WO2008018872A1 - Procédés thérapeutiques utilisant des compositions à base d'œstrogènes - Google Patents

Procédés thérapeutiques utilisant des compositions à base d'œstrogènes Download PDF

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Publication number
WO2008018872A1
WO2008018872A1 PCT/US2006/031117 US2006031117W WO2008018872A1 WO 2008018872 A1 WO2008018872 A1 WO 2008018872A1 US 2006031117 W US2006031117 W US 2006031117W WO 2008018872 A1 WO2008018872 A1 WO 2008018872A1
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composition
estrogenic compound
administration
vaginal
phase
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PCT/US2006/031117
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English (en)
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Jonathan Bortz
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Drugtech Corporation
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Priority to PCT/US2006/031117 priority Critical patent/WO2008018872A1/fr
Publication of WO2008018872A1 publication Critical patent/WO2008018872A1/fr

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    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P5/30—Oestrogens

Definitions

  • the present invention relates to therapeutic methods of use of pharmaceutical compositions suitable for vaginal delivery of an estrogen compound in women having migraine or headache.
  • Migraine is the most common form of disabling headache and may well be one of the most common reasons for patients to see their doctors.
  • the International Headache Society adopted the new International Classification of Headache Disorders- 2nd edition (ICHD-II).
  • Migraine diagnostic criteria according to ICHD-II include recurrent headache disorder manifesting in attacks lasting from 4 to 72 hours; headache with features such as unilateral location, pulsating quality, and moderate or severe pain intensity; aggravation of pain by routine physical activity; and association with nausea, photophobia, and/or phonophobia.
  • Chronic migraine includes these same features but further includes headache on more than 15 days a month.
  • Headache Classification Committee of the International Headache Society (2004) Cephalalgia 24(Supp. 1):1— 160.
  • Menstrual migraine is also classified by ICHD-II with the features as discussed above for general migraine, but this migraine classification is relegated to the Appendix due to uncertainties as to whether pure menstrual migraine and menstrually related migraine should be given separate entries.
  • both types of migraine occur on day 1 of the menstrual cycle, plus or minus 2 days (i.e., days -2 to +3) in at least two out of three menstrual cycles, menstrually related migraine can additionally occur at other times of the cycle while pure menstrual migraine is applicable only to women during menses. Id, at page 138.
  • Estrogen withdrawal migraine is also classified by ICHD-II.
  • ICHD-II mentions that headache or migraine can be induced by estrogen withdrawal following cessation of a course of exogenous estrogens (including the pill-free interval or placebo phase of an oral contraceptive or hormone replacement regimen).
  • the diagnostic criteria include the criteria applicable to general migraine as described above, and additionally, uninterrupted daily use of exogenous estrogen for three or more weeks and migraine that develops within 5 days after last use of estrogen and resolves within 3 days. Id, at page 96.
  • Initial migraine treatments include administration of analgesics and/or nonsteroidal anti-inflammatory drugs (NS AIDs), and when these fail, any one of the triptans (selective serotonin (5-HT) receptor agonists) can be tried.
  • Preventive treatments such as ⁇ -blockers, tricyclics and anticonvulsants leave much to be desired with side effects such as sleepiness, exercise intolerability, erectile dysfunction, nightmares, dry mouth, weight gain, tremor, hair loss, or fetal deformities.
  • New drugs are needed to prevent or treat migraine, in particular menstrual migraine, including pure menstrual migraine, menstrually related migraine, and estrogen withdrawal migraine.
  • High-dose estradiol (100 and 200 ⁇ g patches administered twice daily) can improve symptoms of premenstrual syndrome (including irritability, headache, depression, fatigue, breast tenderness, breast swelling, insomnia, change of appetite and concentration difficulties during the two weeks prior to menstruation) by suppressing ovulation, according to Drugs and Therapy Perspectives (2004) 20(1): 11-15.
  • U.S. Patent No. 6,797,282 to Kafrissen & Taitel mentions daily use of oral progestin and/or estrogen with the potential to treat menstrual migraine. Among other routes, intravaginal administration reportedly causes slow release of actives.
  • U.S. Patent No. 4,551,148 to Riley et al. proposes a controlled release system for vaginal drug delivery, comprising unit cells having a nonlipoidal internal phase and a lipoidal continuous external phase. An active agent is present at least in the internal phase.
  • VagiSite® bioadhesive topical drug delivery system as a high internal phase ratio water-in-oil emulsion system, providing a delivery platform for administration of active drug entities in the vaginal cavity. They disclose that the VagiSite® system is incorporated in Gynazole-1® antifungal vaginal cream.
  • U.S. Patent Application Publication No. 2003/0180366 of Kirscliner et al. proposes a vaginal drug delivery system having globules comprising an internal water- soluble phase that is acid buffered and contains a drug, and an external water-insoluble phase or film.
  • U.S. Patent Application Publication No. 2004/0234606 of Levine et al. proposes a composition for vaginal administration comprising a treating agent (the tocolytic drug terbutaline is exemplified) and a bioadhesive cross-linked water-swellable but water-insoluble polycarboxylic acid such as polycarbophil, designed to give controlled and prolonged release of the drug through the vaginal mucosa. Administration of the composition is said to achieve local tissue concentrations without detrimental blood levels.
  • International Application No. WO 98/20917 of Shah mentions use of a hydrophilic polystyrene graft copolymer delivery vehicle for intravaginal administration of active agents such as progesterone or estrogen.
  • a method for preventing or treating a catamenial migrainous disorder comprising administering to a vulvovaginal surface a pharmaceutical composition that is bioadhesive thereto and comprises at least one estrogenic compound in an amount of about 50 ⁇ g to about 1000 ⁇ g estradiol equivalent per unit dose of the composition.
  • a method for preventing or treating a catamenial migrainous disorder comprising administering to a vulvovaginal surface a pharmaceutical composition comprising at least one estrogenic compound, wherein upon application of the composition to the vulvovaginal surface, a decline in serum estradiol concentration during a luteal phase of a menstrual cycle is moderated.
  • a method for managing serum estradiol concentration during a menstrual cycle in a female subject comprising a regimen that comprises:
  • a first regimen component wherein at least one estrogenic compound is administered to the subject according to a first mode of administration; said first mode of administration resulting in maintenance of a serum estradiol concentration of at least about 25 pg/ml during most or all of the menstrual cycle, except for an estrogen depleting phase of about 5 to about 10 days in duration beginning not earlier than about 7 days prior to menses; and
  • a second regimen component wherein at least one estrogenic compound is administered to the subject according to a second mode of administration; said second mode of administration (i) comprising administering to a vulvovaginal surface a pharmaceutical composition that is bioadhesive thereto and comprises said at least one estrogenic compound; and (ii) resulting in moderation of a decline in serum estradiol concentration during said estrogen depleting phase.
  • the pharmaceutical composition in one embodiment has at least one non-lipoidal internal phase and at least one lipoidal external phase that is bioadhesive to the vulvovaginal surface; and upon application of the composition to the vulvovaginal surface the at least one estrogenic compound is released over a period of about 3 hours to about 14 days.
  • the composition is a vaginal cream that is bioadhesive to a vaginal mucosal surface and is administered to such a surface.
  • kits useful for managing serum estradiol concentration during a menstrual cycle in a female subject comprising:
  • a first regimen component wherein at least one estrogenic compound is administered to the subject according to a first mode of administration; said first mode of administration resulting in maintenance of a serum estradiol concentration of at least about 25 pg/ml during most or all of the menstrual cycle, except for an estrogen depleting phase of about 5 to about 10 days in duration beginning not earlier than about 7 days prior to menses; and
  • a second regimen component wherein at least one estrogenic compound is administered to the subject according to a second mode of administration; said second mode of administration (i) comprising administering to a vulvovaginal surface a pharmaceutical composition that is bioadhesive thereto and comprises said at least one estrogenic compound; and (ii) resulting in moderation of a decline in serum estradiol concentration during said estrogen depleting phase.
  • migraine can be a brain disorder involving abnormal sensory processing.
  • a migrainous disorder herein thus includes migraine and all its symptoms, such as headache and cluster headache with moderate or severe pain, nausea, photophobia, and/or phonophobia, and further includes such symptoms even in absence of a specific diagnosis of migraine.
  • catamenial migrainous disorder herein denotes any migrainous disorder of or relating to the menstrual cycle, menstruation or the menses, or to estrogen withdrawal in pre-, peri- and post-menopausal women.
  • migraine particularly types of migraine such as pure menstrual migraine, menstrually related migraine, and estrogen withdrawal migraine, as well as menstrual headache even where migraine has not been diagnosed, are considered herein to be catamenial migrainous disorders.
  • migrainous disorders can be triggered by a precipitous drop in serum estradiol levels. Serum estradiol levels fluctuate throughout the menstrual cycle, rising gradually during the follicular phase (phase beginning around day 1 of the menstrual cycle), then falling immediately post-ovulation. A secondary rise occurs during the luteal phase (phase beginning post-ovulation and covering the latter half of the menstrual cycle) but a sharp decline typically occurs prior to initiation of menses.
  • serum estradiol levels can occur as a result of the natural menstrual cycle or can be artificially created or modulated by administration of a hormonal preparation, as for example in use of a hormonal contraceptive or in hormone replacement therapy. Serum estradiol levels can also fluctuate due to other types of hormonal change such as in pregnancy, post-partum and perimenopause.
  • Hutchinson (2005) Clinics in Family Practice 7(3:Special Issue): 529-543, while not admitted to be prior art to the present invention, mentions trying to maintain an even estradiol level to help with hormonally related migraine headaches in women.
  • a method of the invention for preventing or treating a catamenial migrainous disorder in a female subject comprises administering to a vulvovaginal surface, e.g., a vaginal mucosal surface, of the subject a pharmaceutical composition that is bioadhesive to such a surface, and comprises at least one estrogenic compound.
  • the at least one estrogenic compound is present in an amount of about 50 ⁇ g to about 1000 ⁇ g estradiol equivalent per unit dose of the composition.
  • a method of the invention for preventing or treating a catamenial migrainous disorder in a female subject comprises administering to a vulvovaginal surface of the subject a pharmaceutical composition comprising at least one estrogenic compound, wherein upon application of the composition to the vulvovaginal surface, a decline in serum estradiol concentration during a luteal phase of a menstrual cycle is moderated.
  • the decline that is moderated occurs within about 3 days prior to, or within about 5 days after, onset of menses.
  • "Moderation" of a decline in serum estradiol concentration herein includes making the decline more gradual, less profound, or both. In some situations, the decline can be substantially eliminated. Where it is desired to maintain at least a baseline serum estradiol concentration, a suitable baseline is typically at least about 25 pg/ml.
  • a “baseline” concentration herein means a minimum concentration consistent with an acceptably low risk or incidence of catamenial migrainous disorder in a particular subject. However, in at least some subjects, serum estradiol concentration can be allowed to decline below a typical baseline without provoking a catamenial migrainous disorder, so long as the decline is gradual.
  • the decline in serum estradiol concentration can be moderated through partial replacement of endogenous or exogenous estrogen supply.
  • this can be accomplished by (a) initial release of estrogen from the composition to compensate for partial or complete shut-down of endogenous estrogen production or withdrawal of exogenous estrogen; and by (b) extended release of estrogen from the composition, e.g., according to first order kinetics, or (c) follow-up administration at reduced (e.g., progressively reducing) dosage.
  • a "vulvovaginal surface” herein denotes any external or internal surface of the female genitalia, including mucosal surfaces in the vaginal cavity and nonmucosal surfaces of the vulva and immediately surrounding areas of skin.
  • the composition is more specifically adapted for application to a vaginal mucosal surface, and is bioadhesive to such a surface.
  • the composition is typically adapted for release of the at least one estrogenic compound over a period of about 3 hours to about 14 days. In various embodiments, the composition is adapted for release of the at least one estrogenic compound over a period consistent with a once daily to once weekly schedule, or a once to three times per week dosing schedule.
  • the composition is adapted for release of the at least one estrogenic compound over a period consistent with a single application during the luteal phase, especially during the second half of the luteal phase, of a menstrual cycle.
  • the composition is adapted for release of the at least one estrogenic compound over a period of about 3 hours to about 10 days, for example about 6 hours to about 7 days, about 12 hours to about 5 days, or about 1 to about 3 days.
  • a "release period" or equivalent phrase herein refers to a period during which the at least one estrogenic compound is made available for absorption at the site of administration, for example the vaginal cavity, in an amount sufficient to provide therapeutic benefit.
  • the "release period” begins when release substantially begins (e.g., immediately to about 1 hour after administration, or later in the case of a delayed- release composition), and ends when substantially no further active agent is available for release (e.g., about 3 hours to about 10 days after the beginning of the release period).
  • a method of the invention results in the serum estradiol concentration being maintained at least at a baseline level during the luteal phase, for example substantially the entire luteal phase or more particularly during the second half of the luteal phase, of the menstrual cycle. This can be accomplished by selecting an appropriate dose and release profile of the at least one estrogenic compound.
  • a dose and release profile of the at least one estrogenic compound can be selected to maintain serum estradiol concentration at or above a baseline of at least about 25 pg/ml, at least about 30 pg/ml, at least about 40 pg/ml, or at least about 50 pg/ml.
  • a baseline of at least about 25 pg/ml, at least about 30 pg/ml, at least about 40 pg/ml, or at least about 50 pg/ml can be desirable to maintain serum estradiol concentration above a certain baseline, it can further be desirable to keep serum estradiol concentration below a certain maximum at the same time.
  • the dose and release profile of the at least one estrogenic compound can be selected to result in a serum estradiol concentration not greater than about 150 pg/ml, not greater than about 125 pg/ml, not greater than about 100 pg/ml, not greater than about 80 pg/ml, or not greater than about 70 pg/ml.
  • the composition is administered during a luteal phase of a menstrual cycle.
  • the composition can be administered not earlier than about 10 days prior to menses, or not earlier than about 7 days prior to menses.
  • composition can be administered during the placebo phase of an oral contraceptive regimen.
  • the composition is administered during menses.
  • the bioadhesiveness of the composition provides a significant benefit in reducing or preventing loss of the composition by flushing out with the flow of menstrual fluid.
  • the composition exhibits sufficient bioadhesion to the vulvovaginal surface to substantially resist elution by menstrual flow.
  • the composition is administered during a luteal phase of a menstrual cycle and again during menses.
  • a suitable regimen of administration for a particular subject can be determined by a prescribing physician, and can be based, for example, on the responsiveness to treatment and/or the timing of specific migraine triggers.
  • a composition useful herein comprises at least one estrogenic compound.
  • An "estrogenic compound” herein is any compound or mixture thereof, whether of natural, biosynthetic or chemosynthetic origin, having estrogenic activity in a human female.
  • Estrogenic compounds include steroidal and nonsteroidal compounds.
  • Illustrative nonsteroidal estrogenic compounds include without limitation broparoestrol, chlorotrianisene, dienestrol, diethylstilbestrol, fosfestrol, hexestrol, methestrol, derivatives such as salts and esters thereof, enantiomers and racemates thereof, mixtures thereof and the like.
  • Illustrative steroidal estrogenic compounds include without limitation conjugated estrogenic hormones ⁇ e.g., Premarin®), equilenin, equilin, estradiol, estriol, estrone, ethinyl estradiol, mestranol, moxestrol, quinestradiol, quinestrol, derivatives such as salts and esters thereof, enantiomers and racemates thereof, mixtures thereof and the like.
  • the at least one estrogenic compound is a steroid.
  • the at least one estrogenic compound comprises a compound selected from the group consisting of conjugated estrogenic hormones, estradiol, ethinyl estradiol, estriol and estrone.
  • the at least one estrogenic compound comprises estradiol or a derivative thereof, e.g., ethinyl estradiol.
  • Amounts of the at least one estrogenic compound are expressed herein as estradiol equivalent amounts unless the context demands otherwise.
  • a composition of the invention provides about 50 to about 500 ⁇ g, for example about 100 to about 500 ⁇ g, about 150 to about 500 ⁇ g, or about 200 to about 500 ⁇ g, estradiol equivalent per unit dose.
  • the at least one estrogenic compound is present in a total estradiol equivalent amount of about 200 to about 450 ⁇ g, about 200 to about 400 ⁇ g, about 250 to about 400 ⁇ g, about 300 to about 400 ⁇ g or, illustratively, about 50 ⁇ g, about 100 ⁇ g, about 150 ⁇ g, about 200 ⁇ g, about 250 ⁇ g, about 300 ⁇ g, about 350 ⁇ g, about 400 ⁇ g, about 450 ⁇ g or about 500 ⁇ g per unit dose of the composition.
  • a unit dose is an amount of the composition suitable for a single administration to a vulvovaginal surface, for example a vaginal mucosal surface, as described herein. Most conveniently for the patient, the composition is provided in unit dose aliquots, typically individually packaged, but this is not a requirement of the present invention.
  • a convenient unit dose aliquot of a vaginal cream is an amount of about 1 to about 1O g, although greater or lesser amounts, for example as little as about 0.1 g or as much as about 25 g, can be used if desired.
  • a particularly suitable unit dosage amount of a vaginal cream is about 2 to about 6 g, for example about 2 g, about 3 g, about 4 g or about 5 g.
  • the total estradiol equivalent concentration in a low- dose composition is suitably about 10 to about 100 ⁇ g/g, for example about 20 to about 100 ⁇ g/g, about 30 to about 100 ⁇ g/g, or about 40 to about 100 ⁇ g ; in various embodiments about 40 to about 90 ⁇ g/g, about 40 to about 80 ⁇ g/g, about 50 to about 80 ⁇ g/g, about 60 to about 80 ⁇ g/g, or, illustratively, about 10 ⁇ g/g, about 20 ⁇ g/g, about 30 ⁇ g/g, about 40 ⁇ g/g, about 50 ⁇ g/g, about 60 ⁇ g/g, about 70 ⁇ g/g, about 80 ⁇ g/g, about 90 ⁇ g/g or about 100 ⁇ g/g.
  • suitable estradiol equivalent concentration ranges will be correspondingly lower or higher respectively.
  • the amount of the at least one estrogenic compound is modulated to compensate for reduced absorption resulting from premenopausal thickness of the vaginal epithelium.
  • a high-dose composition can be used.
  • the estradiol equivalent amount in the composition is about 350 to about 1000 ⁇ g, for example about 350 to about 750 ⁇ g, about 400 to about 500 ⁇ g, or about 400 to about 450 ⁇ g per unit dose.
  • a cream having an estradiol equivalent concentration substantially higher than about 400 ⁇ g per unit dose, for example about 420, about 425, about 440, about 450, about 460 or about 475 ⁇ g per unit dose, can be provided.
  • the pharmaceutical composition can be in any form adapted for application to a vulvovaginal surface, including for example a vaginal cream, thermally gelling formulation, tablet, pessary or implant.
  • the composition is in the form of a vaginal cream.
  • a particular composition useful according to a method of the invention can illustratively comprise a water-in-oil emulsion as generally described in any of above- referenced U.S. Patent No. 4,551,148, U.S. Patent No. 5,266,329 or U.S. Patent Application Publication No. 2003/0180366, or as further described in U.S. Patent Application No. 2005/0095245 of Riley et al, but differs from these at least in that it comprises an estrogenic compound as active agent.
  • Such a water-in-oil emulsion can be presented in a semi-solid form, for example as a vaginal cream as indicated above.
  • the pharmaceutical composition is a vaginal cream having at least one nonlipoidal internal phase and at least one lipoidal external phase that is bioadhesive to a vaginal mucosal surface.
  • Such a composition can be formulated, for example, as the VagiSite® bioadhesive topical drug delivery system described by Thompson & Levinson (2002), op. cit. , or a delivery system substantially equivalent thereto, with inclusion of at least one estrogenic compound as active agent.
  • a unit dosage amount of a vaginal cream used according to the method can be furnished in a prefilled container or applicator, for example an applicator similar to that used for Gynazole-1® vaginal cream of KV Pharmaceutical Co., St Louis, MO.
  • the applicator can be disposable, and more particularly, the applicator can be prefilled with a unit dose of the composition.
  • the at least one estrogenic compound can be present in either one or both of the internal and external phases.
  • the at least one estrogenic compound is present at least in part in the internal phase of the composition, and can be in dispersed form, for example in solution or suspension therein, or in non-dispersed form.
  • substantially all of the at least one estrogenic compound can be present in the internal phase. Solubilization of the at least one estrogenic compound can be achieved, for
  • the at least one estrogenic compound can be present at least in part in particulate form, for example in micronized form, and can be dispersed as a particulate suspension in the internal and/or external phase.
  • the at least one estrogenic compound is present in solution, in aggregates, in liposomes, in microcapsules and/or in micelles within the internal and/or external phase. If present in both internal (nonlipoidal) and external (lipoidal) phases, the at least one estrogenic compound can be present in similar or different amounts in the nonlipoidal and lipoidal phases.
  • the composition is adapted to release the at least one estrogenic compound over a period of about 3 hours to about 14 days, upon application to a vulvovaginal surface, for example a vaginal mucosal surface.
  • a vulvovaginal surface for example a vaginal mucosal surface.
  • Release rate can be determined by in vivo testing or by any suitable in vitro method.
  • An illustrative in vitro method utilizes an open chamber diffusion cell system such as a Franz cell system, typically fitted with an appropriate inert synthetic membrane such as polysulfone, cellulose acetate/nitrate mixed ester or polytetrafluoroethylene of suitable thickness, e.g., 70 ⁇ m.
  • the receptor medium should be one in which the estrogenic compound of interest is soluble, for example a water/ethanol medium.
  • a test composition is placed uniformly on the membrane (illustratively, about 300 mg of a semisolid composition such as a cream is a suitable amount for placement on a 25 mm diameter membrane) and is kept occluded to prevent solvent evaporation and compositional changes. This corresponds to an infinite dose condition.
  • An aliquot of the receptor fluid is removed for analysis at appropriate intervals, and is replaced with an aliquot of fresh receptor fluid, so that the membrane remains in contact with the receptor fluid throughout the period of the release study.
  • a release rate study such as that outlined above is typically replicated and can be conducted using a standard composition having known release properties for comparison.
  • the composition typically comprises unit cells each having internal and external phases.
  • the at least one internal phase can be discontinuous and is nonlipoidal and generally miscible with water.
  • the internal phase comprises water, glycerin, propylene glycol, sorbitol or a combination of two or more thereof.
  • the internal phase can itself be monophasic, biphasic or multiphasic, taking the form for example of a solution, suspension, emulsion or combination thereof.
  • the internal phase can comprise one or more suspended solids, osmotic agents, extenders, diluents, buffers, chelating agents, preservatives or other materials.
  • the internal phase is acid buffered to an internal pH of about 2.0 to about 6.0, for example about 2.5 to about 5.5 or about 3.5 to about 5.0.
  • the internal phase is acid buffered to an internal pH that is substantially optimal to the vaginal environment, i.e., a pH that does not cause substantial irritation, itching or other discomfort and/or is detrimental to common pathogens of the vaginal cavity, including fungal pathogens such as Candida species and bacterial pathogens such as Enterococcus species. Typically such a pH is approximately 4.5.
  • the external phase is lipoidal and generally continuous.
  • lipoidal herein can pertain to any of a group of organic compounds including neutral fats, fatty acids, waxes, phosphatides, petrolatum, fatty acid esters of monoprotic alcohols, mineral oils, etc., having the following properties: insoluble in water; soluble in alcohol, ether, chloroform or other fat solvents; and exhibiting a greasy feel.
  • suitable oils are mineral oils having viscosity of about 5.6 to about 68.7 centistokes, for example about 25 to about 65 centistokes, and vegetable oils such as coconut, palm kernel, cocoa butter, cottonseed, peanut, olive, palm, sunflower, sesame, corn, safflower, rapeseed (canola) and soybean oils and fractionated liquid triglycerides of naturally derived short-chain fatty acids.
  • lipoidal can also pertain to amphiphilic compounds, including for example natural and synthetic phospholipids.
  • Suitable phospholipids can include, for example phosphatidylcholine esters such as dioleoylphosphatidylcholine, dimyristoyl- phosphatidylcholine, dipentadecanoylphosphatidylcholine, dipalmitoylphosphatidyl- choline (DPPC) and distearoylphosphatidylcholine (DSPC); phosphatidylethanolamine esters such as dioleoylphosphatidylethanolamine and dipalmitoylphosphatidylethanol- amine (DPPE); phosphatidylserine; phosphatidylglycerol; phosphatidylinositol; etc.
  • DPPC dipalmitoylphosphatidyl- choline
  • DPPE dipalmitoylphosphatidylethanol- amine
  • Amphiphilic compounds can act as emulsifying agents in a composition of the invention. Any pharmaceutically acceptable emulsifying agent or combination thereof can be used, including without limitation medium and long chain monoglycerides and diglycerides, such as glyceryl monooleate, glyceryl monostearate, glyceryl monoisostearate and glyceryl monopalmitate, and polyglyceryl esters of fatty acids, such as polyglyceryl-3 oleate. Such agents can also function as emollients in the composition.
  • Factors affecting release rate of the estrogenic compound(s) can include the particular estrogenic compound(s) used, the physical form of the estrogenic compound(s) (e.g., whether in solution or in particulate form, and if particulate, average particle size), viscosity of the composition, selection and relative amounts of lipoidal compounds, including amphiphilic compounds, in the external phase, osmotic properties of the internal phase, and the relative volumes of the internal and external phases, among other factors.
  • the external phase tends to form a relatively thick membrane through which the estrogenic compound(s) must pass to be released; accordingly release rate can be significantly slowed in such a composition.
  • a suitable internal phase ratio can be established for any particular system by routine testing.
  • the internal phase ratio is at least about 70% by volume.
  • a semi-solid composition used according to methods of the invention can have a viscosity of about 5,000 to about 1,000,000 centipoise, for example about 5,000 to about 750,000 centipoise, about 100,000 to about 80O 5 OOO centipoise, about 100,000 to about 400,000 centipoise, about 350,000 to about 750,000 centipoise, about 100,000 to about 550,000 centipoise, about 250,000 to about 400,000 centipoise, about 200,000 to about 350,000 centipoise, or about 350,000 to about 550,000 centipoise.
  • a composition useful herein is a thermally gelling formulation comprising a thermosetting polymer, e.g., a poloxamer such as poloxamer 407 (available, for example , as PluronicTM F-127 of BASF).
  • a thermosetting polymer e.g., a poloxamer such as poloxamer 407 (available, for example , as PluronicTM F-127 of BASF).
  • a vaginal cream comprises at least one estrogenic compound, for example estradiol, ethinyl estradiol or estrone, water, sorbitol, propylene glycol, at least one long chain monoglyceride, for example glyceryl monooleate, glyceryl monostearate, glyceryl monoisostearate or glyceryl monopalmitate, a chelating agent, for example edetate disodium, at least one antimicrobial preservative, for example methylparaben and/or propylparaben, mineral oil, microcrystalline wax and colloidal silicon dioxide, for example hydrophobically modified colloidal silicon dioxide.
  • estrogenic compound for example estradiol, ethinyl estradiol or estrone
  • water sorbitol
  • propylene glycol at least one long chain monoglyceride
  • glyceryl monooleate for example glyceryl monostearate, glyceryl monoisost
  • a composition, used according to a method of the invention, in the form of a vaginal cream can be prepared by known batch or continuous processes for preparing pharmaceutical creams.
  • shear force is applied to the components by use of a mixer, homogenizer, mill, impingement surface, ultrasound, shaking or vibration.
  • Mixing shear should be at a relatively low level to prevent destruction of the emulsion by excess energy.
  • the internal and external phases are first prepared separately.
  • the internal phase is added to the external phase while mixing in a planetary-type or other suitable mixer until a stable emulsion is formed.
  • Addition rates and mixing speeds can be adjusted to optimize formation and viscosity of the emulsion.
  • the external phase is introduced into a continuous mixer that comprises a plurality of impellers, until it reaches the level of the lowest impeller in the mixing chamber.
  • the two phases are then simultaneously introduced through the bottom of the mixer in proper proportion as the impellers rotate to apply shear to the components.
  • the finished emulsion emerges through the top of the mixer. Flow rate through the mixing chamber and mixing speed can be adjusted to optimize formation and viscosity of the emulsion.
  • the composition can be administered topically to external surfaces of the vulva and/or to surrounding areas of skin.
  • the composition can be administered intravaginally.
  • the composition is a vaginal cream, i.e., a semi-solid formulation adapted for administration to vaginal mucosal surfaces.
  • the amount of the composition to be administered will depend on the particular estrogenic compound or compounds present, the concentration of such compound or compounds in the composition, the frequency of administration (as determined for example by release rate) and other factors. For example, to allow for greater thickness of the vaginal epithelium, the amount can be increased to deliver desired plasma levels.
  • a vaginal cream of the invention can be administered to contact a mucosal surface in the vaginal cavity by means, for example, of an applicator that is optionally pre- filled with a single unit dosage amount of the cream.
  • an applicator that is optionally pre- filled with a single unit dosage amount of the cream.
  • the tip of the applicator With the patient optionally in a supine position, the tip of the applicator can be gently inserted high in the vagina, for example in the posterior vaginal fornix, and the cream can be released through the tip by pushing on a plunger of the applicator.
  • a prolonged release period is enabled by compositions of some embodiments of the invention. Such a prolonged release period brings a number of benefits to the patient, including without limitation those discussed immediately below.
  • frequency of application can be significantly reduced by comparison with a composition having faster release.
  • frequency of application of a prolonged- release composition for effective treatment is once every 2 to 14 days, for example about 1 to about 3 times per week, illustratively about three times weekly, about twice weekly or about once weekly.
  • frequency of application is once per menstrual cycle, i.e., typically about once per month.
  • the slow release from such a composition can result in controlled serum levels of estradiol. This minimizes serum fluctuations observed with other dosing regimens such as once daily dosing.
  • dosage amounts of the estrogenic compound can be reduced to levels close to the lowest effective dose for prevention or treatment of a migrainous disorder, taking advantage of the drug-sparing effect of slow release and minimizing adverse side effects.
  • a method for managing serum estradiol concentration during a menstrual cycle in a female subject comprises administering at least one estrogenic compound according to a regimen having two components.
  • the first regimen component at least one estrogenic compound is administered to the subject according to a first mode of administration that results in maintenance of a serum estradiol concentration of at least about 50 pg/ml, for example at least about 75 pg/ml, during most or all of the menstrual cycle, except for an estrogen depleting phase of about 5 to about 10 days in duration beginning not earlier than about 7 days prior to menses.
  • the first regimen component can be delivered by any one or more routes, including orally, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transmucosally, buccally, sublingually, intravaginally, by inhalation, by depot injection, or by implantation.
  • the first regimen component can comprise any element of a hormone replacement or contraceptive regimen, including an entire such regimen.
  • Hormone replacement regimens include therapy with estrogen alone, optionally in combination with progestin (including progesterone) and/or testosterone. Any frequency of administration can be utilized with the invention, including sequentially or continuously combined hormone replacement therapy.
  • Contraceptive regimens can include any combined estrogen and progestin regimen, administered for example in the form of oral contraceptives, transdermal patches, vaginal rings or monthly injections: [0076]
  • the second regimen component at least one estrogenic compound is administered to the subject according to a second mode of administration that (i) comprises administering to a vulvovaginal surface a pharmaceutical composition that is bioadhesive to such a surface and comprises the at least one estrogenic compound; and (ii) results in moderation of a decline in serum estradiol concentration during the estrogen depleting phase of the first regimen component. '
  • the at least one estrogen compound administered according to the second regimen component can be the same as or different from the at least one estrogen compound administered according to the first regimen component.
  • the bioadhesive composition and method of administration thereof to a vulvovaginal surface according to the second regimen component can be any such composition and method disclosed herein.
  • the composition is a vaginal cream having at least one nonlipoidal internal phase and at least one lipoidal external phase that is bioadhesive to a vaginal mucosal surface.
  • the at least one estrogenic compound is present in the cream in an amount typically of about 50 to about 500 ⁇ g estradiol equivalent per unit dose of the cream, and, upon application of the cream to the vaginal mucosal surface, is released over a period of about 3 hours to about 14 days.
  • a kit useful for managing serum estradiol concentration during a menstrual cycle in a female subject comprises (a) one to a plurality of compositions adapted for use in a regimen that results in maintenance of a serum estradiol concentration of at least about 50 pg/ml, for example at least about 75 pg/ml, during most or all of the menstrual cycle, except for an estrogen depleting phase of about 5 to about 10 days in duration beginning not earlier than about 7 days prior to menses; and (b) a pharmaceutical composition that is bioadhesive to a vulvovaginal surface and comprises at least one estrogenic compound in an amount of about 50 to about 500 ⁇ g estradiol equivalent per unit dose of the composition.
  • the kit optionally further comprises instructions, in hard-copy and/or electronic form, instructions for vulvovaginal administration of the bioadhesive composition to prevent or treat a catamenial migrainous disorder promoted by the regimen.
  • the bioadhesive composition in such a kit can be any such composition disclosed herein.
  • the composition is a vaginal cream having at least one nonlipoidal internal phase and at least one lipoidal external phase that is bioadhesive to a vaginal mucosal surface.
  • the at least one estrogenic compound is present in the cream in an amount typically of about 50 to about 500 ⁇ g estradiol equivalent per unit dose of the cream, and, upon application of the cream to the vaginal mucosal surface, is released over a period of about 3 hours to about 14 days.
  • a kit as described above further comprises an ovulation indicator, i.e., a device or material that detects timing of ovulation, from which a date of expected onset of menses (and therefore a date of expected onset of an estrogen depleting phase) can be predicted.
  • an ovulation indicator i.e., a device or material that detects timing of ovulation, from which a date of expected onset of menses (and therefore a date of expected onset of an estrogen depleting phase) can be predicted.
  • Any ovulation indicator known in the art for example a test strip for use with a biofluid such as saliva or urine, can be used.
  • Instructions optionally included as part of the kit can provide direction on use of the ovulation indicator in conjunction with vulvovaginal administration of the bioadhesive composition to prevent or treat a catamenial migrainous disorder.
  • Vaginal cream formulations (Table 1) containing estradiol at 50-500 ⁇ g/g can be prepared by any method known in the art for preparing semi-solid emulsions, including batch and continuous processes as described hereinabove.
  • USP refers to U.S. Pharmacopeia
  • NF refers to National Formulary.
  • Compositions of Table 1 can be administered in a dosage amount of about 5 g to a vulvovaginal surface for treatment of a catamenial migrainous disorder, for example menstrual migraine, according to a method as described herein.

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Abstract

L'invention concerne un procédé de prévention ou de traitement d'un trouble migraineux cataménial chez la femme. Ce procédé comprend l'administration sur une surface vulvo-vaginale du sujet d'une composition pharmaceutique qui est bioadhésive à cette surface et qui comprend au moins un composé œstrogène en une quantité allant d'environ 50 µg à environ 1000 µg d'équivalent œstradiol par unité de dose de la composition. Un procédé apparenté comprend l'administration sur une surface vulvo-vaginale du sujet d'une composition pharmaceutique comprenant au moins un composé œstrogène. Après administration de la composition sur la surface vulvo-vaginale, la baisse de la concentration en œstradiol sérique pendant une phase lutéale d'un cycle menstruel est modérée.
PCT/US2006/031117 2006-08-10 2006-08-10 Procédés thérapeutiques utilisant des compositions à base d'œstrogènes WO2008018872A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007112A2 (fr) * 2003-07-16 2005-01-27 Duramed Pharmaceuticals, Inc. Procedes de traitement hormonal utilisant des posologies contraceptives avec administration continue d'oestrogenes
EP1535618A1 (fr) * 2003-11-26 2005-06-01 Schering Aktiengesellschaft Préparation pharmaceutique pour le traitement hormonal continuel sur plus de 21-28 jours comprenant deux compositions d'estrogène et/ou de progestine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007112A2 (fr) * 2003-07-16 2005-01-27 Duramed Pharmaceuticals, Inc. Procedes de traitement hormonal utilisant des posologies contraceptives avec administration continue d'oestrogenes
EP1535618A1 (fr) * 2003-11-26 2005-06-01 Schering Aktiengesellschaft Préparation pharmaceutique pour le traitement hormonal continuel sur plus de 21-28 jours comprenant deux compositions d'estrogène et/ou de progestine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOYLE CAROL A J: "Management of menstrual migraine", NEUROLOGY, vol. 53, no. SUPPL. 1, 1999, pages S14 - S18, XP008031071, ISSN: 0028-3878 *
MERABET JENNIFER ET AL: "Advancing vaginal drug delivery.", EXPERT OPINION ON DRUG DELIVERY JUL 2005, vol. 2, no. 4, July 2005 (2005-07-01), pages 769 - 777, XP009081590, ISSN: 1742-5247 *

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