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WO1999000019A1 - Procedes de traitement des symptomes de la vaginite atrophique et du comportement sexuel modifie chez des femmes postmenopausees - Google Patents

Procedes de traitement des symptomes de la vaginite atrophique et du comportement sexuel modifie chez des femmes postmenopausees Download PDF

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Publication number
WO1999000019A1
WO1999000019A1 PCT/US1998/013460 US9813460W WO9900019A1 WO 1999000019 A1 WO1999000019 A1 WO 1999000019A1 US 9813460 W US9813460 W US 9813460W WO 9900019 A1 WO9900019 A1 WO 9900019A1
Authority
WO
WIPO (PCT)
Prior art keywords
symptoms
sexual behavior
postmenopausal women
treating
atrophic vaginitis
Prior art date
Application number
PCT/US1998/013460
Other languages
English (en)
Inventor
Brian R. Macdonald
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU82718/98A priority Critical patent/AU8271898A/en
Publication of WO1999000019A1 publication Critical patent/WO1999000019A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • the present invention relates to therapeutic agents that bind to the estrogen receptor and cause tissue specific estogen agonist effects, that have been found to be useful in the treatment of the symptoms of atrophic vaginitis and altered sexual behavior in postmenopausal women.
  • Menopause and the perimenopause in women are often marked by the occurrence of symptoms relating to loss of estrogen stimulated vaginal secretions (atrophic vaginitis). Alterations in sexual behavior are also common at the time
  • HRT hormone replacement therapy
  • HRT hypothalamic hormone
  • This invention provides a method for the prevention and treatment of the symptoms of atrophic vaginitis and altered sexual behavior in postmenopausal women without the side 30 effects of Hormonal Replacement Therapy (HRT).
  • the method comprises administering to a human in need thereof an effective amount of a therapeutic agent that binds to the estrogen receptor and produces a tissue specific estrogen agonist effect in the vaginal and cervical glandular/epithelial cells or the specific areas of the brain that control sexual behavior.
  • a therapeutic agent that binds to the estrogen receptor and produces a tissue specific estrogen agonist effect in the vaginal and cervical glandular/epithelial cells or the specific areas of the brain that control sexual behavior.
  • compounds that can be utilized in this invention are compounds of formula I
  • X represents 3- or 4- iodo or bromo and the R* and R ⁇ symbols, which may be the same or different, represent C ⁇ _3 alkyl, especially methyl or ethyl, groups or R! represents a hydrogen atom and R ⁇ a C ⁇ _3 alkyl group or R ! and R ⁇ together with the nitrogen atom to which they are attached represent a saturated heterocyclic group, typically having 5 or 6 ring atoms, especially a pyrrolidino, piperidino, 4-methylpiperidino or morpholino group, and their pharmaceutically acceptable acid addition salts.
  • Preferred is the compound known as idoxifene.
  • the present invention is a therapeutic method for treating the symptoms of atrophic vaginitis and altered sexual behavior in postmenopausal women with agents that bind to the estrogen receptor and, as a consequence of that interaction with the estrogen receptor, cause either estrogenic (estrogen agonist) or antiestrogenic (estrogen antagonist) effects in different tissues.
  • estrogenic estradien agonist
  • antiestrogenic estradien antagonist
  • the same agent may be estrogenic in one tissue but antiestrogenic in another.
  • Some compounds of this description are in clinical use because of the beneficial effects that are produced in specific tissues as a result of binding to the estrogen receptor (for example the use of the antiestrogenic effects of tamoxifen in breast tissue to provide therapeutic benefit in the treatment of breast cancer).
  • the preferred effect of a compound for the desired method of treatment is to produce estrogenic effects in the vaginal epithelial and cervical glandular cells or the specific areas of the brain that control sexual behavior. This would have the clinical effect of reducing the severity of vaginal itching and dryness, pain on sexual intercourse and decreased libido by having the same effect as estrogen in these tissues.
  • An example of such a compound is idoxifene.
  • Preferred compounds are described in formula I above and in U.S. patent 4,839,155.
  • the preferred compound for the described method of treatment is
  • the symptoms that would be treated in this invention are an important component of a menopausal syndrome that also includes vasomotor symptoms (hot flashes), sleep disturbance, agitation, nervousness, mood changes, anxiety, irritability, loss of memory and concentration, crying spells, tiredness, depression, headache, and joint or muscle pain.
  • vasomotor symptoms hot flashes
  • sleep disturbance agitation
  • nervousness mood changes
  • anxiety irritability
  • loss of memory and concentration crying spells
  • crying spells tiredness, depression, headache, and joint or muscle pain.
  • idoxifene caused a dose related protection from the loss of vaginal epithelial stratification/cornification and cervical mucus secretion that was observed in the ovariectomized control animals.
  • a questionaire was also administered to the patients to provide information about the severity of the other symptoms that comprise the menopausal syndrome including those that would be treated in this invention.
  • a loading dose regimen was employed which involved taking three tablets as a single daily dose for the first week and one tablet per day thereafter. Analysis of the data from the patient questionaire revealed that the responses to the questions on sexual function were significantly improved from baseline in the group of patients who received 5mg/day of idoxifene.
  • the compounds of the instant invention and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or coloring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or coloring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmacuetical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmacuetical carrier(s) routinely used for preparing solid formulations.
  • such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • compositions for parenteral administration will generally consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • a typical suppository composition comprises a compound of the instant invention or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or coca butter or other low melting vegetable or synthetic waxes or fats.
  • a binding and/or lubricating agent such as polymeric glycols, gelatins or coca butter or other low melting vegetable or synthetic waxes or fats.
  • a typical transdermal formulation comprises a conventional aqueous or non- aqueous vehicle, for example, a cream, ointment lotion or paste or in the form of a medicated plaster, patch or membrane.
  • the pharmaceutical compositions adapted include solutions, suspensions, ointments, and solid inserts.
  • Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non- toxic polymers, for example, cellulose derivatives such as methyl cellulose.
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting and bodying agents, as for example, polyethylene glycols; antibacterial components such as quaternary ammonium compounds; buffering ingredients such as alkali metal chloride; antioxidants such as sodium metabisulfite; and other conventional ingredients such as sorbitan monolaurate.
  • the composition is in unit dose form.
  • Doses of the compounds of the instant invention in a pharmaceutical dosage unit will be an efficiacious, non-toxic quantity selected from the range of .01 - 200 mg/kg of active compound, preferably .1 - 100 mg kg.
  • the selected dose is administered to a human patient in need of treatment for vasomotor symptoms from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion.
  • Oral dosage units for human administration preferably contain from 10 to 500 mg of active compound. Lower dosages are used generally for parenteral administration. Oral administration is used when safe, effective, and convenient for the patient.
  • Example 1 An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below.
  • sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelating solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

Landscapes

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

Abstract

Nouveau procédé de traitement des symptômes de la vaginite atrophique et du comportement sexuel modifié chez des femmes postménopausées.
PCT/US1998/013460 1997-06-27 1998-06-26 Procedes de traitement des symptomes de la vaginite atrophique et du comportement sexuel modifie chez des femmes postmenopausees WO1999000019A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU82718/98A AU8271898A (en) 1997-06-27 1998-06-26 Methods of treating the symptoms of atrophic vaginitis and altered sexual behavior in postmenopausal women

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5112097P 1997-06-27 1997-06-27
US60/051,120 1997-06-27

Publications (1)

Publication Number Publication Date
WO1999000019A1 true WO1999000019A1 (fr) 1999-01-07

Family

ID=21969467

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/013460 WO1999000019A1 (fr) 1997-06-27 1998-06-26 Procedes de traitement des symptomes de la vaginite atrophique et du comportement sexuel modifie chez des femmes postmenopausees

Country Status (5)

Country Link
AR (1) AR016097A1 (fr)
AU (1) AU8271898A (fr)
CO (1) CO4940467A1 (fr)
WO (1) WO1999000019A1 (fr)
ZA (1) ZA985543B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003070253A1 (fr) * 2002-02-21 2003-08-28 Pantarhei Bioscience B.V. Composant oestrogenique pour traiter la diminution de la libido chez les femmes
US6613796B2 (en) 1996-02-28 2003-09-02 Pfizer Inc. Use of estrogen antagonists and estrogen agonists in inhibiting pathological conditions
EP1623712A3 (fr) * 1998-06-11 2009-12-16 Endorecherche Inc. Combinaisons de modulateurs des récepteurs oestrogène et de déhydroépiandrostérone (DHEA) ou analogues

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4839155A (en) * 1986-09-11 1989-06-13 National Research Development Corporation Iodotamoxifen derivatives and use for estrogen receptor-positive breast cancer detection and therapy
US5472985A (en) * 1993-05-13 1995-12-05 Neorx Corporation Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4839155A (en) * 1986-09-11 1989-06-13 National Research Development Corporation Iodotamoxifen derivatives and use for estrogen receptor-positive breast cancer detection and therapy
US5472985A (en) * 1993-05-13 1995-12-05 Neorx Corporation Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6613796B2 (en) 1996-02-28 2003-09-02 Pfizer Inc. Use of estrogen antagonists and estrogen agonists in inhibiting pathological conditions
EP1623712A3 (fr) * 1998-06-11 2009-12-16 Endorecherche Inc. Combinaisons de modulateurs des récepteurs oestrogène et de déhydroépiandrostérone (DHEA) ou analogues
EP2399582A1 (fr) * 1998-06-11 2011-12-28 Endorecherche Inc. Modulateur sélectif de récepteur d'ýstrogène combiné avec déhydroépiandrostérone (DHEA) ou des analogues
WO2003070253A1 (fr) * 2002-02-21 2003-08-28 Pantarhei Bioscience B.V. Composant oestrogenique pour traiter la diminution de la libido chez les femmes

Also Published As

Publication number Publication date
ZA985543B (en) 1998-12-28
AR016097A1 (es) 2001-06-20
AU8271898A (en) 1999-01-19
CO4940467A1 (es) 2000-07-24

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