US20070111975A1 - Methods of Hormonal Treatment Utilizing Ascending-Dose Extended Cycle Regimens - Google Patents

Methods of Hormonal Treatment Utilizing Ascending-Dose Extended Cycle Regimens Download PDF

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Publication number
US20070111975A1
US20070111975A1 US11/554,571 US55457106A US2007111975A1 US 20070111975 A1 US20070111975 A1 US 20070111975A1 US 55457106 A US55457106 A US 55457106A US 2007111975 A1 US2007111975 A1 US 2007111975A1
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United States
Prior art keywords
estrogen
phase
progestin
daily dosage
days
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Abandoned
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US11/554,571
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English (en)
Inventor
Charles Diliberti
Kathleen Reape
Lance Bronnenkant
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Teva Womens Health Inc
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Duramed Pharmaceuticals Inc
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39864644&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20070111975(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US11/245,471 external-priority patent/US20060135496A1/en
Priority to US11/554,571 priority Critical patent/US20070111975A1/en
Application filed by Duramed Pharmaceuticals Inc filed Critical Duramed Pharmaceuticals Inc
Assigned to DURAMED PHARMACEUTICALS, INC. reassignment DURAMED PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRONNENKANT, LANCE J., DILIBERTI, CHARLES E., REAPE, KATHLEEN Z.
Publication of US20070111975A1 publication Critical patent/US20070111975A1/en
Priority to US11/892,026 priority patent/US8415332B2/en
Priority to EP07873464A priority patent/EP2079461A4/en
Priority to JP2009534693A priority patent/JP2010508275A/ja
Priority to CA002668211A priority patent/CA2668211A1/en
Priority to TW096140829A priority patent/TW200831107A/zh
Priority to PCT/US2007/022832 priority patent/WO2008127303A1/en
Priority to BRPI0716291-0A2A priority patent/BRPI0716291A2/pt
Priority to RU2009120528/15A priority patent/RU2009120528A/ru
Priority to KR1020097011178A priority patent/KR20090094437A/ko
Priority to MX2009004616A priority patent/MX2009004616A/es
Priority to CN200780046391A priority patent/CN101626760A/zh
Priority to IL198441A priority patent/IL198441A/en
Assigned to TEVA WOMEN'S HEALTH, INC. reassignment TEVA WOMEN'S HEALTH, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: DURAMED PHARMACEUTICALS, INC.
Priority to US13/492,138 priority patent/US8450299B2/en
Abandoned legal-status Critical Current

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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
    • A61K31/565—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
    • A61K31/567—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 substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to methods of hormonal treatment by ascending-dose extended administration of an estrogen and a progestin.
  • the human menstrual cycle involves a repetitive sequence of hormonal changes that result in episodic uterine bleeding. Normally, each menstrual cycle has a mean interval of 21 to 35 days, conventionally beginning with the first day of menstrual flow and ending on the day before the next onset of bleeding. Duration of the menstrual flow is usually 2 to 6 days with loss of about 20 to about 60 ml of blood.
  • the menstrual cycle is divided into follicular and luteal phases, each corresponding to changes occurring in the ovary. These phases may also be described as proliferative or secretory, corresponding to changes observed in the uterine endometrium. Variations in the length of the cycle are usually due to alterations in the follicular phase, because the luteal phase length remains relatively constant at 12 to 16 days.
  • lutein cells After ovulation, granulosa cells and the surrounding theca cells enlarge, accumulate lipid, and become transformed into lutein cells. This begins the luteal phase of the menstrual cycle. These cells form a new vascularized structure called the corpus luteum, which secretes estradiol and progesterone. LH maintains the corpus luteum during the luteal phase and, acting via the adenyl cyclase system, stimulates progesterone production. If pregnancy does not occur, lutein cells degenerate, and diminished hormone secretion precedes menstruation. Menstruation is immediately followed by the onset of another menstrual cycle.
  • Progestins can also provide contraception. Endogenous progesterone after estrogen is responsible for the progestational changes of the endometrium and the cyclic changes of cells and tissue in the cervix and the vagina. Administration of progestin makes the cervical mucus thick, tenacious and cellular which is believed to impede spermatozoal transport. Administration of progestin also inhibits luteinizing hormone secretion and blocks ovulation in humans.
  • the present invention provides ascending-dose extended cycle regimens in which a female is administered an estrogen and a progestin for a period of greater than 30 or 31 consecutive days, optionally followed by a hormone-free period of 2 to 10 consecutive days or by administration of estrogen for a period of 2 to 10 consecutive days.
  • the present invention is directed to a method of contraception, the method comprising administering to a female in need thereof an estrogen and a progestin for a period of greater than 30 or 31 consecutive days, wherein the estrogen and progestin are administered in at least three phases, wherein a daily dosage of estrogen in a second phase is equal to or higher than a daily dosage of estrogen in a first phase, wherein a daily dosage of estrogen in a third phase is equal to or higher than the daily dosage of estrogen in the second phase, wherein a total daily dosage of estrogen and progestin in the second phase is higher than a total daily dosage of estrogen and progestin in the first phase, and wherein a total daily dosage of estrogen and progestin in the third phase is higher than the total daily dosage of estrogen and progestin in the second phase.
  • the present invention is also directed to a method of contraception, the method comprising administering to a female in need thereof an estrogen and a progestin for a period of greater than 30, 31, or 42 consecutive days, wherein the estrogen and progestin are administered in at least two phases, wherein a total daily dosage of estrogen and progestin in a second phase is higher than a total daily dosage of estrogen and progestin in a first phase, and wherein a daily dosage of progestin in the second phase is less than twice a daily dosage of progestin in the first phase.
  • the ascending-dose extended cycle regimens provide a number of non-contraceptive benefits, as well as contraceptive benefits.
  • the present invention is also directed to a method of reducing breakthrough bleeding in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the present invention is directed to ascending-dose extended cycle regimens that are useful in the treatment of a variety of conditions and disorders occurring in females of child-bearing age, in peri-menopausal females, and/or in menopausal females.
  • a female is administered an ascending-dose extended cycle regimen of an estrogen and a progestin (or progestogen) for a period of greater than 30 or 31 consecutive days.
  • An “ascending-dose extended cycle regimen” of the present invention refers to a regimen disclosed herein in which an estrogen and a progestin are administered for a period of greater than 30 or 31 consecutive days, wherein the estrogen and progestin are administered in at least three phases, wherein a daily dosage of estrogen in a second phase is equal to or higher than a daily dosage of estrogen in a first phase, wherein a daily dosage of estrogen in a third phase is equal to or higher than the daily dosage of estrogen in the second phase, wherein a total daily dosage of estrogen and progestin in the second phase is higher than a total daily dosage of estrogen and progestin in the first phase, and wherein a total daily dosage of estrogen and progestin in the third phase is higher than the total daily dosage of estrogen and progestin in the second phase.
  • An “ascending-dose extended cycle regimen” of the present invention also refers to a regimen disclosed herein in which an estrogen and a progestin are administered for a period of greater than 30, 31, or 42 consecutive days, wherein the estrogen and progestin are administered in at least two phases, wherein a total daily dosage of estrogen and progestin in a second phase is higher than a total daily dosage of estrogen and progestin in a first phase, and wherein a daily dosage of progestin in the second phase is less than twice a daily dosage of progestin in the first phase.
  • extended cycle regimen refers to a regimen in which a contraceptive composition is administered for a period of greater than 30 or 31 days.
  • female refers to any animal classified as a mammal, including humans and non-humans, such as, but not limited to, domestic and farm animals, zoo animals, sports animals, and pets.
  • Periodic female refers to a woman who has not yet definitely arrived at menopause but who is experiencing symptoms associated with menopause. “Peri-menopause” means “about or around the time of menopause.” It encompasses the years preceding the last menstrual period during which ovarian function declines and ultimately ceases and can include the presence of symptoms and irregular cycles. “Menopausal female” refers to a woman who has definitely arrived at menopause and may be experiencing symptoms associated with menopause. Menopause or post-menopause is the permanent cessation of menstruation after the loss of ovarian activity and is generally defined clinically as the absence of menstruation for about one year.
  • Menopause may occur naturally in a woman or it may be artificially induced, e.g., through surgical or chemical means. For example, removal of the ovaries, which can occur, e.g., through hysterectomy, frequently leads to symptoms associated with menopause.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state, remission (whether partial or total), whether detectable or undetectable; or enhancement or improvement of condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response, without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • continuous or “consecutive” in reference to “administration” means that the frequency of administration is at least once daily. Note, however, that the frequency of administration can be greater than once daily and still be “continuous,” e.g., twice or even three times daily, as long as the dosage levels as specified herein are not exceeded.
  • daily dosage means the total amount of estrogen (and/or progestin) administered per day.
  • continuous administration of a progestin to a woman at a “daily dosage level” of 30 ⁇ g means that the woman receives a total of 30 ⁇ g of progestin on a daily basis, whether the progestin is administered as a single 30 ⁇ g dose or, e.g., three separate 10 ⁇ g doses.
  • a conventional means of continuously administering an estrogen or progestin is as a single daily oral dose at the prescribed daily dosage level.
  • “about” refers to plus or minus 10% of the indicated number. For example, “about 10 ⁇ g” indicates a range of 9 ⁇ g to 11 ⁇ g.
  • the present invention is directed to a method of providing an ascending-dose extended cycle regimen, the method comprising administering to a female in need thereof an estrogen and a progestin for a period of greater than 30 or 31 consecutive days, wherein the estrogen and progestin are administered in at least three phases, wherein a daily dosage of estrogen in a second phase is equal to or higher than a daily dosage of estrogen in a first phase, wherein a daily dosage of estrogen in a third phase is equal to or higher than the daily dosage of estrogen in the second phase, wherein a total daily dosage of estrogen and progestin in the second phase is higher than a total daily dosage of estrogen and progestin in the first phase, and wherein a total daily dosage of estrogen and progestin in the third phase is higher than the total daily dosage of estrogen and progestin in the second phase.
  • the present invention is also directed to a method of providing an ascending-dose extended cycle regimen, the method comprising administering to a female in need thereof an estrogen and a progestin for a period of greater than 30, 31, or 42 consecutive days, wherein the estrogen and progestin are administered in at least two phases, wherein a total daily dosage of estrogen and progestin in a second phase is higher than a total daily dosage of estrogen and progestin in a first phase, and wherein a daily dosage of progestin in the second phase is less than twice a daily dosage of progestin in the first phase.
  • the daily dosage of progestin in the first and second phases are equal to each other. In further aspects of the invention, the daily dosages of progestin in the first, second, and third phases are equal to each other.
  • the daily dosage of progestin can be, but is not limited to, the equivalent of 150 ⁇ g of levonorgestrel for the first, second, and third phases.
  • the daily dosage of progestin in the second phase is higher than the daily dosage of progestin in the first phase.
  • the daily dosage of progestin in the third phase is higher than the daily dosage of progestin in the second phase.
  • the daily dosage of progestin in the second phase is equal to the daily dosage of progestin in the first phase and the daily dosage of progestin in the third phase is higher than the daily dosage of progestin in the second phase. In other aspects of the invention, the daily dosage of progestin in the second phase is higher than the daily dosage of progestin in the first phase and the daily dosage of progestin in the third phase is equal to the daily dosage of progestin in the second phase.
  • the daily dosage of progestin in the second phase is less than twice the daily dosage of progestin in the first phase. In further aspects of the invention, the daily dosage of progestin in the third phase is less than twice the daily dosage of progestin in the second phase.
  • the daily dosage of progestin in the first phase can be, but is not limited to, the equivalent of 95 ⁇ g to 105 ⁇ g, 97 ⁇ g to 102 ⁇ g, or 99 ⁇ g to 101 ⁇ g of levonorgestrel.
  • the daily dosage of progestin in the first phase can be the equivalent of 100 ⁇ g levonorgestrel.
  • the daily dosage of progestin in the second phase can be, but is not limited to, the equivalent of 120 ⁇ g to 130 ⁇ g, 122 ⁇ g to 128 ⁇ g, or 124 ⁇ g to 126 ⁇ g of levonorgestrel.
  • the daily dosage of progestin in the second phase can be the equivalent of 125 ⁇ g of levonorgestrel.
  • the daily dosage of progestin in the third phase can be, but is not limited to, the equivalent of 145 ⁇ g to 155 ⁇ g, 147 ⁇ g to 153 ⁇ g, or 149 ⁇ g to 151 ⁇ g of levonorgestrel.
  • the daily dosage of progestin in the third phase can be the equivalent of 150 ⁇ g of levonorgestrel.
  • the progestin used is trimegestone.
  • the total daily dosage of trimegestone can be, but is not limited to, 0.25 mg to 2.0 mg, 0.5 mg to 1.5 mg, 0.75 mg to 1.25 mg, or 1.0 mg.
  • the total daily dosage of trimegestone can be, but is not limited to, 0.175 mg to 2.0 mg, 0.35 mg to 1.5 mg, 0.52 mg to 1.25 mg, or 0.7 mg to 1.0 mg.
  • the daily dosage of trimegestone in the first and second phases of an ascending-dose extended cycle regimen can be 1.0 mg.
  • the daily dosage of trimegestone in the first, second, and third phases of an ascending-dose extended cycle regimen can be 1.0 mg.
  • the daily dosage of trimegestone in the first and second phases of an ascending-dose extended cycle regimen can be 0.7 mg to 1.0 mg.
  • the daily dosage of transdermally- or vaginally-administered trimegestone in the first, second, and third phases of an ascending-dose extended cycle regimen can be 0.7 mg to 1.0 mg.
  • the daily dosage of trimegestone in the first phase can be, but is not limited to, 0.25 mg to 1.25 mg, 0.5 mg to 1.0 mg, or 0.75 mg.
  • the daily dosage of trimegestone in the second phase can be, but is not limited to, 0.5 mg to 1.5 mg, 0.75 mg to 1.25 mg, or 1.0 mg.
  • the daily dosage of trimegestone in the third phase can be, but is not limited to, 0.75 mg to 1.75 mg, 1.0 mg to 1.5 mg, or 1.25 mg.
  • the daily dosage of trimegestone in the first phase can be, but is not limited to, 0.175 mg to 1.25 mg, 0.35 mg to 1.0 mg, or 0.52 mg to 0.75 mg.
  • the daily dosage of transdermally- or vaginally-administered trimegestone in the second phase can be, but is not limited to, 0.35 mg to 1.5 mg, 0.52 mg to 1.25 mg, or 0.7 mg to 1.0 mg, and the daily dosage in the third phase can be, but is not limited to, 0.52 mg to 1.75 mg, 0.7 mg to 1.5 mg, or 0.87 mg to 1.25 mg.
  • trimegestone can be administered together with an estrogen in the ascending-dose extended cycle regimens of the present invention.
  • the trimegestone can be administered in combination with an estrogen in other oral contraceptive regimens.
  • the daily dosage of trimegestone for an estrogen and progestin combined 28-day oral contraceptive can be, but is not limited to, 0.25 mg to 2.0 mg, 0.5 mg to 1.75 mg, 0.75 mg to 1.25 mg, or 1.0 mg.
  • the daily dosage of estrogen in each of the first and second phases are equal to each other. In further aspects of the invention, the daily dosage of estrogen in each of the first, second, and third phases are equal to each other.
  • the daily dosage of estrogen in the second phase is higher than the daily dosage of estrogen in the first phase. In further aspects of the invention, the daily dosage of estrogen in the third phase is higher than the daily dosage of estrogen in the second phase.
  • the daily dosage of estrogen in the second phase is equal to the daily dosage of estrogen in the first phase and the daily dosage of estrogen in the third phase is higher than the daily dosage of estrogen in the second phase. In other aspects of the invention, the daily dosage of estrogen in the second phase is higher than the daily dosage of estrogen in the first phase and the daily dosage of estrogen in the third phase is equal to the daily dosage of estrogen in the second phase.
  • the daily dosage of estrogen in the second phase is less than twice the daily dosage of estrogen in the first phase. In further aspects of the invention, the daily dosage of estrogen in the third phase is less than twice the daily dosage of estrogen in the second phase.
  • the daily dosage of estrogen in the first phase is the equivalent of 15 ⁇ g to 25 ⁇ g, 17 ⁇ g to 23 ⁇ g, or 19 ⁇ g to 21 ⁇ g of ethinyl estradiol.
  • the daily dosage of estrogen in the first phase can be the equivalent of 20 ⁇ g of ethinyl estradiol.
  • the daily dosage of estrogen in the second phase is the equivalent of 20 ⁇ g to 30 ⁇ g, 22 ⁇ g to 28 ⁇ g, or 24 ⁇ g to 26 ⁇ g of ethinyl estradiol.
  • the daily dosage of estrogen in the second phase can be the equivalent of 25 ⁇ g of ethinyl estradiol.
  • the estrogen and progestin are administered orally and the daily dosage of estrogen is the equivalent of 15 ⁇ g to 50 ⁇ g of ethinyl estradiol and the daily dosage of progestin is the equivalent of 100 ⁇ g to 150 ⁇ g of levonorgestrel.
  • the estrogen and progestin of the ascending-dose extended cycle regimens can be ethinyl estradiol and levonorgestrel, although other suitable estrogens and progestins can be employed. If a different estrogen or progestin is employed, an adjustment in the amount based on the relative potency or activity can be made. Correlations in potency among the various estrogens and among the various progestins are known. See, for example, EP 0 253 607, which is incorporated herein in its entirety by reference. For example, 30 ⁇ g of ethinyl estradiol is about the equivalent of 60 ⁇ g of mestranol or 2,000 ⁇ g of 17 ⁇ -estradiol.
  • levonorgestrel is about the equivalent of 0.175 mg of norethindrone acetate, 0.050 mg of desogestrel, 0.050 mg 3-ketodesogestrel, 0.035 mg of gestodene, 0.100 mg of norgestrel, or 0.35-0.50 mg of trimegestone. It should be understood that when norgestrel is used in place of levonorgestrel, its concentration is twice that of levonorgestrel.
  • Norgestrel (dl-norgestrel) is a racemic mixture of optically active isomers, while levonorgestrel is one of the optically active isomers present in norgestrel.
  • Equivalent concentrations of estrogens and of progestins can be determined using either in vitro or in vivo assay methods. See, for example, Kuhl, H., Drugs 51(2):188-215 (1996); Philibert, D., et al, Gynecol. Endocrinol 13:316-326 (1999); and Lundeen, S., et al., J. Steroid Biochem. Molec. Biol. 78:137-143 (2001), in which the relative potencies of various progestins are compared using both in vitro and in vivo test assays. See also, for example, Dickey, R. P., “Contraceptive Therapy,” OBG Management Supplement (October 2000), pp. 2-6. Each of these documents is incorporated herein by reference in its entirety.
  • Each block in Table 1 describes a specific combination of progestin and estrogen, e.g., norethynodrel and mestranol, and within each block older combinations are listed first, with successively newer combinations following.
  • Suitable progestins for use in the present invention include, but are not limited to, natural and synthetic compounds having progestational activity, such as, for example, progesterone, levonorgestrel, norethindrone, norethindrone acetate, desogestrel, gestodene, dienogest, norgestimate, cyproterone acetate, norelgestromin, etonogestrel, ethynodiol diacetate, norgestrel, trimegestone, medroxyprogesterone acetate, chlormadinone acetate, drospirenone, and other natural and/or synthetic gestagens.
  • Esters, conjugates, and prodrugs of suitable progestins can also be used.
  • prodrug denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug and is transformed into the active drug by an enzymatic or chemical process.
  • Ethynodiol diacetate which is converted in vivo to norethindrone, is an example of a progestin prodrug that can be used in the present invention.
  • progestin prodrugs include, but are not limited to, norgestimate (which is converted in vivo to 17-deacetyl norgestimate, also known as norelgestromin), desogestrel (which is converted in vivo to 3-keto desogestrel, also known as etonogestrel), and norethindrone acetate (which is converted in vivo to norethindrone).
  • Suitable estrogens in the present invention include, but are not limited to, natural and synthetic compounds having estrogenic activity, such as, for example, estradiol (17 ⁇ -estradiol), 17 ⁇ -estradiol, estriol, estrone, and their esters, such as the acetate, sulfate, valerate or benzoate esters of these compounds, including, for example, estradiol 17 ⁇ -cypionate, estradiol 17-propionate, estradiol 3-benzoate, and piperazine estrone sulfate; ethinyl estradiol; conjugated estrogens (natural and synthetic); mestranol; agonistic anti-estrogens; and selective estrogen receptor modulators.
  • estradiol (17 ⁇ -estradiol) 17 ⁇ -estradiol
  • estriol esters
  • esters such as the acetate, sulfate, valerate or benzoate esters of these compounds, including, for example, estradiol 17 ⁇ -cypionate
  • Esters, conjugates and prodrugs of suitable estrogens can also be used.
  • Examples of estrogen prodrugs that can be used in the present invention include, but are not limited to, estradiol acetate (which is converted in vivo to 17 ⁇ -estradiol) and mestranol (which is converted in vivo to ethinyl estradiol).
  • the estrogen and progestin are administered for a period of 31 to 190 consecutive days.
  • Each phase can be, but is not limited to, 7 to 84 days.
  • the estrogen and progestin are administered for a period of 39 to 61 days, of 42 to 60 days, of 45 to 57 days, or of 48 to 54 days.
  • the estrogen and progestin can be administered for a period of 49 days to 53 days.
  • the estrogen and progestin can be administered for a period of 49 days or 53 days.
  • the first phase can be, but is not limited to, 7 to 21 days.
  • the second phase can be, but is not limited to, 14 to 28 days.
  • the third phase can be, but is not limited to, 7 to 25 days.
  • the first phase is 14 days, the second phase is 21 days, and the third phase is 14 days.
  • the first phase is 14 days, the second phase is 21 days, and the third phase is 18 days.
  • the first phase can be, but is not limited to, 7 to 21 days.
  • the second phase can be, but is not limited to, 7 to 21 days.
  • the third phase can be, but is not limited to, 14 to 32 days. In some aspects of the invention, the first phase is 14 days, the second phase is 14 days, and the third phase is 21 days. In other aspects of the invention, the first phase is 14 days, the second phase is 14 days, and the third phase is 25 days.
  • the first phase can be, but is not limited to, 14 to 28 days.
  • the second phase can be, but is not limited to, 7 to 21 days.
  • the third phase can be, but is not limited to, 7 to 25 days. In some aspects of the invention, the first phase is 21 days, the second phase is 14 days, and the third phase is 14 days. In other aspects of the invention, the first phase is 21 days, the second phase is 14 days, and the third phase is 18 days
  • the estrogen and progestin are administered for a period of 74 to 96 days, of 77 to 95 days, of 80 to 92 days, or of 83 to 89 days.
  • the estrogen and progestin can be administered for a period of 84 days to 88 days.
  • the estrogen and progestin can be administered for a period of 84 days or 88 days.
  • the first phase can be, but is not limited to, 14 to 28 days.
  • the second phase can be, but is not limited to, 14 to 28 days.
  • the third phase can be, but is not limited to, 35 to 53 days. In some aspects of the invention, the first phase is 21 days, the second phase is 21 days, and the third phase is 42 days. In other aspects of the invention, the first phase is 21 days, the second phase is 21 days, and the third phase is 46 days.
  • the first phase can be, but is not limited to, 14 to 28 days.
  • the second phase can be, but is not limited to, 35 to 49 days.
  • the third phase can be, but is not limited to, 14 to 32 days. In some aspects of the invention, the first phase is 21 days, the second phase is 42 days, and the third phase is 21 days. In other aspects of the invention, the first phase is 21 days, the second phase is 42 days, and the third phase is 25 days.
  • the first phase can be, but is not limited to, 35 to 49 days.
  • the second phase can be, but is not limited to, 14 to 28 days.
  • the third phase can be, but is not limited to, 14 to 32 days. In some aspects of the invention, the first phase is 42 days, the second phase is 21 days, and the third phase is 21 days. In other aspects of the invention, the first phase is 42 days, the second phase is 21 days, and the third phase is 25 days.
  • the estrogen and progestin are administered for a period of 95 to 117 days, of 98 to 116 days, of 101 to 113 days, or of 104 to 110 days.
  • the estrogen and progestin can be administered for a period of 105 days to 109 days.
  • the estrogen and progestin can be administered for a period of 105 days or 109 days.
  • the first phase can be, but is not limited to, 14 to 28 days.
  • the second phase can be, but is not limited to, 35 to 49 days.
  • the third phase can be, but is not limited to, 35 to 53 days.
  • the first phase is 21 days, the second phase is 42 days, and the third phase is 42 days. In other aspects of the invention, the first phase is 21 days, the second phase is 42 days, and the third phase is 46 days.
  • the estrogen and progestin are administered for a period of 123 to 145 days, of 126 to 144 days, of 129 to 141 days, or of 132 to 138 days.
  • the estrogen and progestin can be administered for a period of 133 days to 137 days.
  • the estrogen and progestin can be administered for a period of 133 days or 137 days.
  • the first phase can be, but is not limited to, 35 to 49 days.
  • the second phase can be, but is not limited to, 42 to 56 days.
  • the third phase can be, but is not limited to, 35 to 53 days.
  • the first phase is 42 days, the second phase is 49 days, and the third phase is 42 days.
  • the first phase is 42 days, the second phase is 49 days, and the third phase is 46 days.
  • the estrogen and progestin are administered for a period of 165 to 187 days, of 168 to 186 days, of 171 to 183 days, or of 174 to 180 days.
  • the estrogen and progestin can be administered for a period of 175 days to 179 days.
  • the estrogen and progestin can be administered for a period of 175 days or 179 days.
  • the first phase can be, but is not limited to, 35 to 49 days.
  • the second phase can be, but is not limited to, 56 to 70 days.
  • the third phase can be, but is not limited to, 63 to 81 days.
  • the first phase is 42 days, the second phase is 63 days, and the third phase is 70 days.
  • the first phase is 42 days, the second phase is 63 days, and the third phase is 74 days.
  • the estrogen and progestin are administered for a period of 180 to 369 days, of 347 to 369 days, of 350 to 366 days, of 353 to 363 days, or of 356 to 362 days.
  • the estrogen and progestin can be administered for a period of 357 days to 361 days.
  • the estrogen and progestin can be administered for a period of 357 days or 361 days.
  • the first phase can be, but is not limited to, 49 to 63 days.
  • the second phase can be, but is not limited to, 168 to 182 days.
  • the third phase can be, but is not limited to, 119 to 137 days.
  • the first phase is 56 days, the second phase is 175 days, and the third phase is 126 days. In other aspects of the invention, the first phase is 56 days, the second phase is 175 days, and the third phase is 130 days. In some aspects of the invention, the estrogen and progestin are administered in four or more phases.
  • the method of providing an ascending-dose extended cycle regimen further includes a hormone-free period.
  • the hormone-free period can be, but is not limited to, 2 to 10 consecutive days.
  • the hormone-free period can be 2 to 8 consecutive days.
  • the hormone-free period can be 3, 5 or 7 days.
  • the hormone-free period can be a non-administration or administration of a placebo.
  • the hormone-free period can include administration of other active ingredients.
  • the method of providing an ascending-dose extended cycle regimen further comprises administering estrogen for a period of 2 to 10 consecutive days (“unopposed estrogen interval”).
  • the unopposed estrogen interval can be for a period of 2 to 8 consecutive days.
  • administration of an ascending-dose extended cycle regimen can be followed by administration of the estrogen for a period of 3, 5 or 7 days.
  • the unopposed estrogen interval can include administration of other active ingredients.
  • Examples of other additional pharmaceutically active ingredients or agents include, but are not limited to, vitamin D or vitamin D analogues; one or more of the B complex vitamins, such as vitamin B3 (niacin (i.e., nicotinic acid and/or nicotinamide)), vitamin B9 (folic acid or folate), vitamin B6 and/or vitamin B12; minerals such as, for example, calcium; iron (e.g., ferrous iron, such as, e.g., ferrous sulfate, ferrous fumarate, ferrous gluconate, or an iron glycine amino acid chelate); agents for preventing and treating bone conditions such as bisphosphonates (e.g., alendronate), teriparatide (e.g., FORTEOTM), and SERMs (selective estrogen receptor modulators, e.g., raloxifene).
  • B3 niacin (i.e., nicotinic acid and/or nicotin
  • additional active agents can be administered during the period of administration of estrogen and progestin, the hormone-free period, the unopposed estrogen interval, or a combination of these periods.
  • vitamin D and/or calcium or a bisphosphonate can be administered during the hormone-free period as a method of maintaining or preventing loss of bone density. Suitable forms of vitamin D and of calcium and bisphosphonate would be known to those of skill in the art.
  • the active ingredients can be provided in the same, different, or separate dosage forms.
  • the estrogen that is administered for a period of, e.g., 2 to 10 consecutive days is in a daily dosage that is the equivalent of 5 ⁇ g to 50 ⁇ g, 5 ⁇ g to 30 ⁇ g, or 10 ⁇ g of ethinyl estradiol.
  • the ascending-dose extended cycle regimens are optionally administered with an antidepressant.
  • the antidepressant is administered in combination with estrogen during the unopposed estrogen interval of the regimen.
  • the antidepressant is administered continuously throughout the regimen, or, in yet other aspects of the invention, the antidepressant is administered intermittently.
  • the antidepressant is administered intermittently during the late luteal phase, which is typically one to two weeks before menses.
  • the antidepressant is administered one time during a menstrual cycle, or once weekly.
  • fluoxetine hydrochloride is administered in a one-time or once-weekly dose of about 90 mg.
  • the antidepressant is administered during the hormone-free period.
  • the antidepressant that is optionally combined with the ascending-dose extended cycle regimens can be a selective serotonin reuptake inhibitor (SSRI), a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), a tricyclic antidepressant or anxiolytic, or any antidepressant known to one of skill in the art.
  • SSRI selective serotonin reuptake inhibitor
  • SSNRI selective serotonin and norepinephrine reuptake inhibitor
  • tricyclic antidepressant or anxiolytic or any antidepressant known to one of skill in the art.
  • Suitable antidepressants include, but are not limited to, alprazolam (X ANAX ®), clomipramine (A NAFRANIL ®), fluoxetine (P ROZAC ®), paroxetine (P AXIL ®), sertraline (Z OLOFT ®), nefazodone (S ERZONE ®), fenfluramine (P ONDIMIN ®) and venlafaxine (E FFEXOR ®).
  • the daily amount of antidepressant administered can vary, depending on the antidepressant used, from about 0.75 to about 2 mg, from about 10 to about 20 mg, or from about 50 to about 100 mg.
  • fluoxetine hydrochloride is administered in a daily amount of about 5 mg to about 120 mg.
  • a suitable daily amount of antidepressant for administration can be determined by one of skill in the art, e.g., a physician.
  • the method of providing an ascending-dose extended cycle regimen further comprises administering an antidepressant.
  • the antidepressant can be administered (i) during a hormone-free period, (ii) in combination with an estrogen for a period of, e.g., 2 to 10 consecutive days, (iii) continuously, (iv) intermittently, (v) one time, or (vi) once weekly.
  • the antidepressant is a SSRI such as fluoxetine.
  • the antidepressant is a SSNRI.
  • the administration of an ascending-dose extended cycle regimen of the present invention is followed by monophasic administration of an estrogen and a progestin.
  • “monophasic” refers to the continuous use of one particular dose of an estrogen and a progestin during the period of administration of the dosage form of the estrogen and progestin.
  • the administration of an ascending-dose extended cycle regimen is followed by monophasic administration of an estrogen and a progestin continuously.
  • the administration of an ascending-dose extended cycle regimen is followed by monophasic administration of an estrogen and a progestin for a period of greater than 30 or 31 consecutive days.
  • the administration of an ascending-dose extended cycle regimen is followed by monophasic administration of an estrogen and a progestin for a period of 350 to 370 consecutive days, of 260 to 280 consecutive days, of 175 to 190 consecutive days, or of 60 to 110 consecutive days.
  • the monophasic administration of an estrogen and a progestin can be optionally followed either by a hormone-free period of, e.g., 2 to 10 consecutive days or by administration of estrogen for a period of, e.g., 2 to 10 consecutive days.
  • An ascending-dose extended cycle regimen disclosed herein can be used as a method of female contraception.
  • the invention is directed to a method of contraception in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • an ascending-dose extended cycle regimen is also useful as a method of treating a variety of conditions and disorders in females.
  • an ascending-dose extended cycle regimen can be used as a method of providing contraception to a female for the treatment of a condition or disorder, or as a method of providing contraception and treating a condition or disorder in a female.
  • Such conditions and disorders include, but are not limited to: breakthrough bleeding; irregular withdrawal bleeding; menstrual bleeding disorders; symptoms associated with an ovarian cyst, uterine leiomyoma (fibroid tumor), and Polycystic Ovarian Syndrome; hirsutism; iron deficiency anemia; menstrual disorders; acne; endometriosis; endometrial cancer; ovarian cancer; benign breast disease; infections; ectopic pregnancy; temporomandibular disorder; catamenial symptoms; non-menstrual related headache, nausea, and depression; peri-menopausal symptoms; hypoestrogenism; menopausal disorders; and loss of bone density.
  • the invention is also directed to a method of providing contraception to a female for the treatment of a condition or disorder, wherein the female is in need of treatment for the condition or disorder, by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • the invention is also directed to a method of providing contraception and treating a condition or disorder in a female, wherein the female is in need of both contraception and treatment of the condition or disorder, by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • An ascending-dose extended cycle regimen disclosed herein includes administration to a female beginning at Day 1 of a menstrual cycle that is defined as beginning at the first day of menstrual flow.
  • an ascending-dose extended cycle regimen disclosed herein can also include administration to a female beginning at Day 1 of a menstrual cycle that is defined as beginning with the day after the ending of the menstrual flow.
  • an ascending-dose extended cycle regimen disclosed herein also can include administration to a female beginning at Day 1 of a menstrual cycle that is defined as beginning with any day within the menstrual cycle.
  • the effect of administration of an ascending-dose extended cycle regimen, with respect to the specified condition can be evaluated in comparison to each other, to the condition or disorder exhibited by the female after administration of a conventional or standard 28-day contraceptive regimen, after administration of an extended cycle contraceptive regimen other than an ascending-dose extended cycle regimen of the present invention, and/or with no contraceptive regimen.
  • the effect of administering an ascending-dose extended cycle regimen to treat a menstrual bleeding disorder can be evaluated by comparing the occurrence and/or severity of the bleeding disorder in females suffering from the disorder who have been administered an ascending-dose extended cycle regimen with the occurrence and/or severity of the bleeding disorder in females suffering from the disorder who have not been treated with a contraceptive regimen, or with females suffering from the disorder who have been administered a contraceptive regimen not disclosed in the present invention.
  • the effect of administering an ascending-dose extended cycle regimen of the invention can also be evaluated by comparing the occurrence and/or severity of a condition in a female before and after administration of an ascending-dose extended cycle regimen of the invention, or by evaluating the condition of the female during the course of one or more cycles.
  • the present invention is directed to a method of reducing breakthrough bleeding in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • the invention is also directed to a method of providing contraception and reducing breakthrough bleeding in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be of childbearing age or peri-menopausal.
  • the invention is directed to a method of inducing regular, predictable withdrawal bleeding in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • Administration of an ascending-dose extended cycle regimen is useful in controlling menstrual cycles in a female by inducing regular, predictable withdrawal bleeding.
  • an ascending-dose extended cycle regimen can establish or restore synchrony to the endometrium. This is particularly useful in the treatment of heavy or intermenstrual bleeding.
  • the resulting predictable timing and shorter duration of bleeding are especially advantageous to peri-menopausal women, who often experience irregular menstrual cycles.
  • the invention is also directed to a method of providing contraception and inducing regular, predictable withdrawal bleeding in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or a peri-menopausal female.
  • the invention is directed to a method of reducing frequency or delaying onset of a menstrual cycle in a female in need of delayed or reduced menstruation by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • particular groups or subpopulations of women can benefit from reduced menstruation, such as women enlisted in the U.S. military and women athletes.
  • Control of the menstrual cycle, or even induction of amenorrhea using an ascending-dose extended cycle regimen, can be an advantage for women on active duty.
  • the non-contraceptive benefits resulting from use of an ascending-dose extended cycle regimen can be desirable and advantageous to women athletes as well.
  • the term “amenorrhea” refers to the absence of bleeding during one or more menstrual cycles of a female.
  • the term encompasses the absence of bleeding and/or spotting during the unopposed estrogen interval of an ascending-dose extended cycle regimen of the present invention when administered to a female, as well as the absence of bleeding or spotting throughout an entire menstrual cycle during administration of an ascending-dose extended cycle regimen.
  • the invention is also directed to a method of providing contraception and reducing frequency or delaying onset of a menstrual cycle in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or a peri-menopausal female.
  • the invention is directed to a method for minimizing uterine bleeding in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • administration of an estrogen and a progestin in an ascending-dose extended cycle regimen can reduce the volume and duration of menstrual flow.
  • a female on a disclosed ascending-dose extended regimen can experience fewer total scheduled days of bleeding than a female on a traditional 28-day regimen, and can experience less blood loss, because an ascending-dose extended cycle regimen involves fewer stop/start transitions per year.
  • the female to be treated can exhibit abnormal uterine bleeding, including, for example, menorrhagia.
  • abnormal uterine bleeding refers to an abnormal duration of bleeding (i.e., greater than 7 days of bleeding, or hypermenorrhea), abnormal amount of bleeding (i.e., greater than about 80 mL blood loss during menses, or menorrhagia), increased frequency of bleeding (i.e., less than 22 days between menstrual cycles, or polymenorrhea), or any combinations thereof.
  • the invention is also directed to a method of providing contraception and minimizing uterine bleeding in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or a peri-menopausal female.
  • the invention is directed to a method of treating a menstrual bleeding disorder in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • the invention is also directed to a method of providing contraception and treating a menstrual bleeding disorder in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or a peri-menopausal female.
  • the invention is directed to a method of treating symptoms associated with ovarian cysts, uterine leiomyomas (fibroids), or Polycystic Ovarian Syndrome in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • the invention is also directed to a method of providing contraception and treating symptoms associated with ovarian cysts, uterine leiomyomas (fibroids), or Polycystic Ovarian Syndrome in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or peri-menopausal.
  • Ovarian cysts, uterine leiomyomas (fibroids), or Polycystic Ovarian Syndrome can cause symptoms including, but not limited to, pelvic pain, dysmenorrhea, abnormal uterine bleeding, acne, and hirsutism.
  • symptoms can be treated by administration of an ascending-dose extended cycle regimen described herein.
  • Ovarian cysts arise from functional cysts that commonly occur around mid-cycle, when a follicle destined to become an egg fails to mature. Instead of leaving the ovary in a process known as ovulation, it remains inside, floating in a tiny sac of fluid. It is that sac that eventually forms into a cyst. Although rarely malignant, ovarian cysts lead to 200,000 hospitalizations in the United States each year. For some women, some studies have shown that the cysts develop cycle after cycle.
  • ovarian cysts can sometimes be asymptomatic, they can also cause pain (constant pelvic pain, pain during intercourse, pain during pelvic movement, and/or pain before or after menses), abnormal bleeding (lengthened, shortened, irregular and/or absent menses), and/or abdominal bloating or distension.
  • Uterine fibroids are benign growths of uterine muscle that sometimes exist singly, but most often are multiple and range in size from microscopic to filling most of the lower abdominal cavity. Many women with fibroids have no symptoms at all. For those that do, the most common complaints are pressure symptoms and heavy, prolonged periods. There may be pressure in the pelvic region from the enlarged uterus, and the resulting symptoms are often related to where the fibroid is exerting pressure (e.g., increased urinary frequency, constipation or difficulty with bowel movements). The pressure can also cause backache, lower abdominal discomfort, and pain during and after intercourse. Fibroids can cause very heavy and prolonged periods, leading to iron-deficiency anemia, as well as painful periods (secondary dysmenorrhea). The presence of fibroids can also cause reproductive problems such as infertility, multiple miscarriages, premature labor, or labor complications.
  • ovarian cyst as used above represents more singular occurrences caused by the failure of an egg to mature.
  • Polycystic Ovarian Syndrome (PCOS)
  • PCOS Polycystic Ovarian Syndrome
  • LH luteinizing hormone
  • FSH follicle stimulating hormone
  • An imbalance of these hormones stops egg production and increases production of androgens, with the ovaries producing higher levels of testosterone and estrogens.
  • PCOS often leads to obesity, diabetes and hypertension.
  • Hirsutism can be described as the growth of excessive hair in women on parts of the body where excessive hair is generally not present, e.g., on the back and chest.
  • Most cases of hirsutism are androgen-dependent, i.e., result from a combination of increased androgen production by the body and increased skin sensitivity to androgens. Normally, small quantities of androgens are produced by the ovaries and the adrenal glands.
  • the invention is also directed to a method of treating hirsutism in a female in need thereof, by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • the invention is also directed to a method of providing contraception and treating hirsutism in a female in need thereof, by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or peri-menopausal.
  • the invention is directed to a method of treating alopecia in a female in need thereof, by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • the invention is also directed to a method of providing contraception and treating alopecia in a female in need thereof, by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or peri-menopausal.
  • the invention is further directed to a method of decreasing risk of iron deficiency anemia in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • a reduction in the volume and duration of menstrual flow that can result from administration of, e.g., an ascending-dose extended cycle regimen can lead to a reduction in the total loss of blood, thus improving the body's iron stores and reducing the morbidity associated with menorrhagia.
  • This effect is particularly desirable in women with coagulation disorders, for example, von Willebrand's disease.
  • the female to be treated can be, but is not limited to, a peri-menopausal female.
  • the invention is also directed to a method of providing contraception and decreasing risk of iron deficiency anemia in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or a peri-menopausal female.
  • the invention is directed to a method of treating a menstrual disorder in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • Menstrual disorders include, but are not limited to, irregular menstrual cycles, dysmenorrhea (painful menstruation), ffenriti, and dysfunctional uterine bleeding, as well as premenstrual symptoms such as, but not limited to, those associated with premenstrual syndrome (PMS) or Premenstrual Dysphoric Disorder (PMDD).
  • the invention is also directed to a method of providing contraception and treating a menstrual disorder in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or a peri-menopausal female.
  • PMDD Premenstrual Dysphoric Disorder
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders
  • the female can be a peri-menopausal female.
  • the invention is directed to a method of treating acne in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • An ascending-dose extended cycle regimen may suppress gonadotropin and decrease ovarian and adrenal androgen production, resulting in an improvement in acne of, e.g., women of childbearing age and older.
  • the invention is directed to a method of treating endometriosis in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • the invention is also directed to a method of providing contraception and treating endometriosis in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or a peri-menopausal female.
  • endometriotc tissue responds to adverse endocrine environments (low estrogen and/or high progestin concentration).
  • Progestins produce marked atrophy of the endometrium and ectopic endometrial tissue and decrease intraperitoneal inflammation associated with endometriosis.
  • progestins alone or in combination with estrogens as oral contraceptives, are an optimal choice for the management of endometriosis in women who desire contraception (American College of Obstetricians and Gynecologists, ACOG Practice Bulletin No. 11 (December 1999)).
  • the use of an ascending-dose extended cycle regimen of the present invention can be beneficial for treating or preventing endometriosis.
  • the invention is also directed to a method of treating chronic pelvic pain in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • the invention is also directed to a method of providing contraception and treating chronic pelvic pain in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or a peri-menopausal female.
  • the invention is further directed to a method of reducing the risk of endometrial cancer in a female in need thereof by administering to the female an ascending-dose extended cycle regimen, disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • the invention is also directed to a method of providing contraception and reducing the risk of endometrial cancer in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or peri-menopausal.
  • the invention is directed to a method of reducing the risk of ovarian cancer in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • the frequency of ovulation and thereby the frequency of ovarian stimulation can be reduced, suppressed, or eliminated by use of an ascending-dose extended cycle regimen.
  • the invention is also directed to a method of providing contraception and reducing the risk of ovarian cancer in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age, peri-menopausal, or menopausal.
  • the invention is further directed to a method of treating benign breast disease, including, but not limited to, fibrocystic breast disease, in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal. About a third of all women between the ages of 30 and 50 will be diagnosed with fibrocystic breast disease or other benign breast condition. Other terms for this condition include chronic mastitis (inflammation) and mammary dysplasia.
  • the invention is also directed to a method of providing contraception and treating benign breast disease in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or peri-menopausal.
  • the invention is also directed to a method of reducing the risk of colorectal cancer in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • An ascending-dose extended cycle regimen of the present invention is thought to protect against colorectal cancer as a result of changes in bile synthesis and secretion due to the female hormones in the regimen, which is thought to lead to a reduced concentration of bile acids in the colon.
  • estrogen inhibits the growth of colon cancer cells in vitro, and estrogen receptors have been identified in normal and neoplastic colon epithelial cells. See Fernandez, E., et al., British J. Cancer 84:722-727 (2001).
  • an ascending-dose extended regimen can be beneficial in the prevention or reduction in the occurrence of colorectal cancer.
  • the invention is also directed to a method of providing contraception and reducing the risk of colorectal cancer in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, a female of childbearing age or peri-menopausal.
  • the invention is directed to a method of preventing or treating an infection in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • sexually transmitted diseases STDs
  • STDs sexually transmitted diseases
  • An ascending-dose extended cycle regimen is believed to have a protective role against the development of some STDs because it stimulates the body to produce a thicker cervical mucous, which acts as a barrier to semen carrying bacteria that cause sexually transmitted diseases.
  • the invention is also directed to a method of providing contraception and treating an infection in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, but is not limited to, a female of childbearing age or peri-menopausal.
  • Pelvic Inflammatory Disease is a complication that can result from STD infections.
  • PID is a serious syndrome of the female reproductive tract that results from the spread of infections (most often sexually transmitted infections such as Chlamydia trachomatis and Nisseris gonnorrheoea ) from the vagina and endocervix to the uterus, fallopian tubes and ovaries.
  • PID is commonly manifested as endometritis (infection of the lining of the uterus) or salpingitis (infection of the fallopian tubes), and less commonly as pelvic peritonitis and/or inflammation of contiguous structures.
  • PID is a major cause of infertility and ectopic pregnancy. Ectopic pregnancy results from the implantation of a fertilized ovum in the fallopian tube or in the abdominal cavity and is thought to be caused by ciliary dysfunction within the fallopian tube resulting from prior tubal infection with N. gonorrhoea and/or C. trachomatis , which often results in loss of ciliated epithelial cells from the fallopian tubes. It has been estimated that prior tubal infection with STD agents causes about 50% of the cases of ectopic pregnancy. (MacDonald, N. E., and Brunham, R., Canadian Journal of Human Sexuality 6(2):161-170 (1997).)
  • An ascending-dose extended cycle regimen is believed to have a protective role against the development of PID because it stimulates the body to produce thicker cervical mucous, which helps prevent semen carrying STD-causing bacteria from gaining access to the uterus and eventually causing PID and PID-related complications, such as ectopic pregnancy.
  • an ascending-dose extended cycle regimen of the present invention can be useful in the prevention or reduction in occurrence of sexually transmitted diseases, Pelvic Inflammatory Disease, and ectopic pregnancy.
  • the invention is directed to a method of preventing or reducing the occurrence of a sexually transmitted disease or Pelvic Inflammatory Disease in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the invention is also directed to a method of preventing ectopic pregnancy in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, but is not limited to, a female of childbearing age or a peri-menopausal female.
  • the invention is also directed to a method of providing contraception and treating a sexually transmitted disease or Pelvic Inflammatory Disease in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the invention moreover, is directed to a method of providing contraception and preventing ectopic pregnancy in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, but is not limited to, a female of childbearing age or a peri-menopausal female.
  • an ascending-dose extended cycle regimen in comparison to the use of a conventional 28-day contraceptive regimen, can lead to a reduction in the reported occurrences of infection such as urinary tract infections, pharyngitis, upper respiratory tract infections, and sinusitus.
  • the invention is further directed to the prevention or reduction in occurrence of certain infections, such as urinary tract infections, pharyngitis, upper respiratory tract infections, and sinusitus, in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • the invention is also directed to a method of providing contraception and treating certain infections, such as urinary tract infections, pharyngitis, upper respiratory tract infections, and sinusitus, in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • the invention is also directed to a method of treating temporomandibular disorder in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • Temporomandibular disorders (TMD) are disorders of the jaw muscles, temporomandibular joints, and/or the nerves associated with chronic facial pain.
  • An ascending-dose extended cycle regimen of the present invention can be useful in the treatment of TMD.
  • the invention is also directed to a method of providing contraception and treating temporomandibular disorder in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • the invention is directed to a method of treating a catamenial symptom in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • Catamenial symptoms are those associated with conditions, disorders, or diseases that can worsen around the time of menses. Such conditions, disorders, or diseases include, but are not limited to, asthma, rheumatoid arthritis, migraine headaches, seizure disorders or epilepsy, multiple sclerosis, and diabetes.
  • the invention is also directed to a method of providing contraception and treating a catamenial symptom in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • Arthritis is a prevalent chronic condition in women. Hormonal factors can influence the frequency and severity of arthritis. In some women, arthritis symptoms such as joint stiffness, swelling and pain peak during the postovulatory phase of the menstrual cycle, and cyclic changes in local antibody release, white blood cell subpopulations and altered pain perception have been proposed as possible mechanisms (Case, A. M. and Reid, R. L., Arch. Intern. Med. 158:1405-1412 (1998)). Estrogen administered as a single agent, and as part of a combined oral contraceptive has been reported to benefit some women (Kay, C. R. and Wingrave, S.
  • an ascending-dose extended cycle regimen can be beneficial as a method of treating a catamenial symptom, such as, e.g., a symptom associated with rheumatoid arthritis, in a female in need thereof.
  • Catamenial epilepsy refers to seizure disorders that occur or worsen around menstruation. It is believed to result from cyclic alterations in both ovarian hormone levels and drug metabolism (Case, A. M. and Reid, R. L., Arch. Intern. Med. 158:1405-1412 (1998)). Thus, use of an ascending-dose extended cycle regimen can be beneficial as a method of treating a catamenial symptom such as, e.g., a symptom associated with epilepsy, in a female in need thereof.
  • a catamenial symptom such as, e.g., a symptom associated with epilepsy
  • the invention is directed to a method of treating headache or nausea unrelated to the menstrual cycle in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • Use of an ascending-dose extended cycle regimen, in comparison to the use of a conventional 28-day contraceptive regimen, can lead to a reduction in the reported occurrences of non-menstrual-related headache and nausea.
  • a disclosed ascending-dose extended cycle regimen can be used as a method of preventing or treating non-menstrual-related headache and nausea.
  • the invention is also directed to a method of providing contraception and treating headache or nausea unrelated to the menstrual cycle in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age or peri-menopausal.
  • the invention is directed further to a method of treating depression unrelated to the menstrual cycle in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, for example, of childbearing age, peri-menopausal, or menopausal.
  • “Depression” is a term that is often used to refer to different forms of depressive disorders and includes major depression, bipolar disorder (sometimes called manic-depressive illness), and dysthymia, a less severe form of depression.
  • Major depression is manifested by a combination of symptoms that interfere with the ability to work, study, sleep, eat and enjoy once pleasurable activities.
  • Bipolar disorder which is not nearly as prevalent as other forms of depressive disorders, is characterized by cycling mood changes.
  • Dysthymia a less severe type of depression, involves long-term, chronic symptoms that do not disable, but keep one from functioning well or from feeling well. “Depression” also includes the less severe, temporary sadness and loneliness often felt from time to time.
  • Use of an ascending-dose extended cycle regimen compared to use of a conventional 28-day contraceptive regimen, can lead to a reduction in the reported occurrences of non-menstrual-related depression.
  • a disclosed ascending-dose extended regimen can be used as a method of preventing or treating non-menstrual-related depression.
  • the invention is further directed to a method of increasing contraceptive effectiveness in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the female can be, but is not limited to, a female of childbearing age or a peri-menopausal female.
  • a female in need of contraceptive effectiveness can be, but is not limited to, a higher weight female.
  • a “higher weight female” refers to a human female weighing about 70 kg or more or having a body mass index (BMI) of greater than about 25.
  • BMI body mass index
  • the invention is directed to a method of increasing contraceptive effectiveness in a higher-weight female in need thereof, by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the invention is directed to a method of increasing the contraceptive effectiveness in a human female weighing about 70 kg or more, weighing about 80 kg or more, or weighing about 90 kg or more, by administering to the female an ascending-dose extended cycle regimen.
  • agents that induce ovulation include, but are not limited to, menotropins (Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), e.g., Pergonal®) and chlomiphene citrate (Clomid®).
  • FSH Follicle Stimulating Hormone
  • LH Luteinizing Hormone
  • Clomid® chlomiphene citrate
  • the ovulation-inducing agent can be administered during a suitable time as can be determined by one of skill in the art, e.g., a physician.
  • the ovulation-inducing agent can be administered, e.g., within about one week to about one month, or within about one week to about two weeks, after discontinuation of an ascending-dose extended cycle regimen of the present invention. In some aspects of the invention, the ovulation-inducing agent is administered, e.g., 2 to 10 days, or 5 to 9 days after discontinuation of an ascending-dose extended cycle regimen.
  • the invention is also directed to a method of providing contraception and treating conditions, such as the physical conditions described above, resulting from hypoestrogenism in a peri-menopausal female in need thereof by administering an ascending-dose extended cycle regimen disclosed herein to the peri-menopausal female.
  • the invention is further directed to a method of providing contraception and treating conditions, such as the physical conditions described above, resulting from ovarian failure in a peri-menopausal female in need thereof by administering an ascending-dose extended cycle regimen disclosed herein to the peri-menopausal female.
  • menopausal and peri-menopausal women experience a large variety of other symptoms ranging from depression, insomnia, and nervousness, to symptoms of arthritis and so forth.
  • estrogen is the most effective agent for the control or prevention of menopausal flushes and vaginal atrophy. It is effective in retarding or preventing the appearance of clinical evidence of osteoporosis. In appropriate doses, when combined with progestin, a favorable effect upon blood lipids can also be seen. Problems with estrogen therapy do exist, however, and have been widely explored and documented in the medical literature. The means by which estrogen has been administered, generally speaking, involves either the use of estrogen alone or estrogen plus a progestin.
  • Estrogen alone given in small doses on a continuous basis, is effective in most patients for the control of the above symptoms and problems associated therewith.
  • Estrogen alone, given in small doses on a continuous basis, is effective in most patients for the control of the above symptoms and problems associated therewith.
  • This term refers, of course, to an overstimulation of the lining of the uterus which can become pre-malignant, coupled with the possibility that the patient will eventually develop cancer of the uterine lining even under such a low-dose regimen (Gusberg et al., Obstetrics and Gynecology 17:397-412 (1961)).
  • Estrogen alone can also be given in cycles, usually 21-25 days on treatment and 5-7 days off treatment. Again, if small doses of estrogen are required to control the symptoms and it is used to this fashion, only about 10% of women will experience withdrawal bleeding between the cycles of actual treatment. However, one must again be concerned by the risk of developing endometrial hyperplasia and by the increased relative risk of developing cancer of the uterus (Research on the Menopause: Report of a W.H.O. Scientific Group, 53-68 (1981)).
  • progestin with estrogen, however, as in an ascending-dose extended cycle disclosed herein, will virtually eliminate the concern about developing endometrial hyperplasia and reduce the risk of developing endometrial carcinoma below that of the untreated general population.
  • the invention is directed to a method of treating a menopausal disorder or a peri-menopausal disorder or symptom in a female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • the invention is also directed to a method of providing contraception and treating a peri-menopausal disorder or symptom in a peri-menopausal female in need thereof by administering to the female an ascending-dose extended cycle regimen disclosed herein.
  • An ascending-dose extended cycle regimen can be used as a method of maintaining bone density or preventing loss of bone density in a female.
  • An ascending-dose extended cycle regimen can also be used in this way by administering calcium and/or vitamin D, e.g., in combination with the administration of an estrogen and a progestin.
  • An ascending-dose extended cycle regimen is not limited to administration to peri-menopausal or menopausal females as a method of maintaining bone density or preventing bone loss.
  • An ascending-dose extended cycle regimen can also be used in a method of maintaining bone density or preventing bone loss by administration to a female of childbearing age that is not peri-menopausal or menopausal.
  • an ascending-dose extended cycle regimen can be used with females 12-16 years of age who have not yet achieved peak bone density, but who, due to various conditions such as anorexia, are at risk of loss of bone density or at risk of not achieving a normal physiologic bone density for age and developmental maturity.
  • an ascending-dose extended cycle regimen can also be used as a method of treating a condition resulting from menopausal or peri-menopausal estrogen decline, including osteoporosis.
  • An ascending-dose extended cycle regimen can also be used as a method of providing contraception and treating a condition in a peri-menopausal female in need thereof resulting from peri-menopausal estrogen decline, including osteoporosis.
  • An ascending-dose extended cycle regimen can also be used as a method of treating a female in need of hormone replacement therapy.
  • the estrogen and/or progestin are administered in the conventional manner by any route where they are active.
  • administration can be by, but is not limited to, oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes, or intravaginally, by inhalation, by depot injections, or by hormone implants.
  • the dosage forms for the estrogen and/or progestin can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), vaginal creams, suppositories, pessaries, rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams.
  • compositions containing the estrogen and/or progestin and a suitable carrier can be solid dosage forms which include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders and granules; topical dosage forms which include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms which include, but are not limited to, solutions, suspensions, emulsions, and dry powder.
  • the active ingredients can be contained in such compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • pharmaceutically acceptable diluents fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • the means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, “Modern Pharmaceutics”, Banker & Rhodes, Marcel Dekker, Inc. 1979; and “Goodman & Gilman's The Pharmaceutical Basis of Therapeutics,” 6 th Edition, MacMillan Publishing Co., New York 1980 can be
  • the estrogen and/or progestin can be formulated readily by combining these compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP).
  • disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • compositions of the estrogen and/or progestin also can comprise suitable solid or gel phase carriers or excipients such as calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols.
  • suitable solid or gel phase carriers or excipients such as calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols.
  • Dragee cores can be provided with suitable coatings.
  • suitable coatings can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as, e.g., lactose, binders such as, e.g., starches, and/or lubricants such as, e.g., talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers can be added. All compositions for oral administration should be in dosages suitable for such administration.
  • the estrogen and progestin compositions can take the form of tablets or lozenges formulated in conventional manner.
  • the estrogen and/or progestin for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoro
  • the estrogen and/or progestin can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • the compounds can be administered by continuous infusion subcutaneously over a period of about 15 minutes to about 24 hours.
  • Compositions for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the estrogen and/or progestin can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the estrogen and/or progestin can also be formulated as a depot preparation.
  • Such long acting compositions can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be administered at about 1 to about 6 months or longer intervals.
  • the estrogen and/or progestin can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the estrogen and/or progestin can be applied by any transdermal, therapeutic system that is consequently supplied to the organism, such as, for example, as a transdermal patch, transdermal cream or plaster.
  • the estrogen and/or progestin can be formulated as a transdermal patch.
  • the preparation and use of transdermal patches are well known to those of skill in the art and are available in different designs, including matrix-type or reservoir-type designs.
  • transdermal patches can contain additional components such as penetration-enhancing agents and/or additional excipients that are conventionally employed, such as, e.g., carriers, gelling agents, suspending agents, dispersing agents, preservatives, stabilizers, wetting agents, emulsifying agents, and the like.
  • penetration-enhancing agents such as, e.g., carriers, gelling agents, suspending agents, dispersing agents, preservatives, stabilizers, wetting agents, emulsifying agents, and the like.
  • the estrogen and/or progestin can be formulated as vaginal gels, creams, tampons, suppositories, vaginal rings, intrauterine devices and the like.
  • the preparation of each of these formulations is well known to those of skill in the art.
  • the estrogen and/or progestin can also be administered with other active ingredients.
  • the hormone-free period or the unopposed estrogen interval can also include administration of other active ingredients.
  • estrogen and/or progestin can be administered in combination with an antidepressant.
  • Estrogen and/or progestin can also be administered with vitamin D and/or calcium in the ascending-dose extended cycle regimens as a method of maintaining or preventing loss of bone density.
  • vitamin D and/or calcium can be administered in the ascending-dose extended cycle regimens during the unopposed estrogen interval following administration of estrogen and/or progestin.
  • the form of vitamin D and of calcium used in the present invention would be well known to those of skill in the art, as would the amount.
  • calcium can be administered in the form of calcium carbonate, at a dosage level of e.g., 500 mg.
  • the estrogen and/or progestin are in a oral, transdermal, intravaginal, implantable pellet, or injectable liquid dosage form.
  • the estrogen and/or progestin can be in an oral dosage form, a transdermal dosage form, or an intravaginal dosage form.
  • the estrogen and progestin can be combined in one dosage form. In other aspects of the invention, the estrogen and progestin can be provided in different or separate dosage forms. Similarly, other active ingredients can be provided in the same, different, or separate dosage forms.
  • each phase of the regimen of the invention can be administered in a separate, single dosage form. In other aspects of the invention, each phase of the regimen of the invention can be administered in one or more separate dosage forms. For example, each phase can be administered using a separate ring or transdermal device (such as a patch). As another example, each phase can be administered using one or more rings or transdermal devices.
  • the present invention also provides a combination of two or more modes of administration with each regimen.
  • the estrogen can be provided by transdermal administration and the progestin can be provided by vaginal administration.
  • the estrogen can be provided by transdermal administration, the progestin can be provided by transdermal administration, and an SSRI can be provided by oral administration.
  • the dosages or compositions for the ascending-dose extended cycle regimens of the invention can be provided in the form of a kit or package, with the dosages arranged for proper sequential administration.
  • the present invention provides a pharmaceutical package which contains combination-type contraceptives in multiple dosage units in a synchronized, fixed sequence, wherein the sequence or arrangement of the dosage units corresponds to the stages of daily administration.
  • administration can be for 40-190 consecutive days, using tablets containing both estrogen and the progestin, followed by administration for, e.g., at least 2-10 days with estrogen, using tablets containing estrogen.
  • administration can be for 75-95 days, using tablets containing both an estrogen and a progestin, followed by administration for, e.g., at least 2-10 days with estrogen, using tablets containing estrogen.
  • administration can be for 168-186 days, using tablets containing both an estrogen and a progestin, followed by administration for, e.g., at least 2-10 days with estrogen, using tablets containing estrogen.
  • Some aspects of the invention provide a pharmaceutical kit comprising a first oral dosage capable of providing a daily dosage of estrogen and a daily dosage of progestin; a second oral dosage capable of providing a daily dosage of estrogen that is equal to or higher than that of the first oral dosage and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first oral dosage; and a third oral dosage capable of providing a daily dosage of estrogen that is equal to or higher than that of the second oral dosage and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the second oral dosage; wherein the oral dosages are capable of providing estrogen and progestin for a period of greater than 30 or 31 consecutive days.
  • kits comprising a first oral dosage capable of providing a daily dosage of estrogen and a daily dosage of progestin; a second oral dosage capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first oral dosage and capable of providing a daily dosage of progestin that is less than twice that of the first oral dosage; wherein the oral dosages are capable of providing estrogen and progestin for a period of greater than 42 consecutive days.
  • the second oral dosage is capable of providing a daily dosage of estrogen that is equal to or higher than that of the first oral dosage.
  • the pharmaceutical kit includes greater than 30 or 31 oral daily dosages.
  • a pharmaceutical kit of the present invention comprises 14 to 28 first oral dosages, 14 to 28 second oral dosages, and 35 to 53 third oral dosages.
  • a pharmaceutical kit of the present invention can contain 21 first oral dosages, 21 second oral dosages, and 42 third oral dosages.
  • a pharmaceutical kit of the present invention comprises 14 to 28 first oral dosages, 35 to 49 second oral dosages, and 14 to 32 third oral dosages.
  • a pharmaceutical kit of the present invention can contain 21 first oral dosages, 42 second oral dosages, and 21 third oral dosages.
  • a pharmaceutical kit of the present invention comprises 35 to 49 first oral dosages, 14 to 28 second oral dosages, and 14 to 32 third oral dosages.
  • a pharmaceutical kit of the present invention can contain 42 first oral dosages, 21 second oral dosages, and 21 third oral dosages.
  • the first oral dosage is capable of providing 20 ⁇ g of ethinyl estradiol and 150 ⁇ g of levonorgestrel
  • the second oral dosage is capable of providing 25 ⁇ g of ethinyl estradiol and 150 ⁇ g of levonorgestrel
  • the third oral dosage is capable of providing 30 ⁇ g of ethinyl estradiol and 150 ⁇ g of levonorgestrel.
  • a pharmaceutical kit comprising a first vaginal ring capable of providing a daily dosage of estrogen and a daily dosage of progestin; a second vaginal ring capable of providing a daily dosage of estrogen that is equal to or higher than that of the first vaginal ring and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first vaginal ring; and a third vaginal ring capable of providing a daily dosage of estrogen that is equal to or higher than that of the second vaginal ring and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the second vaginal ring; wherein the vaginal rings are capable of providing estrogen and progestin for a period of greater than 30 or 31 consecutive days.
  • kits comprising a first vaginal ring capable of providing a daily dosage of estrogen and a daily dosage of progestin; a second vaginal ring capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first vaginal ring and capable of providing a daily dosage of progestin that is less than twice that of the first vaginal ring; wherein the vaginal rings are capable of providing estrogen and progestin for a period of greater than 30 or 31 consecutive days.
  • the second vaginal ring is capable of providing a daily dosage of estrogen that is equal to or higher than that of the first vaginal ring.
  • Some aspects of the invention provide a pharmaceutical kit comprising a first transdermal device capable of providing a daily dosage of estrogen and a daily dosage of progestin; a second transdermal device capable of providing a daily dosage of estrogen that is equal to or higher than that of the first transdermal device and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first transdermal device; and a third transdermal device capable of providing a daily dosage of estrogen that is equal to or higher than that of the second transdermal device and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the second transdermal device; wherein the transdermal devices are capable of providing estrogen and progestin for a period of greater than 30 or 31 consecutive days.
  • kits comprising a first transdermal device capable of providing a daily dosage of estrogen and a daily dosage of progestin; a second transdermal device capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first transdermal device and capable of providing a daily dosage of progestin that is less than twice that of the first transdermal device; wherein the transdermal devices are capable of providing estrogen and progestin for a period of greater than 30 or 31 consecutive days.
  • the second transdermal device is capable of providing a daily dosage of estrogen that is equal to or higher than that of the first transdermal device.
  • the pharmaceutical kits of the invention can further include instructions for proper sequential administration in accordance with the regimens of the present invention.
  • the present invention is also directed to a method of delivering a pharmaceutical composition for an ascending-dose extended cycle regimen of the present invention to a patient in need thereof, the method comprising (a) registering in a computer readable medium the identity of a physician permitted to prescribe a pharmaceutical composition for an ascending-dose extended cycle regimen; (b) providing the patient with counseling information concerning the risks attendant to the pharmaceutical composition; (c) obtaining informed consent from the patient to receive the pharmaceutical composition despite the attendant risks; (d) registering the patient in a computer readable medium after obtaining their informed consent; and (e) permitting the patient access to the pharmaceutical composition.
  • the drug delivery methods of the present invention involve, inter alia, registering in a computer readable storage medium physicians who are qualified to prescribe the ascending-dose extended cycle regimen of the present invention.
  • the physician can be eligible to prescribe the pharmaceutical composition to a patient in need thereof.
  • the physician may be required to comply with various aspects of, for example, providing patient education and counseling.
  • the registration of the physician in the computer readable storage medium can be achieved by providing the physician, for example, by mail, facsimile transmission, or on-line transmission, with a registration card or form, preferably together with educational materials concerning the pharmaceutical composition of the present invention.
  • the physician can complete the registration card or form by providing information requested therein, and the registration card or form can be returned to the manufacturer or distributor of the pharmaceutical composition of the present invention, or other authorized recipient of the registration materials, for example, by mail, facsimile transmission or on-line transmission.
  • the physician's information in the registration card or form is then entered into the computer readable storage medium. Suitable computer readable storage media which can be employed for registration of the physicians (as well as patients, as discussed below) will be apparent to one of ordinary skill in the art, once in possession of the teaching of the present application.
  • the physician may determine that the patient's condition can be improved by the administration of the pharmaceutical composition of the present invention.
  • the physician can counsel the patient, for example, on the various risks and benefits associated with the pharmaceutical composition of the present invention.
  • the patient can be provided full disclosure of all the known and suspected risks associated with the pharmaceutical composition of the present invention.
  • counseling can be provided verbally, as well as in written form.
  • the physician can provide the patient with literature materials on the pharmaceutical composition of the present invention, such as product information, educational materials, and the like.
  • the methods of the invention further require the patient to fill out an informed consent form which is signed by the patient.
  • the patient can be registered in a computer readable storage medium.
  • the computer readable storage medium in which the patient is registered can be the same as, or different from, the computer readable storage medium in which the physician is registered.
  • the registration into one or more computer readable storage media of the physician and patient, according to the methods describe herein, provides a means to monitor and authorize access to the pharmaceutical composition of the present invention.
  • the computer readable storage medium can serve to deny access to patients who fail to abide by the methods of the present invention.
  • access to the pharmaceutical composition of the present invention is in the form of a prescription, wherein the prescribing physician is registered in a computer readable storage medium, has provided counseling to the patient concerning the attendant risks of the pharmaceutical composition of the present invention, and has obtained informed consent from the patient, prior to prescribing the pharmaceutical composition of the present invention to the patient in need thereof.
  • Tables 2-6 below show examples of ascending-dose extended cycle regimens for 2-month, 3-month, 4-month, 5-month, and 6-month cycles, respectively. All regimens below comprise three phases, wherein an equivalent of 20 ⁇ g of ethinyl estradiol is administered in the first phase, 25 ⁇ g of ethinyl estradiol is administered in the second phase, and 30 ⁇ g of ethinyl estradiol is administered in the third phase. For all regimens below, an equivalent of 150 ⁇ g of levonorgestrel is administered in all three phases.
  • the primary objective of this study is to evaluate and compare bleeding patterns and hormone-related symptoms in women receiving one of the following three different ascending dose extended cycle (91-day) oral contraceptive regimens, each having combination active tablets containing ethinyl estradiol (EE) and levonorgestrel (LNG), followed by EE tablets during the seven-day interval between each 84-day cycle of combination therapy:
  • 91-day ascending dose extended cycle
  • Regimen I Subjects will utilize a regimen of 42 days combination active tablets (20 ⁇ g EE/150 ⁇ g LNG) followed by 21 days combination active tablets (25 ⁇ g EE/150 ⁇ g LNG) followed by 21 days combination active tablets (30 ⁇ g EE/150 ⁇ g LNG) followed by 7 days of 10 ⁇ g EE tablets for two consecutive 91-day cycles.
  • Regimen II Subjects will utilize a regimen of 21 days combination active tablets (20 ⁇ g EE/150 ⁇ g LNG) followed by 42 days combination active tablets (25 ⁇ g EE/150 ⁇ g LNG) followed by 21 days combination active tablets (30 ⁇ g EE/150 ⁇ g LNG) followed by 7 days of 10 ⁇ g EE tablets for two consecutive 91-day cycles.
  • Regimen III Subjects will utilize a regimen of 21 days combination active tablets (20 ⁇ g EE/150 ⁇ g LNG) followed by 21 days combination active tablets (25 ⁇ g EE/150 ⁇ g LNG) followed by 42 days combination active tablets (30 ⁇ g EE/150 ⁇ g LNG) followed by 7 days of 10 ⁇ g EE tablets for two consecutive 91-day cycles.
  • the duration of the study is approximately 9 months, depending on where the subject is in her cycle at the time of screening.
  • a conventional 28-day cycle contraceptive regimen such as Portia® (Barr Laboratories, Inc., Woodcliff Lake, N.J.) can be used prior to administering the ascending-dose extended cycle regimens of the present invention.
  • the ascending-dose extended cycle regimens will be administered for two consecutive 91-day extended cycles (26 weeks). There will be 9 study visits, which will include a screening visit, a run-in visit, a randomization visit, five study visits occurring every 4-6 weeks during the 26 week treatment period (weeks 4, 10, 16, 22, and 26), and a final study visit occurring 14-21 days after completion of study medication

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US11/554,571 US20070111975A1 (en) 2004-10-07 2006-10-30 Methods of Hormonal Treatment Utilizing Ascending-Dose Extended Cycle Regimens
US11/892,026 US8415332B2 (en) 2004-10-07 2007-08-17 Methods of hormonal treatment utilizing ascending-dose extended cycle regimens
RU2009120528/15A RU2009120528A (ru) 2006-10-30 2007-10-30 Способы гормональной терапии возрастающими дозами в режиме пролонгированного цикла
JP2009534693A JP2010508275A (ja) 2006-10-30 2007-10-30 用量漸増長期サイクル治療プログラムを利用するホルモン処置の方法
EP07873464A EP2079461A4 (en) 2006-10-30 2007-10-30 HORMONE TREATMENT METHODS USING PROLONGED CYCLIC DOSAGE SCHEMES WITH GROWING DOSES
MX2009004616A MX2009004616A (es) 2006-10-30 2007-10-30 Metodos de tratamiento hormonal que utilizan regimenes de ciclo extendido de dosis ascendente.
KR1020097011178A KR20090094437A (ko) 2006-10-30 2007-10-30 상승-약량 연장 주기 요법을 이용한 호르몬 치료 방법
CN200780046391A CN101626760A (zh) 2006-10-30 2007-10-30 利用递增剂量长周期给药方案进行激素治疗的方法
CA002668211A CA2668211A1 (en) 2006-10-30 2007-10-30 Methods of hormonal treatment utilizing ascending-dose extended cycle regimens
TW096140829A TW200831107A (en) 2006-10-30 2007-10-30 Methods of hormonal treatment utilizing ascending-dose extended cycle regimens
PCT/US2007/022832 WO2008127303A1 (en) 2006-10-30 2007-10-30 Methods of hormonal treatment utilizing ascending-dose extended cycle regimens
BRPI0716291-0A2A BRPI0716291A2 (pt) 2006-10-30 2007-10-30 Método de contracepção e kits farmacêuticos
IL198441A IL198441A (en) 2006-10-30 2009-04-28 Contraception methods in females using rising hormone doses
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