WO2000074684A1 - Formulations pharmaceutiques pour traiter des femmes en periode de postmenopause et de perimenopause, et leur utilisation - Google Patents

Formulations pharmaceutiques pour traiter des femmes en periode de postmenopause et de perimenopause, et leur utilisation Download PDF

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Publication number
WO2000074684A1
WO2000074684A1 PCT/US2000/040061 US0040061W WO0074684A1 WO 2000074684 A1 WO2000074684 A1 WO 2000074684A1 US 0040061 W US0040061 W US 0040061W WO 0074684 A1 WO0074684 A1 WO 0074684A1
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pharmaceutical formulation
woman
derivatives
progestin
postmenopausal
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PCT/US2000/040061
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English (en)
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Kathryn A. Martin
William F. Crowley, Jr.
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The General Hospital Corporation
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Priority to AU51812/00A priority Critical patent/AU5181200A/en
Priority to JP2001501220A priority patent/JP2003501390A/ja
Priority to EP00936507A priority patent/EP1187618A1/fr
Publication of WO2000074684A1 publication Critical patent/WO2000074684A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—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 having an oxo group in position 17, e.g. estrone
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • 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
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to pharmaceutical formulations and methods for treating postmenopausal and perimenopausal women.
  • Postmenopausal women including young women who suffer from ovarian dysfunction due to surgical, radiation, or chemotherapy induced ablation, for example, typically exhibit particular physiological signs associated with impairment of ovarian function. For example, such women typically experience a loss of calcium from the skeleton, leading to a reduction in bone density or in the quantity of bone. In addition, such women may have increased cholesterol levels, leading to atherosclerosis. Other symptoms include depression, headaches , and nausea . Perimenopausal women experience a change in the intermenstrual cycle interval, along with other associated symptoms of estrogen deficiency, such as vasomotor flushes, vaginal dryness, or worsening premenstrual syndromes .
  • An exemplary pharmaceutical formulation of the invention includes (i) an androgen or a selective androgen receptor modulator (SARM) , (ii) an estrogen or a selective estrogen receptor modulator (SERM) , and (iii) a progestin or a selective progestin receptor modulator (SPRM) in a pharmaceutically acceptable carrier.
  • SARM selective androgen receptor modulator
  • SERM selective estrogen receptor modulator
  • SPRM progestin or a selective progestin receptor modulator
  • the invention features a pharmaceutical formulation that includes (i) a SERM and (ii) an androgen or a SARM in a pharmaceutically acceptable carrier.
  • this pharmaceutical formulation also includes (iii) a progestin or a SPRM.
  • Pharmaceutical formulations containing a therapeutically effective amount of a SERM and an androgen or SARM, and optionally a progestin or SPRM, can be used to treat postmenopausal women and perimenopausal women.
  • a pharmaceutical formulation that includes (i) a SERM and (ii) an estrogen, and optionally (iii) a progestin or SPRM.
  • a pharmaceutical formulation containing a therapeutically effective amount of the SERM and estrogen, and optionally progestin, can be used in methods of treating postmenopausal and perimenopausal women.
  • the invention includes a pharmaceutical formulation containing (i) a SERM, (ii) an estrogen, and (ii) an androgen or SARM, and optionally (iv) a progestin or SPRM.
  • a pharmaceutical formulation containing the SERM, estrogen, androgen, and optionally progestin, in a therapeutically effective amount can be used in methods of treating postmenopausal and perimenopausal women.
  • estrogens progestins, androgens, SERMs, SARMs, and SPRMs
  • suitable estrogens include conjugated estrogens, esterified estrogens, estradiol valerate, estradiol benzoate, 17- ⁇ estradiol, estradiol cypionate, estrone, piperazine estrone sulfate, estriol, ethyl estradiol, polyestradiol phosphate, estrone potassium sulfate, benzestrol, chlorotrianisene, methallenestril, dienestrol, diethylstilbestrol diphosphate, mestranol, diethylstilbestrol (DES) , quinestranol, and phytoestrogens .
  • Animal-derived estrogens e.g., equine estrogens
  • metabolic derivatives also are suitable for use in the invention, and are commercially available.
  • progestins examples include progesterone, 17-hydroxy progesterone derivatives, 19-nor testosterone derivatives, norethindrone, norethindrone acetate, norethynodrel, norgestrel, norgestimate, ethynodiol diacetate, allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone, dimethiderome, ethisterone, cyproterone levo-norgestrel, dl-norgestrel, cyproterone acetate, gestodene, desogestrol , phytoprogestins, dydrogesterone, ethynodiol diacetate, medroxyprogesterone acetate, phytoprogestins, and megestrol acetate.
  • Animal- derived progestins e.g
  • Suitable androgens include testosterone, methyltestosterone, fluoxymesterone, testosterone cypionate, testosterone enanthate, testosterone propionate, oxymetholone , ethylestrenol, oxandrolone, nandrolone phenpropionate, nandrolone decanoate, stanozolol, dromostanolone propionate, androstenedione, dehydropepiandrosterone, dehydroepiandrosterone sulfate (DHEAS) , dihydrotestosterone, and phytoandrogens .
  • Animal-derived androgens e.g., equine androgens
  • metabolic derivatives also are suitable for use in the invention.
  • SERMs examples include tamoxifen, raloxifene, clomiphene, droloxifene, idoxifene, toremifene, tibolone, ICI 182,780, ICI 164,384, diethylstilbesterol, genistein, nafoxidine, moxestrol, 19-nor-progesterone derivatives, and 19- nor-testosterone derivatives.
  • SARMs include cyproterone acetate, hydroxyflutamide, bicalutamide, spironolactone, 4- (trifluoromethyl) -2 (1H) - pyrrolidino [3 , 2-g] quinolinone derivatives, 1,2- dihydropyridono [5, 6-g] quinoline derivatives, and piperidino [3 , 2-g] quinolinone derivatives .
  • SPRMs examples include RU486, CDB2914, 19-nor-progesterone derivatives, 19-nor- testosterone derivatives, 6-aryl-l, 2-dihydro-2 , 2 , 4- trimethylquinoline derivatives, 5-aryl-l, 2-dihydro- 5H-chromeno [3 , 4-f] quinoline derivatives, 5-alkyl 1, 2-dihydrochomeno [3 , 4-f] quinoline derivatives, and 6-thiophenehydroquinoline derivatives .
  • the pharmaceutical formulations described herein are contained within a transdermal patch or an intravaginal ring for delivery of the pharmaceutical formulation to the woman.
  • transdermal routes e.g., through the use of topically applied creams, ointments, and the like
  • intravaginal routes e.g., through the use of suppositories, creams, and the like
  • the pharmaceutical formulations can be prepared for administration via routes such as oral, intranasal, buccal , ocular, aural, injectable depot, subcutaneous, intraperitoneal, intrauterine, sublingual, or intramuscular routes of administration.
  • routes of administration can be used to deliver the estrogen, androgen, progestin, SERM, SARM, and/or SPRM to the woman (e.g., oral and transdermal routes) .
  • multiple estrogens, androgens, progestins, SERMs, SARMs, and/or SPRMs can be used to prepare the pharmaceutical formulation or to treat the woman in lieu of a single estrogen, androgen, progestin, SERM, SARM, and/or SPRM.
  • a "postmenopausal" woman is one who in the absence of hormone replacement therapy or other medication would experience at least 12 months of amenorrhea or levels of serum follicle-stimulating hormone greater than 30 mlU/ml .
  • a "perimenopausal" woman is one who in the absence of hormone replacement therapy or other medication would experience a change in her intermenstrual cycle interval and have associated symptoms of estrogen deficiency, such as vasomotor flushes, vaginal dryness, and worsening premenstrual syndrome. Also included are women who in the absence of hormone replacement therapy or other medication would experience less than 12 months of amenorrhea .
  • an "androgen” is a natural or synthetic agent that stimulates activity of the accessory male sex organs and/or muscle development and/or encourages development of male sex characteristics.
  • suitable androgens include, without limitation, testosterone, methyltestosterone, fluoxymesterone, testosterone cypionate, testosterone enanthate, testosterone propionate, oxymetholone, ethylestrenol, oxandrolone, nandrolone phenpropionate, nandrolone decanoate, testosterone buccilate, stanozolol, dromostanolone propionate, androstenedione, dehydropepiandrosterone, DHEAS, dihydrotestosterone, phytoandrogens , animal-derived androgens, and metabolic derivatives of animal- derived androgens .
  • progestin is an agent, natural or synthetic, that effects some or all of the biological changes produced by progesterone, which is a hormone of the corpus luteum.
  • progesterone which is a hormone of the corpus luteum.
  • a progestin can induce secretory changes in the endometrium.
  • progestins include, without limitation, progesterone, 17-hydroxy progesterone derivatives, 19-nor-testosterone derivatives, 19-nor-progesterone derivatives norethindrone, norethindrone acetate, norethynodrel, norgestrel, norgestimate, ethynodiol diacetate, allylestrenol, lynoestrenol , fuingestanol acetate, medrogestone, norgestrienone, dimethiderome, ethisterone, cyproterone levo-norgestrel, dl- norgestrel, cyproterone acetate, gestodene, desogestrol, dydrogesterone, ethynodiol diacetate, medroxyprogesterone acetate, megestrol acetate, phytoprogestins, animal-derived prog
  • estradiol is an agent, natural or synthetic, that exerts biological effects characteristic of estrogenic hormones such as estradiol.
  • estradiol also encompasses "conjugated estrogens, " which are an amorphous preparation of naturally occurring, water- soluble, conjugated forms of mixed estrogens that typically are obtained from the urine of pregnant mares (e.g., sodium estrone sulfate). Also included are “esterified estrogens, " which are a mixture of the sodium salts of sulfate esters or glucanoride of sulfate conjugates of estrogenic substances.
  • suitable estrogens include, without limitation, estradiol valerate, estradiol benzoate, 17- ⁇ estradiol, estradiol cypionate, estrone, piperazine estrone sulfate, estriol, ethyl estradiol, polyestradiol phosphate, estrone potassium sulfate, benzestrol, chlorotrianisene, methallenestril, dienestrol, diethylstilbestrol diphosphate, mestranol, DES, quinestranol , phytoestrogens, animal-derived estrogens (e.g., equine estrogens) , and metabolic derivatives of animal-derived estrogens.
  • SERM is a compound that is an estrogen analog and which exerts tissue-selective effects. Such compounds can function as estrogen antagonists or partial agonists.
  • a "selective androgen receptor modulator” (SARM) is a compound that is an androgen analog and which exerts tissue-selective effects. Such compounds can function as androgen antagonists or partial agonists.
  • a “selective progestin receptor modulator” (SPRM) is a compound that is an progesterone analog and which exerts tissue-selective effects. Such compounds can function as progesterone antagonists or partial agonists.
  • SPRM selective progestin receptor modulator
  • the hormone replacement methods of the invention can be used to restore normal physiologic levels of all gonadal steroids for optimal management of symptoms .
  • Other features and advantages of the invention will be evident from the following detailed description of the preferred embodiments, and from the claims. Description of the Preferred Embodiments The pharmaceutical formulations and therapeutic methods of the invention are suitable for virtually all postmenopausal and perimenopausal women .
  • compositions of the invention include a pharmaceutically acceptable carrier and one of the following combinations of active ingredients:
  • A (i) an androgen or SARM, (ii) an estrogen or SERM, and (iii) a progestin or SPRM;
  • B (i) a SERM and (ii) an androgen or SARM, and optionally (iii) a progestin or SPRM;
  • (D) (i) a SERM, (ii) an estrogen, and (iii) an androgen or SAM, and optionally (iv) a progestin or SPRM.
  • Such formulations typically contain from about 0.1 to 90% by weight (such as 1 to 20% or 1 to 10%) of the active ingredients in a pharmaceutically acceptable carrier.
  • the pharmaceutical formulations are prepared for delivery via an intravaginal ring.
  • Intravaginal rings are well known in the art, and such rings can readily be adapted to contain the above-described combinations of active ingredients in a pharmaceutically acceptable carrier.
  • an oil or water is used as the carrier.
  • intravaginal rings examples include Suitable intravaginal rings in U.S. Patents No. 4,762,717; 5,130,137; 4,012,496; 3,854,480; 4,391,797; 4,591,496; and 5,330,768, which are incorporated herein by reference .
  • Typical intravaginal rings that can be adapted for use in the invention are made of ethylvinylacetate .
  • the intravaginal ring includes estrogen or a SERM at a level sufficient to recreate estrogen effects equivalent to those encountered in the early follicular phase of a typical, normal menstrual cycle.
  • the androgen or SARM typically is contained within the ring at a level sufficient to recreate androgen effects equivalent to those encountered in the early follicular phase of a typical, normal menstrual cycle.
  • the progestin or SPRM is included at a level sufficient to recreate progestin effects equivalent to those encountered in the luteal phase of a typical, normal menstrual cycle. Examples of suitable dosages are described below.
  • the pharmaceutical formulations of the invention are contained within a transdermal patch.
  • transdermal patches are known in the art and can readily be adapted to contain and deliver the pharmaceutical formulations of the invention. Examples of suitable transdermal patches are disclosed in U.S. Patents No. 5,223,261; 3,598,123; 4,460,372; 3,598,122; 4,573,996; and 4 , 624 , 665 , which are incorporated herein by reference.
  • Typical transdermal patches have a flexible backing, a drug reservoir layer, a semipermeable membrane, and an adhesive layer coated on the exterior surface of the semipermeable membrane.
  • Theratech patch technology for example, can be used in the invention.
  • the patch may contain a skin penetration enhancer (e.g., a fatty acid ester of a fatty acid such as ethyl oleate, glyceryl monolaurate, and/or isopropyl myristate) .
  • a skin penetration enhancer e.g., a fatty acid ester of a fatty acid such as ethyl oleate, glyceryl monolaurate, and/or isopropyl myristate
  • the pharmaceutical formulation is contained within the adhesive coating, rather than in a distinct drug reservoir layer.
  • a patch may contain, for example, a flexible backing (e.g., polyethylene, polypropylene, polyurethane, and the like) and a pressure-sensitive adhesive coating contiguously adhered to one surface of the backing and containing a homogenous mixture of: (i) an acrylic polymer containing a hydrophobic monomeric acrylic or methacrylic ester of an alkyl alcohol (containing 4-10 carbons) , polyanhydrides, polyvinylacetate, polylactide or polyglycolide mixes; ( ii) the active ingredients, each in an amount of about 0.2 to 12 percent of the total weight of the adhesive coating; and (iii) a skin penetration enhancer that includes isopropyl myristate and glyceryl monolaurate each in an amount of about 1 to 20 percent of the weight of the adhesive coating.
  • Solid formulations for oral administration can contain suitable carriers or excipients, such as corn starch, gelatin, lactose, liposomes, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, or alginic acid.
  • suitable carriers or excipients such as corn starch, gelatin, lactose, liposomes, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, or alginic acid.
  • Disintegrators that can be used include, without limitation, micro- crystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
  • Tablet binders that may be used include acacia, methylcellulose, sodium carboxy ethylcellulose, polyvinylpyrrolidone (Povidone) , hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose .
  • Lubricants that may be used include magnesium stearates, stearic acid, silicone fluid, talc, waxes, oils, and colloidal silica.
  • Liquid formulations for oral or sublingual administration typically are prepared in water or other aqueous vehicles.
  • the liquid formulations also can include solutions, emulsions, syrups, and elixirs containing, together with the active ingredients, wetting agents, sweeteners, and coloring and flavoring agents.
  • Various liquid and powder formulations can be prepared by conventional methods for inhalation by the woman.
  • Injectable formulations can contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polylactide, polyglycolide, polyols, (glycerol, propylene glycol, liquid polyethylene glycol, and the like) .
  • the compounds may be administered by the drip method, whereby a pharmaceutical formulation containing the active ingredients and a pharmaceutically acceptable carrier is infused.
  • Pharmaceutically acceptable carries can include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable carriers.
  • a sterile formulation containing the active ingredients can be administered in a pharmaceutical carrier such as Water-for-Injection, 0.9% saline, or 5% glucose solution.
  • a topical semi-solid ointment formulation typically contains a concentration of the active ingredients from about 1 to 20% (e.g., 5 to 10%) in a carrier such as a pharmaceutical cream base.
  • compositions for topical use include drops, tinctures, lotions, creams, solutions, and ointments containing the active ingredient and various supports and vehicles.
  • the pharmaceutical formulations of the invention can be administered to the woman via a variety of combinations of routes of administration.
  • an androgen, estrogen, and progestin can be combined and delivered transdermally (e.g., via a transdermal patch) .
  • an estrogen can be administered orally, while the progestin and androgen are administered transdermally.
  • an androgen, estrogen, and progestin are administered orally.
  • the androgen, estrogen, and progestin can be administered via an intravaginal ring.
  • Therapeutic Regimens Virtually all postmenopausal and perimenopausal women can be treated with the methods of the invention. If desired, such a woman can be identified as being in need of hormone replacement therapy (using standard criteria, as described, for example, by the American College of Physicians
  • the androgen typically is administered at a daily dosage of 0.01 ⁇ g to 5 mg/kg of body weight (e.g., 1 ⁇ g/kg to 5 mg/kg)
  • the estrogen typically is administered at a dosage of 0.01 ⁇ g/kg to 4 mg/kg (e.g., 0.2 ⁇ g/kg to 100 ⁇ g/kg)
  • the progestin typically is administered at a dosage of 0.02 mg/kg to 200 mg/kg (e.g., 2 ⁇ g/kg to 10 mg/kg).
  • a SARM typically is administered at a daily dosage of 0.01 ⁇ g/kg to 100 mg/kg of body weight (e.g., 1 ⁇ g/kg to 4 mg/kg)
  • a SERM typically is administered at a dosage of 0.01 ⁇ g/kg to 100 ⁇ g/kg (e.g., 1 ⁇ g/kg to 2 mg/kg)
  • a SPRM typically is administered at a dosage of O.Ol ⁇ g/kg to 100 mg/kg (e.g., 1 ⁇ g/kg to 30 mg/kg) .
  • the pharmaceutical formulation can be administered in multiple doses per day, if desired, to achieve the total desired daily dose. Typically, the woman will be treated over the course of several months or years, or even life-long to ameliorate the signs and symptoms resulting from natural or induced impairment of ovarian function.
  • the therapeutic regimen entails administering to the woman a pharmaceutical formulation containing each of (i) an androgen or SARM, (ii) an estrogen or SERM, and (iii) a progestin or SPRM at least once daily for 13 to 14 days, followed by administering each of (i) an estrogen or SERM and (ii) an androgen or SARM at least once daily for 13 to 14 days.
  • a pharmaceutical formulation containing each of (i) an androgen or SARM, (ii) an estrogen or SERM, and (iii) a progestin or SPRM at least once daily for 13 to 14 days.
  • the dosages listed above are suitable.
  • the woman is treated with a pharmaceutical formulation containing each of (i) a SERM, (ii) an androgen or SARM, and, optionally, (iii) a progestin or SPRM.
  • this pharmaceutical formulation is administered to the woman at least once daily (e.g., orally, or delivered by transdermal or depot methods) for at least 30 days, at the dosages listed above.
  • the woman will be treated over the course of several months or years, or even life-long to relieve her of the signs and symptoms resulting from natural or induced impairment of ovarian function.
  • the woman can be treated with a pharmaceutical formulation containing each of (i) a SERM and (ii) an estrogen, and, optionally, (iii) a progestin or SPRM.
  • this pharmaceutical e.g., orally or delivered by transdermal or depot methods
  • this pharmaceutical is administered to the woman at least once daily for at least 30 days at the dosages listed above.
  • the woman will be treated over the course of several months or years, or even life-long to relieve her of the signs and symptoms resulting from natural or induced impairment of ovarian function.
  • the woman can be treated with a pharmaceutical formulation containing each of (i) a SERM, (ii) an estrogen, (iii) an androgen or SARM, and, optionally, (iv) a progestin or SPRM.
  • this pharmaceutical formulation is administered to the woman at least once daily for at least 30 days at the dosages listed above.
  • the woman will be treated over the course of several months or years, or even life-long to relieve her of the signs and symptoms resulting from natural or induced impairment of ovarian function.
  • the progestin can be given continuously or cyclicly (i.e., by administering it on only some of the days that the other drugs are administered) .
  • Conventional methods known to those of ordinary skill in the art of medicine, can be used to administer the pharmaceutical formulation (s) to the woman.
  • the pharmaceutical formulation will be administered to the woman by applying to the skin of the woman a transdermal patch containing the pharmaceutical formulation, and leaving the patch in contact with her skin (generally for 1 to 5 hours per patch) .
  • an intravaginal ring containing the pharmaceutical formulation is inserted into the woman and left in place for 1 to 90 days (e.g., 15 to 30 days) per intravaginal ring.
  • transdermal and intravaginal routes of administration can be used by applying conventional techniques.
  • the pharmaceutical formulations can also be administered via other conventional routes (e.g., oral, subcutaneous, intraperitoneal, intrauterine, sublingual, or intramuscular routes) by using standard methods.
  • the pharmaceutical formulations can be administered to the woman via injectable depot routes of administration such as by using 1, 3, or 6-month depot injectable or biodegradable materials and methods.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur des formulations pharmaceutiques contenant diverses combinaisons d'un oestrogène, d'une progestérone, d'un androgène, d'un modulateur de récepteur d'oestrogène sélectif, d'un modulateur de récepteur d'androgène sélectif, ces formulations étant destinées à être utilisées pour traiter les femmes en période de postménopause ou de périménopause. L'invention porte également sur des procédés de traitement au moyen des formulations pharmaceutiques précitées.
PCT/US2000/040061 1999-06-04 2000-06-02 Formulations pharmaceutiques pour traiter des femmes en periode de postmenopause et de perimenopause, et leur utilisation WO2000074684A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU51812/00A AU5181200A (en) 1999-06-04 2000-06-02 Pharmaceutical formulations for treating postmenopausal and perimenopausal women, and their use
JP2001501220A JP2003501390A (ja) 1999-06-04 2000-06-02 閉経後及び閉経期の女性を治療するための薬学的製剤、及びそれらの利用
EP00936507A EP1187618A1 (fr) 1999-06-04 2000-06-02 Formulations pharmaceutiques pour traiter des femmes en periode de postmenopause et de perimenopause, et leur utilisation

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US13744099P 1999-06-04 1999-06-04
US60/137,440 1999-06-04

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WO2000074684A1 true WO2000074684A1 (fr) 2000-12-14

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JP (1) JP2003501390A (fr)
AU (1) AU5181200A (fr)
WO (1) WO2000074684A1 (fr)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002092102A2 (fr) * 2001-05-16 2002-11-21 Endeavor Pharmaceuticals Traitement d'etats lies a un deficit en hormones par administration de progestatifs
WO2003063859A1 (fr) * 2002-01-14 2003-08-07 Nordic Bioscience A/S Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes
WO2003082299A1 (fr) * 2002-04-03 2003-10-09 Jencap Research Ltd. Hormonotherapie substitutive amelioree
WO2004022065A1 (fr) * 2002-09-05 2004-03-18 Pantarhei Bioscience B.V. Application pharmaceutique d'analogues de testosterone a substitution 15 ou 16
JP2004515531A (ja) * 2000-12-15 2004-05-27 ノボ ノルディスク アクティーゼルスカブ 萎縮性膣炎の治療のためのエストロゲンを含有する組成物の製造におけるエストロゲンの使用
EP1494679A1 (fr) * 2002-04-03 2005-01-12 Barr Laboratories, Inc. Therapie oestrogenique a diminution graduelle
EP1522306A1 (fr) * 2003-10-08 2005-04-13 Liconsa, Liberacion Controlada de Sustancias Activas, S.A. Un produit pharmaceutique pour le traitement hormonal substitutif contenant la tibolone ou un de ses dérivés et l'estradiol ou un de ses dérivés
JP2005511725A (ja) * 2001-12-13 2005-04-28 バイタル ヘルス サイエンシズ プロプライアタリー リミティド 化合物の経皮輸送
EP1583536A2 (fr) * 2003-01-17 2005-10-12 Erik P. Castle Méthode de traitement du cancer de la prostate et composition pour son traitement
US7030157B2 (en) 2001-07-31 2006-04-18 Pfizer Inc. Pharmaceutical compositions, kits and methods comprising combinations of estrogen agonists/antagonists, estrogens and progestins
AU2002243411B2 (en) * 2000-12-22 2007-02-08 Barr Laboratories, Inc. Combination of an estrogen and an androgen for treating hormonal deficiencies in women undergoing estrogen replacement therapy
EP1862165A2 (fr) * 2001-11-29 2007-12-05 GTX, Inc. Prévention et traitement des bouffées de chaleur à carence androgène
WO2007144151A1 (fr) * 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Schéma posologique décroissant d'œstrogène pour des femmes recevant une thérapie par œstrogène
US20100317635A1 (en) * 2009-06-16 2010-12-16 Endorecherche, Inc. Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
US8580294B2 (en) 2010-10-19 2013-11-12 International Partnership For Microbicides Platinum-catalyzed intravaginal rings
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
WO2016028903A1 (fr) * 2014-08-20 2016-02-25 Professional Compounding Centers Of America Compositions pharmaceutiques pour l'administration par voie transmuqueuse orale comprenant de la testostérone et un c-serm
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US10137031B2 (en) 2013-11-14 2018-11-27 International Partnership For Microbicides, Inc. Combination therapy intravaginal rings
WO2020010205A1 (fr) * 2018-07-05 2020-01-09 Celista Pharmaceuticals Llc Pulvérisateur transdermique de testostérone et d'estradiol
EP3613418A1 (fr) * 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Procédés et compositions de modulation des niveaux d'hormones
WO2020247653A1 (fr) * 2019-06-06 2020-12-10 Evestra, Inc. Contraception hormonale au moyen d'un anneau vaginal qui libère l'estriol et la trimégestone
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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JP2005298450A (ja) * 2004-04-15 2005-10-27 Taisho Pharmaceut Co Ltd 更年期症候群の予防又は治療剤組成物
UY33103A (es) * 2009-12-15 2011-07-29 Techsphere S A De C V Formulacion farmaceutica parenteral en suspension, de liberacion sostenida, en dosis baja y ultra baja, en terapia hormonal en el sindrome climaterico

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US5340585A (en) * 1991-04-12 1994-08-23 University Of Southern California Method and formulations for use in treating benign gynecological disorders
US5846960A (en) * 1991-06-28 1998-12-08 Endorecherche, Inc. Methods for preventing and treating osteoporosis with low dose non-masculinizing androgenic compounds
US5955455A (en) * 1993-01-19 1999-09-21 Endorecherche, Inc. Therapeutic methods and delivery systems utilizing sex steroid precursors
US5770226A (en) * 1996-07-10 1998-06-23 Wake Forest University Combined pharmaceutical estrogen-androgen-progestin oral contraceptive

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9132089B2 (en) 2000-08-30 2015-09-15 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
JP4851057B2 (ja) * 2000-12-15 2012-01-11 ノボ・ノルディスク・フェムケア・アーゲー 萎縮性膣炎の治療のためのエストロゲンを含有する組成物の製造におけるエストロゲンの使用
JP2004515531A (ja) * 2000-12-15 2004-05-27 ノボ ノルディスク アクティーゼルスカブ 萎縮性膣炎の治療のためのエストロゲンを含有する組成物の製造におけるエストロゲンの使用
AU2002243411B2 (en) * 2000-12-22 2007-02-08 Barr Laboratories, Inc. Combination of an estrogen and an androgen for treating hormonal deficiencies in women undergoing estrogen replacement therapy
WO2002092102A2 (fr) * 2001-05-16 2002-11-21 Endeavor Pharmaceuticals Traitement d'etats lies a un deficit en hormones par administration de progestatifs
WO2002092102A3 (fr) * 2001-05-16 2003-03-20 Endeavor Pharmaceuticals Traitement d'etats lies a un deficit en hormones par administration de progestatifs
US8076319B2 (en) 2001-05-16 2011-12-13 Barr Laboratories, Inc. Treatment of conditions relating to hormone deficiencies by administration of progestins
US7683047B2 (en) 2001-05-16 2010-03-23 Barr Laboratories, Inc. Treatment of conditions relating to hormone deficiencies by administration of progestins
US7427609B2 (en) 2001-05-16 2008-09-23 Barr Laboratories, Inc. Treatment of conditions relating to hormone deficiencies by administration of progestins
US7030157B2 (en) 2001-07-31 2006-04-18 Pfizer Inc. Pharmaceutical compositions, kits and methods comprising combinations of estrogen agonists/antagonists, estrogens and progestins
EP1862165A2 (fr) * 2001-11-29 2007-12-05 GTX, Inc. Prévention et traitement des bouffées de chaleur à carence androgène
EP1862165A3 (fr) * 2001-11-29 2008-06-25 GTX, Inc. Prévention et traitement des bouffées de chaleur à carence androgène
JP2005511725A (ja) * 2001-12-13 2005-04-28 バイタル ヘルス サイエンシズ プロプライアタリー リミティド 化合物の経皮輸送
WO2003063859A1 (fr) * 2002-01-14 2003-08-07 Nordic Bioscience A/S Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes
WO2003082299A1 (fr) * 2002-04-03 2003-10-09 Jencap Research Ltd. Hormonotherapie substitutive amelioree
EP1494679A4 (fr) * 2002-04-03 2009-10-28 Barr Lab Inc Therapie oestrogenique a diminution graduelle
EP1494679A1 (fr) * 2002-04-03 2005-01-12 Barr Laboratories, Inc. Therapie oestrogenique a diminution graduelle
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
WO2004022065A1 (fr) * 2002-09-05 2004-03-18 Pantarhei Bioscience B.V. Application pharmaceutique d'analogues de testosterone a substitution 15 ou 16
US7943602B2 (en) 2002-09-05 2011-05-17 Pantarhei Bioscience B.V. Pharmaceutical application of 15- or 16-substituted testosterone analogues
EP1583536A4 (fr) * 2003-01-17 2009-07-15 Erik P Castle Méthode de traitement du cancer de la prostate et composition pour son traitement
EP1583536A2 (fr) * 2003-01-17 2005-10-12 Erik P. Castle Méthode de traitement du cancer de la prostate et composition pour son traitement
EP1522306A1 (fr) * 2003-10-08 2005-04-13 Liconsa, Liberacion Controlada de Sustancias Activas, S.A. Un produit pharmaceutique pour le traitement hormonal substitutif contenant la tibolone ou un de ses dérivés et l'estradiol ou un de ses dérivés
WO2005037288A1 (fr) * 2003-10-08 2005-04-28 Liconsa, Liberación Controlada de Sustancias Activas, S.A. Produit pharmaceutique pour traitement hormonal substitutif comprenant de la tibolone ou un derive de celle-ci et de l'estradiol ou un derive de celui-ci
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
WO2007144151A1 (fr) * 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Schéma posologique décroissant d'œstrogène pour des femmes recevant une thérapie par œstrogène
US20100317635A1 (en) * 2009-06-16 2010-12-16 Endorecherche, Inc. Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9427400B2 (en) 2010-10-19 2016-08-30 International Partnership For Microbicides Platinum-catalyzed intravaginal rings
US8580294B2 (en) 2010-10-19 2013-11-12 International Partnership For Microbicides Platinum-catalyzed intravaginal rings
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
US11793669B2 (en) 2013-11-14 2023-10-24 The Population Council, Inc. Combination therapy intravaginal rings
US10137031B2 (en) 2013-11-14 2018-11-27 International Partnership For Microbicides, Inc. Combination therapy intravaginal rings
US11259956B2 (en) 2013-11-14 2022-03-01 International Partnership For Microbicides, Inc. Combination therapy intravaginal rings
US10874638B2 (en) 2014-01-17 2020-12-29 Ligand Pharmaceuticals Incorporated Methods and compositions for modulating hormone levels
EP3613418A1 (fr) * 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Procédés et compositions de modulation des niveaux d'hormones
WO2016028903A1 (fr) * 2014-08-20 2016-02-25 Professional Compounding Centers Of America Compositions pharmaceutiques pour l'administration par voie transmuqueuse orale comprenant de la testostérone et un c-serm
US9452174B2 (en) 2014-08-20 2016-09-27 Professional Compounding Centers Of America Oral transmucosal pharmaceutical compositions including testosterone and a C-SERM
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process
WO2020010205A1 (fr) * 2018-07-05 2020-01-09 Celista Pharmaceuticals Llc Pulvérisateur transdermique de testostérone et d'estradiol
WO2020247653A1 (fr) * 2019-06-06 2020-12-10 Evestra, Inc. Contraception hormonale au moyen d'un anneau vaginal qui libère l'estriol et la trimégestone

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AU5181200A (en) 2000-12-28
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