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WO2001062260A2 - Amelioration d'un taux d'implantation - Google Patents

Amelioration d'un taux d'implantation Download PDF

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Publication number
WO2001062260A2
WO2001062260A2 PCT/EP2001/001691 EP0101691W WO0162260A2 WO 2001062260 A2 WO2001062260 A2 WO 2001062260A2 EP 0101691 W EP0101691 W EP 0101691W WO 0162260 A2 WO0162260 A2 WO 0162260A2
Authority
WO
WIPO (PCT)
Prior art keywords
mas
oocytes
implantation rate
analogues
rate
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/EP2001/001691
Other languages
English (en)
Other versions
WO2001062260A3 (fr
Inventor
Christa Hegele-Hartung
Peter Esperling
Thorsten Blume
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.)
Bayer Pharma AG
Novo Nordisk AS
Original Assignee
Schering AG
Novo Nordisk AS
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 Schering AG, Novo Nordisk AS filed Critical Schering AG
Priority to AU33765/01A priority Critical patent/AU3376501A/en
Publication of WO2001062260A2 publication Critical patent/WO2001062260A2/fr
Publication of WO2001062260A3 publication Critical patent/WO2001062260A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis

Definitions

  • the present invention relates to a method of increasing the implantation rate of preimplantational embryos.
  • Fertilization of the mammalian egg is preceded by the maturation of the ⁇ ocyte.
  • This maturation process in mammalian oocytes includes nuclear and cytoplasmic changes.
  • the first meiotic division from prophase I to metaphase II is reinitiated and completed. Only little is known about the mechanism which controls the initiation of meiosis.
  • the presence of a diffusible meiosis regulating substance was first described by Byskov et al. in a culture system of fetal mouse gonads [Byskov, A. G. et al. Dev Biol 52 (1976) 193-200].
  • a meiosis activating substance (MAS) was secreted by the fetal mouse ovary in which meiosis was ongoing, and a meiosis preventing substance (MPS) was released from the morphologically differentiated testis with resting, non-meiotic germ cells. It was suggested that the relative concentrations of MAS and MPS regulated the beginning, arrest and resumption of meiosis in the male and in the female germ cells (Byskov, A.G. et al. in The Physiology of Reproduction [eds. Knobil. E. and Neill, J. D., Raven Press, New York (1994)].
  • T-MAS and FF-MAS sterols that activate oocyte meiosis have been isolated from bull testes and from human follicular fluid [Byskov, A. G. et al. Nature 374 (1995), 559-562].
  • the present invention provides a method to increase the implantation rate of oocytes in females, preferably humans.
  • the present invention relates to the use of FF-MAS and /or one or more FF-MAS analogues for the preparation of a medicament that increases the implantation rate of preimplantational embryos.
  • FF-MAS is 4,4-dimethyl-5a-cholesta-8, 14,24- triene-3 ⁇ -ol. Its synthesis is described in WO99/52930. FF-MAS analogues and their synthesis are described in e.g. WO 96/00235, WO 96/27658, WO97/00884, WO98/28323,WO98/52965 and WO 98/55498. FF-MAS analogues have a percentage germinal vesicle breakdown (GVB) which is significantly higher than the control. Preferred FF-MAS analogues are such having a percentage GVB of at least 50%, preferably at least 80%. Implantation rate means the rate by which a preimplantational embryo is able to interact with the endometrium thereby giving rise to the development of a postimplantational embryo and a fetus.
  • GVB germinal vesicle breakdown
  • FF-MAS and its analogues When given to a woman before and during ovulation, FF-MAS and its analogues increase the implantation rate by at least 20%. More preferably, the implantation rate is increased by at least 50 %.
  • the medicament of this invention can therefore be used to treat females who have problems with infertility. It may also be used to increase the implantation rate in animals which is important in animal breeding.
  • compositions comprising FF- MAS and/or one or more FF-MAS analogues.
  • the compositions may further comprise pharmaceutically acceptable excipients well known in the art like carriers, diluents, absorption enhancers, preservatives, buffers, agents for adjusting the osmotic pressure, tablet disintegrating agents and other ingredients which are conventionally used in the art.
  • solid carriers examples include magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, low melting waxes and cacao butter.
  • Liquid compositions include sterile solutions, suspensions and emulsions. Such liquid compositions may be suitable for injection. The liquid compositions may contain other ingredients which are conventionally used in the art, some of which are mentioned in the list above. Further, a composition for transdermal administration of FF-MAS and/or one or more FF-MAS analogues may be provided in the form of a patch and a composition for nasal administraton may be provided in the form of a nasal spray in liquid or powder form.
  • compositions of the invention are prepared by intimately bringing into association the active compound with the liquid or solid auxiliary ingredients and then, if necessary, shaping the product into the desired formulation.
  • not more than 1000 mg, preferably not more than 100 mg, and in some preferred instances not more than 10 mg of FF-MAS and/or one or more FF-MAS analogues is to be administered to mammals, e.g. to humans, per day. Treatment may either be continuously or intermittent. Intermittent treatment preferably starts before the ovulation and is continued until some days after ovulation.
  • the route of administration of FF-MAS and/or one or more FF-MAS analogues may be any route which brings the active compound(s) to its or their site of action.
  • routes of administration are intravenous, subcutaneous, oral, intranasal or transdermal administration.
  • Example 1 Method used for electing MAS compounds
  • Oocytes were obtained from immature female mice (C57BI/6J x DBA/2J F1 -hybrids, Bomholtgaard, Denmark) weighing 13 - 16 grams, that were kept under controlled lighting and temperature.
  • the mice received an intra-peritoneal injection of 0.2 ml gonadotropins (Gonal F, Serono, Solna, Sweden , containing 20 IU FSH, alternatively, Puregon, Organon, Swords, Ireland containing 20 IU FSH) and 48 hours later the animals were killed by cervical dislocation.
  • the ovaries were dissected out and the oocytes were isolated in Hx-medium (see below) under a stereo microscope by manual rupture of the follicles using a pair of 27 gauge needles.
  • Spherical, naked oocytes (NO) displaying an intact germinal vesicle (GV) were placed in ⁇ -minimum essential medium ( ⁇ -MEM without ribonucleosides, Gibco BRL, Cat.No. 22561) supplemented with 3 mM hypoxanthine (Sigma Cat. No. H-9377), 8 mg/ml Human Serum Albumin (HSA, State Serum Institute, Denmark), 0,23 mM pyrubate (Sigma, Cat. No.
  • Hx-medium 2 mM glutamine (Flow Cat. No. 16-801), 100 lU/ml penicillin and 100 ⁇ g/ml streptomycin (Flow, Cat No. 16-700).
  • This medium was designated Hx-medium.
  • the oocytes were rinsed three times in Hx-medium and cultured in 4-well multidishes (Nuncion, Denmark) in which each well contained 0.4 ml of Hx-medium and 35 - 45 oocytes.
  • One control i.e. 35 - 45 oocytes cultured in Hx-medium with no addition of test compound
  • the cultures were performed at 37 °C and 100 % humidity with 5 % CO 2 in air.
  • the culture time was 22 - 24 hours.
  • the number of oocytes with germinal vesicle (GV) or germinal vesicle breakdown (GVB) and those with polar body (PB) was counted using a stereo microscope or an inverted microscope with differential interference contrast equipment.
  • the percentage of oocytes with GVB per total number of oocytes and the percentage of oocytes with PB per total number of oocytes was calculated in the test cultures and compared to the control culture.
  • %GVB ((number of GVB + number of PB)/total number of oocytes)x100
  • the animals were divided in one control group (group 1 ) and two treatment groups (group 2-3) consisting of 5 animals/group, respectively.
  • mice were treated for eight days (d1-d8), once daily, subcutaneously with the test compounds (treatment groups) or vehicle (control group), respectively.
  • treatment groups treatment groups
  • vehicle control group
  • animals were mated.
  • the success of mating was checked by the presence of sperms in the vagina at d ⁇ .
  • animals were sacrificed. Uteri were removed and checked for the presence of implantation sides. In each animal the number of implantation sides were determined.
  • Control group 1 received vehicle alone [ethanol/arachisoil, 1+9 (v/v)].
  • Group 2 received 20 mg/kg FF-MAS, prepared in an ethanol/arachisoil vehicle.
  • Group 2 received 20 mg/kg FF-MAS-succinate, prepared in an ethanol/arachisoil vehicle.
  • Table 1 Effect of subcutaneous FF-MAS and FF-MAS-succinate treatment on implantation rate in the adult, cycling rat treatment starts at metestrus

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Reproductive Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pregnancy & Childbirth (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne l'utilisation de FF-MAS et/ou de ses analogues pour la préparation d'un médicament pouvant augmenter le taux d'implantation d'embryons préimplantatoires.
PCT/EP2001/001691 2000-02-25 2001-02-15 Amelioration d'un taux d'implantation Ceased WO2001062260A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU33765/01A AU3376501A (en) 2000-02-25 2001-02-15 Improvement of implantation rate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP00250067.6 2000-02-25
EP00250067 2000-02-25

Publications (2)

Publication Number Publication Date
WO2001062260A2 true WO2001062260A2 (fr) 2001-08-30
WO2001062260A3 WO2001062260A3 (fr) 2002-04-04

Family

ID=8172594

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2001/001691 Ceased WO2001062260A2 (fr) 2000-02-25 2001-02-15 Amelioration d'un taux d'implantation

Country Status (2)

Country Link
AU (1) AU3376501A (fr)
WO (1) WO2001062260A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062258A3 (fr) * 2000-02-25 2002-03-07 Schering Ag Amelioration du taux d'implantation
US6916921B2 (en) 2001-03-26 2005-07-12 Schering Ag Steroid compounds, use of these compounds for the preparation of meiosis-regulating medicaments and method for the preparation of these compounds

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5716777A (en) * 1994-06-23 1998-02-10 Novo Nordisk A/S Regulation of meiosis using sterols
DE69804611T2 (de) * 1997-06-04 2002-10-02 Akzo Nobel N.V., Arnheim/Arnhem 17-beta.-allyloxy(thio)alkyl-androstan derivative zur modulation von meiose
KR20010043828A (ko) * 1998-05-26 2001-05-25 에바-마리아 시마-메이어, 얼설라 멜져, 마거, 하르트만 ｃＡＭＰ-증강 화합물 단독 또는 감수분열-자극 화합물하나 이상과의 조합에 의한 불임 치료 방법
AU2794000A (en) * 1999-02-24 2000-09-14 Novo Nordisk A/S Treatment of infertility
AU2794100A (en) * 1999-02-24 2000-09-14 Novo Nordisk A/S Treatment of infertility
AU2659200A (en) * 1999-02-26 2000-09-21 Novo Nordisk A/S Meiosis activating sterol augments implantation rate

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062258A3 (fr) * 2000-02-25 2002-03-07 Schering Ag Amelioration du taux d'implantation
US6916921B2 (en) 2001-03-26 2005-07-12 Schering Ag Steroid compounds, use of these compounds for the preparation of meiosis-regulating medicaments and method for the preparation of these compounds

Also Published As

Publication number Publication date
WO2001062260A3 (fr) 2002-04-04
AU3376501A (en) 2001-09-03

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