WO2003077926A1 - Extended cycle estrogen and sulfatase inhibiting progestogen contraceptive regimens - Google Patents
Extended cycle estrogen and sulfatase inhibiting progestogen contraceptive regimens Download PDFInfo
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- WO2003077926A1 WO2003077926A1 PCT/US2003/007601 US0307601W WO03077926A1 WO 2003077926 A1 WO2003077926 A1 WO 2003077926A1 US 0307601 W US0307601 W US 0307601W WO 03077926 A1 WO03077926 A1 WO 03077926A1
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- progestogen
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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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- 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 extended cycle contraceptive regimens for menstruating females. More particularly, the present invention relates to extended cycle contraceptive regimens containing a potent sulfatase inhibiting progestogen, such as, norgestimate (NGM) or norelgestromin (NGMN), and an estrogen.
- a potent sulfatase inhibiting progestogen such as, norgestimate (NGM) or norelgestromin (NGMN)
- an estrogen such as, norgestimate (NGM) or norelgestromin (NGMN)
- estradiol is one of the main factors involved in supporting growth of hormone-dependent breast tumours and the sulfatase pathway is the main pathway for the formation of estradiol in the breast, then a decrease of estradiol formation by suppression of the sulfatase pathway would have potential therapeutic activity in the management of breast cancer, (see refs #1 at 493, #3 at 55, #4 at 17, #5 at 931, #6 at 123 and #11 at 631) Suppression of the sulfatase pathway will have a breast protective effect.
- Local formation of estrogens in the breast is only one source for exposure of breast tissues to estrogens. Another source of estrogen present in breast tissues is estrogen containing contraceptive regimens.
- a 91 day cycle would include 7 days without administration of a hormone, including estrogen, preceded by 84 days of combined administration of progestogen and estrogen.
- a 91 day cycle would require the administration of an estrogen for 84 of 91 days rather than 21 of 28 days. On a yearly basis this would mean 4 weeks without estrogen administration for the 91 day cycle as compared to 13 weeks without estrogen administration for the 28 day cycle.
- the increased exposure to estrogen is recognized as a possible disadvantage (see refs #14 at 275 and #15 at 94).
- a method of contraception comprising the step of administering to a menstruating female a cycle of contraceptive therapy, said cycle of therapy including, for at least 42 successive days, the administration of a combination of an estrogen and a progestogen in a contraceptively effective daily dosage wherein said progestogen is a potent sulfatase inhibiting progestogen and said cycle of therapy including 4-8 days which are free of estrogen administration following said at least 42 successive days.
- a contraceptive therapy unit for administration to a menstruating female comprising a cycle of separate dosage units, said cycle of dosage units including at least 42 dosage units adapted for successive daily oral administration, wherein said dosage units contain, in admixture with a pharmaceutically acceptable carrier, a combination of an estrogen and a progestogen in a contraceptively effective daily dosage wherein said progestogen is a potent sulfatase inhibiting progestogen and, optionally, said cycle of dosage units including 4-8 dosage units containing no estrogen.
- a contraceptive therapy unit for administration to a menstruationg female comprising a cycle of transdermal patches, said cycle of transdermal patches including a sufficient number of patches adapted for successive administration to provide for at least 42 successive days of therapy, wherein said transdermal patches contain, in a suitable matrix, a combination of an estrogen and a progestogen for delivery in a contraceptively effective daily dosage wherein said progestogen is a potent sulfatase inhibiting progestogen and, optionally, said cycle of transdermal patches including a patch for 4-8 days of use containing no estrogen.
- a contraceptive therapy unit for administration to a menstruationg female comprising a cycle of vaginal rings, said cycle of vaginal rings including a sufficient number of rings adapted for successive administration to provide for at least 42 successive days of therapy, wherein the vaginal rings contain, in a suitable matrix, a combination of an estrogen and a progestogen for delivery in a contraceptively effective daily dosage wherein said progestogen is a potent sulfatase inhibiting progestogen and, optionally, said cycle of vaginal rings including a ring for 4-8 days of use containing no estrogen.
- Applicants have surprisingly discovered that such a regimen is expected to have reduced levels of estrogen in the breast as compared to other extended cycle contraceptive regimens having equivalent doses of estrogens.
- Figure 1 - Shows the enzymatic process involved in the formation and transformation of estrogens in human breast cancers.
- the contraceptive regimen according to the present invention is administered cycle after cycle to a menstruating female to achieve a long term contraceptive effect.
- Menstruating female is intended to refer to fertile women of child bearing age.
- the method of administration might be transdermal, vaginal or oral. Where administration is transdermal, a suitable patch is continuously worn with replacement as required. Where administration is vaginal, a suitable vaginal device, such as a ring, is continuously inserted with replacement as required. Where administration is oral, daily oral dosage units are administered.
- Extended cycle contraceptive regimen is intended to refer to contraceptive regimens having combined estrogen and progestogen administration of 42 days or longer followed by an off period of time without or with reduced administration of these hormones to allow menstruation.
- a minimum extended cycle would cover a period of time, which is 42 days of drug administration plus an off period of 4-8 days without drug or with reduced drug.
- a preferred extended cycle is 11 or 12 weeks of drug administration followed by an off period off 4-8 days without drug or with reduced drug.
- Another preferred extended cycle is 25 weeks of drug administration followed by an off period of 4-8 days without drug or with reduced drug.
- the off period without or with reduced administration of hormone is to allow for menstruation as stated. During the off period there should be no estrogen administered.
- a full dose is intended to mean a continuation of the dose administered in the active period of the cycle or of a progestogen dose named below as suitable for administration in the active period of the cycle.
- a reduced or minimized dose might be a tablet delivered oral norgestimate equivalent dose of 30 or 60 meg or device delivered systemic circulation norgestimate equivalent dose of 18 or 30 meg.
- a preferred off period of time without or with reduced hormone to allow for menstruation is 7 days.
- the extended cycle regimens herein may include a regimen in which there is a day to day or week to week variation in the dose of active administered according to a set pattern. In such a case the regimen, including variation of dose, is repeated in cycle following cycle.
- the extended cycle regimen may also be one in which there is no variation in the dose of the active administered.
- an extended cycle contraceptive product utilizing the contraceptive regimen of the present invention is prescribed, sold and administered in units of cycles.
- the contraceptive product based on a cycle might be 4 to 25 vaginal rings that are inserted and then replaced every 7, 14 or 21 days according to their design.
- the contraceptive product based on a cycle might be 4 to 25 transdermal patches that are attached and then replaced every 7, 10 or 14 days according to their design.
- the contraceptive product based on a cycle might be 42, 49, 63, 84, 91, 126 or 182 tablets that are orally administered daily in a cycle that is 42/7, 49/7, 63/7, 84/7, 91/7, 126/7 or 182/7.
- the estrogen in combination with the progestogen is administered in sufficient amounts to provide a contraceptive effect. Additionally, the estrogen dose in contraceptive regimens described herein is closely associated with the control of bleeding and spotting in the cycle. Between menstruations, bleeding and spotting should be minimized. Thus, 17 -ethinylestradiol might be also administered in sufficient amounts to control or minimize or eliminate bleeding and spotting during the inter-menstruation period of the cycle.
- Estrogen herein refers to an estrogen receptor modulator having either an agonistic or antagonistic effect on the estrogen receptor, but preferably an agonistic effect. Any conventional estrogen may be employed as a suitable component in the contraceptive regimen of this invention. The particular estrogen employed should be selected and administered such that it is equivalent in contraceptive effect to a daily dosage of about 0.005-0.050 mg of 17 ⁇ -ethinylestradiol. The preferred dosage of the estrogen employed is one equal to a daily dosage of about 0.010- 0.035 mg of 17 ⁇ - ethinylestradiol.
- 17 ⁇ -estradiol there can be also be employed 17 ⁇ -ethinylestradiol, esters and ethers of 17 ⁇ -ethinylestradiol such as, for example, 17 ⁇ -ethinylestradiol 3-dimethylamino propionate, 17 ⁇ -ethinylestradiol 3- cyclopentyl ether (quienestrol) and 17 ⁇ -ethinylestradiol 3-methyl ether (mestranol) as the estrogen component.
- Natural estrogens such as estrone, estrone sulfate, estrone sulfate piperazine salt, estradiol and estriol, and their esters, may also be employed.
- Conjugated equine estrogens (CEE) or conjugated estrogens (CE) are well known for this use.
- Suitable synthetic estrogens or synthetic estrogen modulators for use herein include tamoxifen, toremifene, ormeloxifene, modrefen, fulvestrant, lasofoxifene, avalycation, EM-652 (Sch-57068), 3339 (Aventis), Ospemifene (Fc 1271 A), ERA-923, GTx-006, HM-101, DPC-974, A- 007, SP-8490, WAY-140424, tibolone, levodoxiphen, raloxifene.
- a daily oral tablet there is administered a preferred dose of 17 - ethinylestradiol (or contraceptively equivalent amount of a suitable estrogen) between about 0.005 mg to about 0.050 mg and more preferably between about 0.010 mg to about 0.035 mg.
- Specific daily oral tablets might contain 0.015, 0.020, 0.025 or 0.035 mg of 17 ⁇ -ethinylestradiol.
- the preferred ring delivers to systemic circulation a daily dose of 17 ⁇ -ethinylestradiol (or contraceptively equivalent amount of a suitable estrogen) between about 0.003 mg to about 0.030 mg and more preferrably between about 0.006 mg to about 0.020 mg.
- a specific vaginal ring might be inserted for one week and deliver to systemic circulation in that period of time an average daily dose of 0.009, 0.012, 0.015 or 0.020 mg of 17 ⁇ -ethinylestradiol.
- a preferred patch delivers to systemic circulation a daily dose of 17 ⁇ -ethinylestradiol (or contraceptively equivalent amount of a suitable estrogen) between about 0.003 mg to about 0.030 mg and more preferrably between about 0.006 mg to about 0.020 mg.
- a specific patch might be worn for one week and deliver to the surface of the skin in that period of time an average daily dose of 0.009, 0.012, 0.015 or 0.020 mg of 17 ⁇ -ethinylestradiol. Regardless of the foregoing, it is intended herein to use conventional amounts of estrogen since it is not the estrogen component which is critical to the invention. Persons skilled in the art well understand required doses of estrogen required in contraceptive regimens.
- a potent sulfatase inhibiting progestogen is preferably herein defined as a progestogen which has (or a progestogen with a substantial metabolite thereof which has) an IC 5 o in the conversion of EiS to E 2 in either the MCF-7 or T-47D breast cancer cell lines of about the corresponding IC 5 o of norelgestromin or lower.
- a potent sulfatase inhibiting progestogen may also be a progestogen which has (or a progestogen with a substantial metabolite thereof which has) an IC 5 o in the conversion of Ei S to E 2 in either the MCF-7 or T-47D breast cancer cell lines of substantially less than the corresponding IC 5 o of medroxyprogesterone acetate, for example, on the order of 1/3, 1/2 or 1/5 of the IC 5 o of medroxyprogesterone acetate.
- a potent sulfatase inhibiting progestogen can also be defined as a progestogen having (or a progestogen with a substantial metabolite thereof which has) an IC 5 o in the conversion of EiS to E 2 in either the MCF-7 or T-47D breast cancer cell lines of at most about 1/10, or about preferably 1/100, the corresponding IC 5 o of medroxyprogesterone acetate (MPA).
- MPA medroxyprogesterone acetate
- a potent sulfatase inhibiting progestogen can also be defined as a progestogen which inhibits (or a progestogen with a substantial metabolite thereof which inhibits) at least about 70%) and preferably at least about 90%> of the conversion of EiS to E 2 in either the MCF-7 or T-47D breast cancer cell lines where employed in the test at a concentration of 50 x l0 "6 mol/l.
- Norgestimate or norelgestromin (NGMN) are the preferred progestogens utilized herein and are each known to the art of contraceptive therapy.
- norgestimate is now used in a number of commercially available contraceptive products.
- the most preferred progestogen is norelgestromin (17-d-norgestimate).
- Norelgestromin is the major metabolite of norgestimate in humans with 80% and higher of norgestimate being converted to norelgestromin in vivo. For this reason, inhibition of sulfatase enzyme activity which is demonstrated for norelgestromin is inferred to norgestimate.
- progestogen is administered in conjunction with the estrogen in an amount sufficient to produce a contraceptive effect.
- the progestogen will also oppose the action of the estrogen on the endometrium. It has been observed that the long term administration of an estrogen which is unopposed by the administration of a progestogen leads to a substantial increase in the incidence of endometrial cancer. Thus, it is also desirable in a contraceptive regimen that the progestogen be administered in an amount which is an effective endometrium protective amount.
- the progestogen be administered in an amount which is an effective breast protective amount. More specifically, in a first characterization of a breast protective and otherwise suitable amount of progestogen, there is selected and administered sufficient sulfatase inhibiting progestogen such that it is at least equivalent in both contraceptive and breast protecting effect to about 0.030 mg to about 0.500 mg of orally administered norgestimate. Preferably, there is selected and administered sufficient sulfatase inhibiting progestogen such that it is at least equivalent in both contraceptive and breast protecting effect to about 0.050 mg to about 0.300 mg of orally administered norgestimate.
- a substantial supression of sulfatase activity for example, of 50% or greater and preferably of 67% or greater and most preferably of 75% or greater.
- a substantial portion of a day is intended to mean a period of at least 4 hours, but within the invention might mean a period of at least 8 hours or 12 hours or even 24 hours.
- norgestimate or norelgestromin in the case of a daily oral tablet, there is administered a preferred dose of norgestimate or norelgestromin (or contraceptively equivalent amount of a suitable progestogen) between about 30 meg to about 500 meg and more preferably between about 50 meg to about 300 meg.
- Specific daily oral tablets might contain 125, 180, 215, 250 or 300 meg of norgestimate or norelgestromin.
- a preferred ring delivers to systemic circulation a daily dose of norgestimate or norelgestromin (or contraceptively equivalent amount of a suitable progestogen) between about 18 meg to about 300 meg and more preferrably between about 30 meg to about 175 meg.
- a specific vaginal ring might be inserted for one week and deliver to systemic circulation in that period of time an average daily dose of 70, 100, 125, 140 or 175 meg of norgestimate or norelgestromin.
- a preferred patch delivers to systemic circulation a daily dose of norgestimate or norelgestromin (or contraceptively equivalent amount of a suitable progestogen) between about 18 meg to about 300 meg and more preferrably between about 30 meg to about 175 meg.
- a specific patch might be worn for one week and deliver to systemic circulation in that period of time an average daily dose of 70, 100, 125, 140 or 175 meg of norgestimate or norelgestromin.
- Each of the regimens of Table 1 might be modified by continuing the administration of a NGM or NGMN in a progestogen only tablet for all days of the off period.
- the dose might be full dose, which is the same as that administered in the active period, or it might be a dose of 125 meg or it might be a minimized dose of 50 meg.
- Each of the regimens of Table 2 might be modified by continuing the administration of a NGM or NGMN in a progestogen only device during the off period.
- the dose might be full dose, which is the same as that administered in the active period, or it might be a dose of 70 meg or it might be a minimized dose of 30 meg.
- the estrogen and progestogen component are orally administered preferably together in tablets also containing a pharmaceutically acceptable non-toxic carrier, but they can also be administered separately.
- Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, methylcellulose, sodium carboxylmethylcellulose, and the like.
- the tablet may also contain one or more substances, which act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents as well as encapsulating materials.
- the active agents are processed, together with the usual additives, vehicles and/or flavor-ameliorating agents normally employed in Galenic pharmacy, in accordance with generally accepted pharmaceutical practices.
- the hormone containing tablets might also contain nutritional supplements such as, for example, iron supplements, folic acid, calcium, vitamin B 6 , vitamin B] 2 , etc.
- the active agents are granulated with spray dried lactose, a lubricating agent and a colorant and compressed.
- Oral tablets are preferably packaged in the form of a pharmaceutical kit or package in which the daily dosages are arranged for proper sequential administration.
- This invention also relates, therefore, to a pharmaceutical unit which contains the tablets of the regimen in a synchronized, fixed sequence, wherein the sequence or arrangement of the dosage units corresponds to the regimen of daily administration.
- the estrogen and progestogen component may be transdermally administered, preferably together, by use of a patch.
- patches are devices which contain at a minimum a drug reservoir matrix for holding the drug and metering the drug deposition or delivery to the skin, a backing, and an adhesive layer for adhering the device to the patient.
- the device may contain other layers such as a drug release rate controlling layer for modulating delivery rate, and the like.
- the device may contain permeation enhancers to increase the rate of penetration of drugs across the skin.
- Patches are well known and understood by persons skilled in the art. Patches are now employed in marketed products for the administration of certain progestogens and estrogens. Specific patches and even their application to steroids of the type described herein are described in U.S. Pat. Nos. 5474783; 5656286; 5958446; 6024976; 5252334; 5006342; and 4906463.
- rings are devices having an elastomeric portion or body into which the active steroid is dispersed and which acts as a reservoir and meter for the diffusion of active to the lining of the vagina.
- the ring may be composed entirely of elastomer with steroid homogenously dispersed throughout as described in US Pat. No. 3545397.
- the ring may have an inert inner core surrounded by an active containing elastomeric layer as described in US Pat. No. 4012496.
- the ring may have an elastomeric active containing inner core surrounded by a thin elastomeric layer initially containing no active.
- the ring may have an inert core, surrounded by an active containing elastomeric layer and further surrounded by an elastomeric outer layer of variable thickness initially containing no active as described in US Pat. No. 4292965.
- the elastomer, the layered design of the ring, its surface area, the concentration of active, the nature of the active, etc. all combine to determine the release rate of active. Rings are well known and understood by persons skilled in the art. Rings are now employed in marketed products for the administration of certain steroids. Further specific rings and their application to steroids of the type described herein are described in U.S. Pat. Nos 4871543 and 5188835. BIOLOGICAL TEST METHODS Chemicals
- [6,7- 3 H(N)]-estrone sulfate ( 3 H-E ⁇ S), ammonium salt (sp. act. 53 Ci/mmol) and [4- 14 C]-estradiol ( 14 C-E ) (sp. act. 57 mCi/mmol) were purchased from New England Nuclear Division (DuPont de Nemours, Les Ulls, France). The purity of the radioisotopes was assessed by thin-layer chromatography (TLC) in the appropriate system before use.
- EiS, ammonium salt, unlabeled Ei and E 2 , (analytical grade) were obtained from Sigma-Aldrich Chimle, (St Quentin Fallavier, France).
- the hormone-dependent MCF-7 and T-47D human mammary cancer cell lines were grown in Eagle's Minimal Essential Medium (MEM) buffered with 10 mmol/1 HEPES (pH 7.6), supplemented with 2 mmol/1 L-glutamine, 100 U/ml penicillin- streptomycin and 5% fetal calf serum (FCS) (A.T.G.C, Marne-la-Vallee, France) for T- 47D, or 10% FCS for MCF-7 cells, and incubated at 37 ° C n a humidified atmosphere of 5% CO 2 . Media were changed twice a week.
- MEM Eagle's Minimal Essential Medium
- HEPES pH 7.6
- FCS fetal calf serum
- the cells were passed every 10-12 days and replated in 75 cm flasks (A.T.G.C.) at 3 x 10 cells/flask. Four days before the experiments, the cells were transferred to MEM containing 5%> steroid-depleted treated FCS. The FCS had been treated overnight at 4 C with dextran-coated charcoal (DCC)(0.1-1% w/v, DCC-FCS).
- DCC dextran-coated charcoal
- MCF-7 and T-47D cell lines used herein were deposited in accordance with the Budapest Treaty under the references MCF7_JJPRD and T47DJJPRD on May 17, 2002 at The Belgian Co-ordinated Collections of Microorganisms (BCCM), Laboratorium voor Mole Les Biologie, Universiteit Gent, K. L. Ledeganckstraat 35, B-9000 Gent, Belgium and are publicly available under accession numbers LMBP 5862CB and LMBP 5863CB, respectively. Isolation and quantification of [ 3 H]-estradiol from human mammary cancer cells incubated with [ H]-E ⁇ S
- Preconfluent cells were incubated for 4 hours at 37 °C in MEM-DCC-FCS with the addition of 5x10 "9 mol/1 of [ 3 H]-E ⁇ S, alone (control cells) or in combination with the different compounds: NGMN or MPA, dissolved in ethanol (final concentration ⁇ 0.2%>), at a range of concentrations of 5xl0 "5 -5xl0 "9 mol/1.
- Control cells received ethanol vehicle only. After 24 hours, the medium was removed, the cells washed twice with ice-cold Hank's Buffered Saline Solution (HBSS, calcium-magnesium- free)(A.T.G.C.) and harvested by scraping.
- HBSS Hank's Buffered Saline Solution
- Table 3 shows the effects of ⁇ GM ⁇ and medroxyprogesterone acetate (MPA) concentrations on the conversion of EiS to E in the hormone-dependent human breast cancer cell line T-47D The data are the mean + . SEM of duplicate determinations of 3 independent experiments. * p ⁇ 0.05 vs contol values (non-treated cells); ** p ⁇ 0.005 vs contol values (non-treated cells)
- Table 4 shows the effects of NGMN and medroxyprogesterone acetate (MPA) concentrations on the conversion of EiS to E 2 in the hormone-dependent human breast cancer cell line MCF-7.
- the data are the mean + .
- Table 5 shows the IC 50 values for NGMN and medroxyprogesterone acetate
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Abstract
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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CA002478336A CA2478336A1 (en) | 2002-03-11 | 2003-03-11 | Extended cycle estrogen and sulfatase inhibiting progestogen contraceptive regimens |
EP03714106A EP1482947A1 (en) | 2002-03-11 | 2003-03-11 | Extended cycle estrogen and sulfatase inhibiting progestogen contraceptive regimens |
JP2003575979A JP2005519963A (en) | 2002-03-11 | 2003-03-11 | Long-term estrogen and sulfatase-inhibited progestogen contraceptive regimen |
AU2003218119A AU2003218119A1 (en) | 2002-03-11 | 2003-03-11 | Extended cycle estrogen and sulfatase inhibiting progestogen contraceptive regimens |
Applications Claiming Priority (4)
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US36316702P | 2002-03-11 | 2002-03-11 | |
US60/363,167 | 2002-03-11 | ||
US38158502P | 2002-05-17 | 2002-05-17 | |
US60/381,585 | 2002-05-17 |
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WO2003077926A1 true WO2003077926A1 (en) | 2003-09-25 |
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PCT/US2003/007601 WO2003077926A1 (en) | 2002-03-11 | 2003-03-11 | Extended cycle estrogen and sulfatase inhibiting progestogen contraceptive regimens |
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EP (1) | EP1482947A1 (en) |
JP (1) | JP2005519963A (en) |
CN (1) | CN1652796A (en) |
AU (1) | AU2003218119A1 (en) |
CA (1) | CA2478336A1 (en) |
WO (1) | WO2003077926A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004080442A1 (en) * | 2003-03-11 | 2004-09-23 | Janssen Pharmaceutica N.V. | Extended transdermal contraceptive regimens |
US8580294B2 (en) | 2010-10-19 | 2013-11-12 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
US10137031B2 (en) | 2013-11-14 | 2018-11-27 | International Partnership For Microbicides, Inc. | Combination therapy intravaginal rings |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996040355A1 (en) * | 1995-06-07 | 1996-12-19 | Cygnus, Inc. | Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen |
WO1999013882A1 (en) * | 1997-09-12 | 1999-03-25 | American Home Products Corporation | Oral contraceptive preparation having a first phase comprising progestin/estrogen and a second phase comprising progestin |
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2003
- 2003-03-11 WO PCT/US2003/007601 patent/WO2003077926A1/en active Application Filing
- 2003-03-11 JP JP2003575979A patent/JP2005519963A/en not_active Withdrawn
- 2003-03-11 CN CNA038107104A patent/CN1652796A/en active Pending
- 2003-03-11 CA CA002478336A patent/CA2478336A1/en not_active Abandoned
- 2003-03-11 EP EP03714106A patent/EP1482947A1/en not_active Withdrawn
- 2003-03-11 AU AU2003218119A patent/AU2003218119A1/en not_active Abandoned
Patent Citations (2)
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WO2004080442A1 (en) * | 2003-03-11 | 2004-09-23 | Janssen Pharmaceutica N.V. | Extended transdermal contraceptive regimens |
US8580294B2 (en) | 2010-10-19 | 2013-11-12 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
US9427400B2 (en) | 2010-10-19 | 2016-08-30 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
US10137031B2 (en) | 2013-11-14 | 2018-11-27 | International Partnership For Microbicides, Inc. | Combination therapy intravaginal rings |
US11259956B2 (en) | 2013-11-14 | 2022-03-01 | International Partnership For Microbicides, Inc. | Combination therapy intravaginal rings |
US11793669B2 (en) | 2013-11-14 | 2023-10-24 | The Population Council, Inc. | Combination therapy intravaginal rings |
Also Published As
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JP2005519963A (en) | 2005-07-07 |
CA2478336A1 (en) | 2003-09-25 |
CN1652796A (en) | 2005-08-10 |
EP1482947A1 (en) | 2004-12-08 |
AU2003218119A1 (en) | 2003-09-29 |
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