen die für eine solche Methode geeignet sind
EP1462106A1 (fr) * 2003-03-28 2004-09-29 Pantarhei Bioscience B.V. Compositions pharmaceutiques et trousses comprenant 17-beta estradiol et progesteron pour le traitement des troubles gynecologiques
WO2006036055A3 (fr) * 2004-09-27 2008-01-10 Pantarhei Bioscience Bv Methode de contraception destinee a des mammiferes femelles et trousse d'utilisation associe
WO2006036055A2 (fr) * 2004-09-27 2006-04-06 Pantarhei Bioscience B. V. Methode de contraception destinee a des mammiferes femelles et trousse d'utilisation associe
RU2582272C2 (ru) * 2009-12-15 2016-04-20 Течсфере, С.А.Де К.В. Фармацевтическая композиция для парентерального введения в форме суспензии с длительным высвобождением в низкой и очень низкой дозе при гормональной терапии климактерического синдрома
WO2011134944A2 (fr) 2010-04-26 2011-11-03 Besins Healthcare Luxembourg Sarl Compositions d'émulsion pharmaceutique à faible teneur en huile comprenant du progestogène
WO2011134944A3 (fr) * 2010-04-26 2012-02-09 Besins Healthcare Luxembourg Sarl Compositions d'émulsion pharmaceutique à faible teneur en huile comprenant du progestogène
US8476252B2 (en) 2010-04-26 2013-07-02 Besins Healthcare Luxembourg Sarl Pharmaceutical emulsion compositions comprising progestogen
US8765149B2 (en) 2010-04-26 2014-07-01 Besins Healthcare Luxembourg Sarl Low-oil pharmaceutical emulsion compositions comprising progestogen
EP2801353A1 (fr) 2010-04-26 2014-11-12 Besins Healthcare Luxembourg Compositions d'émulsions pharmaceutiques comprenant un progestogène
EP2857042A1 (fr) 2010-04-26 2015-04-08 Besins Healthcare Luxembourg Compositions d'émulsion pharmaceutique à faible teneur en huile comportant du progestogène
WO2011134937A3 (fr) * 2010-04-26 2012-02-02 Besins Healthcare Luxembourg Sarl Compositions d'émulsion pharmaceutique comprenant du progestogène
EA022460B1 (ru) * 2010-04-26 2016-01-29 Безен Хелткэа Люксембург Сарл Фармацевтические композиции в виде эмульсии с низким содержанием масла, содержащие прогестоген
WO2011134937A2 (fr) 2010-04-26 2011-11-03 Besins Healthcare Luxembourg Sarl Compositions d'émulsion pharmaceutique comprenant du progestogène
AU2011246527B2 (en) * 2010-04-26 2016-09-15 Besins Healthcare Luxembourg Sarl Low-oil pharmaceutical emulsion compositions comprising progestogen
US9572818B2 (en) 2010-04-26 2017-02-21 Besins Healthcare Luxembourg Sarl Pharmaceutical emulsion compositions comprising progestogen

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Publication number Publication date
SE9403389D0 (sv) 1994-10-06
AU3690495A (en) 1996-05-02

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