CN1950092A - Management of breakthrough bleeding in extended hormonal contraceptive regimens - Google Patents

Management of breakthrough bleeding in extended hormonal contraceptive regimens Download PDF

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Publication number
CN1950092A
CN1950092A CNA200580013899XA CN200580013899A CN1950092A CN 1950092 A CN1950092 A CN 1950092A CN A200580013899X A CNA200580013899X A CN A200580013899XA CN 200580013899 A CN200580013899 A CN 200580013899A CN 1950092 A CN1950092 A CN 1950092A
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days
amount
day
cycle
progestogen
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安德烈亚斯·萨克塞
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Bayer Pharma AG
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Schering AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/565—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin

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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Orthopedics, Nursing, And Contraception (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a flexible extended use regimen for a hormonal contraceptive useful to manage bleeding problems associated with fixed extended use of hormonal contraceptives and to a pharmaceutical package containing the respective hormonal contraceptive.

Description

Control to break-through bleeding in the hormonal contraceptive regimens that prolongs
Technical field
The present invention relates to a kind of application scheme of prolongation of hormonal contraceptive, it can be used for controlling and the hormonal contraceptive such as the Seasonale that carry out at present Fixed prolongation use relevant bleeding problems, the invention still further relates to the medicated bag that contains hormonal contraceptive (pharmaceutical package) of the scheme that can be used for this prolongation.
Background technology
Take oral contraceptive (OC) and cut out pill (pill break) mainly caused annual 13 menstruations in 7 days based on the hope imitation with the idea that allows withdrawal bleeding normal menstrual cycle after 21 days.According to Dutch telephone poll (Contraception, 1999; Find that 59:357-362) most of women prefer using oral contraceptive and hemorrhage frequency being reduced to be less than and once or fully eliminating January by prolonging.In addition, most of women (80.5%) prefer that the menstrual phase misery is less, amount big during (heavy period) short or amount reduce and even ideal complete menolipsis.
Loudon and his colleague have delivered large-scale research (British Medical Journal, 1977 of first term about fixed prolongation oral contraceptive regimen (90 days=84 days active pills, 6 days subsequently not administration hormones (placebo pill)) in 1977; 2:487-490).In this research, used single-phase (monophasic) OC (50 μ g ethinylestradiol (EE)/2.5mg lynestrenol).Break-through bleeding reduced with the quarter-yearly cycle, and no longer included break-through bleeding after using 9 months.Intermenstrual bleeding account for from the research, drop by the wayside 11%.
After 17 years, Kovacs etc. have delivered perspective study (The British Journalof Family Planning, 1994 of using 30 μ g EE+150 μ gLNG (Nordette ) to take all placebo then about continuous 84 days; 19:274-275).In the women of 203 these researchs of participation, only 59 (29.1%) has finished 12 months treatment (4 * 84+7 days).The common cause that causes ending is to have 73 patients (50.7%) that break-through bleeding takes place and breast tenderness and headache take place respectively 31 patients (21.5%).In first prolongation cycle (13 week) to withdraw from rate the highest, the participation women who accounts for 34.5% (n=70) withdraws from, and the rate that withdraws from second to the 4th prolongation cycle (26,39+52 week) reaches 21.8% (43), 12.3% (25) and 3.0% (6) respectively.Author's statement, although reduce the approval that the ability of menstruation incidence rate obtains many women, it owing to the high rate of break-through bleeding is negated to a certain extent.
Hodgen discloses a kind of fixed solution of oral contraceptive use, and it also should keep curative effect (US 5,898,032) when providing endometrial bleeding control reinforcement.Except that the hemorrhage less and patient's anemia of menstruation, the higher rate of complying with (compliance rate) and the facility of patient's life style is listed in the advantage of this method.As described in its claim, continuously 60-110 day uninterrupted administration estrogen and the single-phase combination of progestogen, 3-10 days not administration then (during fixing, predetermined).Measure the estrogen that these are claimed and the every day of progestogen the norethindrone acetate (NETA) that is equivalent to 5-35 μ g EE and 0.025-10mg.Other progestogen such as levonorgestrel (LNG) or desogestrel have wherein also been put down in writing.
Hesch (United States Patent (USP) 6,500,814) discloses a kind of prolongation cycle product/regimen of low dose fixed, and this inventor claims that it can unexpectedly be guaranteed the height reliability of practising contraception and prevent intermenstrual bleeding.In addition, also put down in writing the minimizing of OC related side effects (as thrombosis) and to the advantageous effect of syndrome before menstrual period (PMS).And the product of this invention may can be used for prevention and treatment breast carcinoma.The claimed associating hormonal contraceptive of Hesch is more than the continuously and not interruption of the administration in 110 days period.Various natural or synthetic estrogen have wherein been put down in writing.Dosage claimed when using EE is between 1-20 μ g/ days.
Kulmann (WO 02/22110) discloses the method for another kind of hormonal contraceptive, and it has reduced the number of times of withdrawal bleeding when guaranteeing reliable contraception.The cycle (=" medicining cycle " (takingperiods)) that in succession (successive) that the method is characterized in that a series of persistent period increases prolongs.Therefore, for example the patient can be the medicining cycle of n * 42/7 from the medicining cycle of 21 tablets of active tablets succeeded by 7 tablets of placebo (21/7) subsequently.Except that last medicining cycle, all cycles formerly all are predetermined (fixed).As described in this invention, it also can one after the other reduce hormone dosage (listed various progestogen and/or estrogen) between medicining cycle.
(Am J Obstet Gynecol, 2002 such as Sulak; 186:1142-1149) studied the acceptance that many patients that have hormone to withdraw symptom (withdrawal symptoms) used the prolongation cycle retrospective.The mainspring of the OC scheme that consider to prolong is: reduce headache symptom (35%), dysmenorrhea (21%), menorrhagia (19%) and through preceding symptom (13%).Allow the patient by prolonging specific all numbers as 6,9 or 12 weeks or extend to and produce break-through bleeding or petechial hemorrhage (spotting), stopped 3-7 days and restart, change their standard 21+7 scheme.If they finish 12 all active pills, and wish to continue, can allow them to do like this without the interruption of no hormone.The natural law that can prolong the patient without limits.All the patient is a user of formerly taking the single-phase pill of one of 30-35 μ g ethinylestradiol and following progestogen: norethindrone, levonorgestrel, norgestimate or desogestrel.Begin to prolong among the patient of cycle regimen at 267,57 (21%) is because of all reasons are nauseating as comprising, the side effect of headache, acne, cramp in the leg, hypertension, yeast infection (yeast infections), break-through bleeding and PMS worsens (24 patients) and wishes that conceived (13 patients) selects inactive OC.Continue to use among the patient of OC at 210,38 (18%) selects 21/7 scheme of the standard of getting back to, and modal reason is break-through bleeding (11 patients), breakthrough petechial hemorrhage (9) and serious withdrawal bleeding (2 patients).The typical way of the applied prolongation of patient OC is that 12 ± 12 weeks, (active pills of meansigma methods ± SD), median was that 9 weeks and scope were for 104 weeks to the maximum.The typical interval of being reported of not taking medicine is 6 ± 2 days, and median is that 5 days and scope are 0-7 days.
(Contraception, 2003 such as Anderson; 68:89-96) delivered result recently about the III phase multiple center trial in 1 year by a definite date of fixing prolongation OC normal relatively 28 day cycle of scheme (21 days active pills+7 day placebo pills) of 91 day cycle natural law.Test finds that the prolongation cycle regimen of Hodgen (US 5,898,032) can effectively prevent pregnancy and relative 28 days scheme (each 30 μ g EE/150 μ g LNG) to have safe characteristic (profile).Yet, 18.3 days of relative 28 day regimen, the patient who prolongs cycle regimen has reported a large amount of irregular (breakthrough) hemorrhage adding up 37.6 days.With respect to 50.8 days of normal period, this research during 1 year (364 days) irregularly+regularly (=menstrual bleeding) hemorrhage total natural law is 48.2 days.According to reports, the break-through bleeding (BTB) that prolongs the cycle reduces with each subsequent cycles (each 84+7), the median from the median during the cycle 1 12 days to the cycle 44 days.
The common cause that given research is ended is hemorrhage, weight increase, anxious state of mind and acne (=adverse events).1.8% of relative 28 day regimen groups, owing to unacceptable hemorrhage end account for 91 day regimen patients' 7.7%.The rate that always withdraws from reaches 40.6% and 28.8% respectively.
In the U.S., the product that in this research, is tried in JIUYUE, 2003 (Seasonale , Barr Laboratories) put goods on the market.This Product labelling (label) is gone up statement, accepts 28 days treatment cycle with them and compares, and originally the patient of 91 days treatment cycle will expect during their warp and have more hemorrhage or petechial hemorrhage.Last its absorption of pointing out Seasonale  should not stop because of hemorrhage.
Reported extra result at Clinical Review of NDA 21-544 (on JIUYUE 4th, 2003) about Seasonale  Ultra-Lo (μ g EE/100 μ g LNG every days 20).Fixing (84+7 days) prolongation scheme of observing with low EE dosage causes worse hemorrhage control.Therefore, 7.7% of relative Seasonale , Seasonale  Ultra-Lo is because the rate that withdraws from that bleeding problems causes is increased to 13.8% (table 23).By contrast, it is reported the corresponding standard cycle that the withdraw from rate of (21+7 days) product Levlite  in same research only is 0.9%.
In the most frequent relating in the hemorrhage adverse events of being in the news, the most normal discovery is menorrhagia.Its value is respectively: Seasonale  11.6%, 2.6% (table 24) of 14.9% and the Levlite  of Seasonale  Ultra-Lo.It should be noted the MedDRA term menorrhagia that is used for the research comprise many with as that be interrupted, vaginal hemorrhage related adverse events such as unexpected, breakthrough.
Between Loestrin 30 (30 μ g EE/1.5mg NETA) and Loestrin 20 (20 μ g EE/1.0mgNETA), compare and to obtain similar observed result.Loestrin 30 is widely used provides the oral contraceptive of outstanding periodic Control.Well-known Loestrin 30 is suitable for administration in prolonging application scheme.Loestrin 20 provides the periodic Control of extreme difference, and (Szarewski 1991, Szarewski﹠amp; Guillebaud 1994,1998,2000,2002, Wilkinson﹠amp; Szarewski2003), therefore be not proposed to be used in fixed prolongation use (Opposition proceedings againstEP 0 911 029 B1, Declaration of Anne Szarewski, par.9-11).
(United States Patent (USP) RE 37 such as Spona, 564E) a kind of oral contraception combination product of instruction, it comprises 23 or 24 dosage units that all contain estrogen (20 μ g EE) and progestogen (2.5 to 3.0mg drospirenones or 1 to 2mg cyproterone acetate) and 5 or 4 blank or placebo to finish cycle of 28 days.This product causes the remarkable inhibition to ovary, makes the sophisticated frequency of follicular development reduce.
Hodgen (United States Patent (USP) 5,552,394) has put down in writing a kind of method of female contraception, and this method has solved the problem that increases than the bleeding problems during the early stage some months of low dosage (estrogen+progestin) (28 day regimen) OC normal period using.Therefore, as by break-through bleeding (untimely menstrual onset (flow) or petechial hemorrhage) increase reflected, total the case of the hemorrhage control problem of OC increases with the minimizing of dosage.Stop administration 2-5 days after the Consecutive Days by single-phase administering drug combinations estrogen and progestogen 23-25, can unexpectedly observe the break-through bleeding incidence rate at first 28 days all after dates and reduce.Amount every day of estrogen described in the claim and progestogen is equivalent to about 1-35 μ g EE and about 0.025-10mg NETA respectively, wherein calculates than NETA with EE, and the weight ratio of estrogen and progestogen is 1: 45 at least.When using other estrogen or progestogen, should adjust use amount based on relative effectivenes.Therefore, the NETA of 3.5mg roughly is equivalent to the LNG of 1mg or the gestodene of desogestrel or 0.7mg.
According to the prior art (seeing above) that prolongs the cycle regimen field, even can think low dosage (estrogen) hormonal contraceptive, also cycle (intermenstrual bleeding promptly not occurring) that can even in the period of administration first, obtain and keep the fixedly stable prolongation of persistent period.Yet the clinical data of being delivered is not supported this opinion.Antithesis, in extensive contrast clinical research, observe, compare with the prolongation cycle regimen of using higher EE dosage (〉=30 μ g), cause higher hemorrhage complication and in clinical practice, cause the higher rate that withdraws from thus with the fixing estrogen compositions (＜30 μ g EE) that prolongs cycle regimen administration low dosage.It should be noted that most and find that the fixing hemorrhage complication that prolongs cycle regimen is much higher than the corresponding standard cycle (21+7 days) scheme usually.
Henzl and Polan reach a conclusion in the summary of the nearest one piece of prior composition used about the OC that prolongs and method, think and be devoted to seek the alternative route of administration of oral route or use the hormonal medicaments different to improve the shortcoming of present timetable (schedule), particularly break-through bleeding and petechial hemorrhage (Journal ofReproductive Medicine 2004 with those existing products; 49:162-174).
Therefore, clearly need to reduce or to eliminate the OC scheme of the prolongation of the problem of viewed disagreeable intermenstrual bleeding (break-through bleeding and/or petechial hemorrhage) in the scheme of fixed prolongation.This scheme can meet great majority and prefer hemorrhage frequency being reduced to be less than January once or the women's who eliminates fully requirement by prolong using oral contraceptive.Also further need the scheme of this prolongation should be preferably low dosage (particularly estrogen) scheme.
Has special importance aspect low dose of in above-mentioned continuous dosing regimens, its objective is for remedy with normal period (21+7 days) scheme compare the extra hormone of administration because the no hormone phase reduces, thereby minimize (every year) the total dosage of hormone (total hormone exposure).
By allowing to shorten the pill time that cuts out, the scheme of this prolongation should further minimize intermenstruum and/or menstrual bleeding, and reduce the disease that during no hormone interval, takes place extraly, for example comprise the symptom relevant (promptly relevant disease) of headache, dysmenorrhea and pelvic pain (pelvic pain), menorrhagia and acne with menstruation with PMS (syndrome before menstrual period).
In addition, this prolongation OC scheme should provide the motility (flexibility) about its persistent period to make this scheme (being the time and the frequency of menstruation) adapt to their a specific biology/medical science and a human needs to allow the patient.
In addition, this OC scheme that prolongs flexibly should allow relative existing standard cycle product (as 21+7 or 24+4 days) further to reduce the dosage of estrogen and/or progestogen.
At last, should to provide to the patient be not the direct extra treatment benefit (as the positive impact to endometriosis, PMS, PMDD, polycystic ovarian syndrome (PCOS)) relevant with hemorrhage disease to this contraceptive regimens.Therefore this scheme also is applicable to treatment endometriosis, PMS, PMDD or polycystic ovarian syndrome (PCOS).
Summary of the invention
Can prove, can unexpectedly avoid the fixing intermenstrual bleeding problem that prolongs during using hormonal contraceptive in the women by a kind of new contraceptive device (estrogenic/progestogenic combination or scheme), this method comprises the minulet that comprises estrogen and progestogen at least in the first short period to described women's administration, observe unacceptable hemorrhagely up to described women, this women promptly begins to cut out voluntarily the longest 6 days time of pill (=control over bleeding) then.
The present invention relates to the estrogen method of contraception, this method be included in first short period of described women's Len req or observe up to described women unacceptable when hemorrhage till, to the ethinylestradiol of described women's successive administration 5 to＜30 μ g amount or be equivalent to other estrogen of amount of 5 to＜30 μ g ethinylestradiols and the monophasic preparation of the progestogen of contraception amount, described then women promptly begins to cut out active ingredient, " cutting out pill " as mentioned below 1 to 6 day, and wherein saidly have at least a persistent period to be at least the most short-period first further administration cycle after cutting out pill.(the following explanation of being made of term " pill " just for convenience.The present invention includes the administering mode of mentioning in other places like this (being route of administration+types of drug preparations)).
Control over bleeding step (managed bleeding approach) is meant in case be characterized as in the cycle regimen that prolongs and just begin to cut out pill (=no hormone phase or cut out active ingredient) when the women caused the unacceptable hemorrhage generation of trouble.The petechial hemorrhage that can't dissipate naturally (not needing the healthy prevention) is the most normal see unacceptable hemorrhage.Perhaps/in addition, break-through bleeding (needing the healthy prevention) may take place.Under this bothersome hemorrhage situation, the women can after intermenstrual bleeding 1 to 10 Consecutive Days, after preferred 2 to 8 days and more preferably begin to cut out pill after 3 to 5 days.
Cut out pill and foreshorten to 1 to 6 day and cause intermenstruum and/or menstrual bleeding and the disease relevant with menstruation, for example headache, PMS, PMDD, dysmenorrhea, menorrhagia and endometriosis further reduce.Preferably cutting out the pill time (promptly not pills or placebo (inactive) pill) is 3 or 4 days.
In a preferred specific embodiments, described owing to the unacceptable hemorrhage pill that cuts out only begins behind break-through bleeding.Under preferred situation, the time that cuts out pill is fixed to single natural law.
The shortest described activity was taken in the phase between 7 to 59 days.
The preferred active absorption phase is 14 to 35 days, more preferably 21 to 28 days and most preferably be 21 to 24 days.
After cutting out pill (no hormone phase), before next withdrawal the patient must begin once more during minimum at least absorption, preferably at least 14-35 days, more preferably 21 to 28 days and most preferably use active pills in 21 to 24 days.
In the preferred case, because endometrial stabilisation, compare with the cycle formerly, these subsequent cycle can be extended for longer during (non-predetermined persistent period).Yet, occur accepting under the hemorrhage situation or for other consideration, the women can select not prolong subsequent cycle but keep described minimum absorption interval (as 14-35 days) in the circulation of plurality of continuous in the minimum absorption phase.
Do not take place if there is bleeding problems, this cycle can be as the desired prolongation of women, the Cycle Length that this representative is the longest.In the preferred case, cutting out pill only requires to induce menstruation for example to carry out when guaranteeing not have pregnancy the women.Usually, the Cycle Length that the women should be just suitable is to her doctor/caring professional consulting, and they will instruct it accordingly based on the state/needs of individual patient and in the scope of Product labelling separately.
The longest prolongation Cycle Length can reach in 2 years that begin the control over bleeding scheme certainly usually.In the preferred case, after the longest Cycle Length has reached 6 to 12 months.Owing to be subjected to law/regulations requirement, to decide according to existing long-term safety data (before clinical and/or clinical), maximum cycle length may be subject to fixed maximum (as 77-91,112-126 days, 175-189 days or 336-364 days).
As Seasonale , this scheme of the present invention will make at clinical setting (clinicalsettings) down owing to the rate that withdraws from of bleeding problems significantly reduces relatively.Therefore, such scheme also will obtain high compliance and high acceptance in the patient who uses this contraceptive device.
Preferred estrogen be every day amount be 5 to＜30 μ g, more preferably 10 to 25 μ g reach the most preferably ethinylestradiol of 20 μ g (EE).
Estradiol and ester thereof also can be used as estrogen.Every day of the estradiol of institute's administration, amount was 0.5 to 3mg, preferred 1 to 2mg.
In addition, synthetic estrogen can be to be equivalent to the dose application of 5 to＜30 μ g EE (promptly with regard to the inhibition of promoting sexual gland hormone and ovulation and to equivalence with regard to the proliferative effect of endometrium and vagina epithelium).
All known progestogen of hormonal contraceptive that are applicable to all can be used as progestogen of the present invention.
Advantageous applications drospirenone, dienogest, levonorgestrel, gestodene, desogestrel, 3-keto-desogestrel, norethindrone acetate, norgestimate, norelstromin (norelgestromin), trimegestone, cyproterone acetate or etonogestrel (etonogestrel).
Wherein, more preferably drospirenone and dienogest are used for the scheme of prolongation of the present invention, drospirenone to menstrual period before symptom, PMDD, dysmenorrhea and acne have significant effect, and the periodic Control effect that dienogest can be played very well, and acne, dysmenorrhea and endometriosis also had significant effect.
The dosage of administration every day progestogen is the known amounts that can effectively practise contraception.Amount every day of the progestogen of mentioning especially is: drospirenone 1.0 to 4.0mg, preferred 2.5 is to 3.5mg, dienogest 0.5 is to arriving 2.5mg to 3.0mg, preferred 1.0, levonorgestrel 0.050 to 0.15mg, the gestodene 0.04 to 0.1mg, desogestrel 0.075 to 0.15mg, 3-keto-desogestrel (etonogestrel) 0.075 to 0.15mg, norethindrone acetate 0.5 to 1mg, norgestimate 0.1 to 0.25mg, norelstromin 0.075 to 0.15mg, trimegestone 0.1 to 0.5mg or cyproterone acetate 1 to 2mg.
In a kind of method of the present invention, product to be administered will be prepared and administration traditionally, promptly comprise standard route of administration, and other dosage forms that are applicable to hormonal contraceptive also can be used for implementing the present invention as various known drug preparations (delivery system) type of transdermal patch, IUS and pessary.
The preferred oral route of administration.
The product that uses in the inventive method is supported the control over bleeding method and can be guaranteed that the packaged form of compliance provides with a kind of.In the preferred case, electronic installation is used for this packaging scheme and takes in pill to remind the women.Packing of this product comprises that how the instruction patient uses special patient's description of this product according to the method described in the claim.
Advantage
According to the present invention, with respect to fixed prolongation cycle regimen and/or normal period (as 21+7 or 24+4) product, the advantage of control over bleeding method comprises:
● even may administration first in the period of realize improving hemorrhage rate (=hemorrhage total natural law reduces) comprehensively, and/or
● reduce intermenstrual bleeding (break-through bleeding and/or petechial hemorrhage), and/or
● improve compliance/reduction termination rate, and/or
● the scheme motility relevant improvement with needs user, and/or
● the disease that minimizing is relevant with cycle and/or menstruation, as PMS, PMDD, headache (migraine), dysmenorrhea and pelvic pain, menorrhagia, endometriosis, PCOS and acne, and/or
● reduce side effect (as feel sick, headache, acne, hypertension, anxious state of mind, weight increase, hemorrhage) and/or
● improve the quality of living.
Embodiment
Following examples reply the present invention does further detailed description, but not with these specific embodiment restrictions the present invention.
Embodiment 1
Can carry out following clinical trial protocol to detect the hemorrhage characteristic that control over bleeding method of the present invention obtains.This test project plan is used to prove that relative fixed prolongs cycle regimen, has the good hemorrhage character of the prolongation cycle OC scheme of low EE dosage.Because actual cause (promptly studying the persistent period), the maximum cycle length in the testing program is standardized to the fixed value between 112-140 days, this value will be fixed up before the research beginning (as 120 days).
With comprise ethinylestradiol that 20 μ g are the Benexate Hydrochloride form and 3mg drospirenone to the young women of child-bearing age of 18-35 year launch the multicenter, opening in 1 year by a definite date, at random, parallel control (parallel-group) comparative study.Employing is used for the selected and exclusion standard of standard of OC research.
In this testing program, with fixed prolongation cycle regimen with flexibly (control over bleeding) scheme compare, described scheme flexibly allows to occur for three days on end after the lowest activity pill is taken in 24 days to cut out pill 4 days under the situation of break-through bleeding or petechial hemorrhage.After cutting out pill, the beginning minimum length in time is 24 days, the maximum length in time cycle as 120 days new prolongation.In addition, also comprise as a comparison OC normal period (24+4).
Estimate hemorrhage type (Bleeding pattern) and periodic Control parameter by electronics or paper diary.Estimate the number (Pearl Index, Life table analysis) of unplanned pregnancy.
Also studied the standard security parameter of OC.
Consider that based on the biostatistics experimenter's number is defined as each research at least 150 patient of branch (studyarm).
Embodiment 2
Possible label according to the product of embodiment 2 test:
Before the no pill of taking 4 days interrupts, must take in " product " at least 24 days every day and may take in product maximum 120 days every day.Take between the end of term (the 120th day) at the 25th day and predetermined tablet (/ whenever) occur can cutting out pill 4 days under the unacceptable hemorrhage situation.In 4 days no pill, have no progeny, begin the new cycle, and take to take in " product " at least 24 days and the longest 120 days once more before 4 days the no pill interruption in next time.
Embodiment 3
Following clinical trial protocol is used to prove the good hemorrhage character of the prolongation cycle OC scheme of low EE and LNG dosage with respect to corresponding normal cycle OC.Because actual cause (promptly studying the persistent period), the maximum cycle length in the testing program is standardized to the fixed value between 77 and 126 days, this value will be fixed up before the research beginning (as 84 days).
With the OC that comprises 20 μ g ethinylestradiols and 100 μ g levonorgestrels to the young women of child-bearing age in 18-40 year launch the multicenter, opening in 1 year by a definite date, at random, the parallel control comparative study.Employing is used for the selected and exclusion standard of standard of OC research.
In this testing program, (control over bleeding) scheme flexibly of the present invention and corresponding standard cycle regimen (21+7 is as Alesse ) are compared.The scheme of this control over bleeding allows to cut out pill 3-4 days the situation of break-through bleeding or petechial hemorrhage appearred in 1-10 days in minimum absorption active pills continuously after 21 days under.After cutting out pill, the beginning minimum length in time is 21 days, the maximum length in time cycle as 84 days new prolongation at every turn.
Estimate hemorrhage type and periodic Control parameter by electronics or paper diary.Estimate the number (Pearl Index, Life table analysis) of unplanned pregnancy.
Also studied the standard security parameter of OC.
Consider that based on the biostatistics experimenter's number is defined as each research at least 150 patient of branch.
Comparative example
If need, disagreeable break-through bleeding or petechial hemorrhage with control over bleeding (that is, when taking place) in the active pills interval of the standard OC that cuts out pill (non-activity pill) of shortening of being consulted whether to prolong have minimum absorption 21 days and 3-4 days by the Ob/Gyn doctor of OC user with them.Use has 35 μ g or EE still less and various progestogen (norethindrone, levonorgestrel, desogestrel, norgestimate+drospirenone).
About 95% the patient through consulting selects to change their standard 21+7 days cycle regimen owing to following a variety of causes: symptom before menstrual period (45%), dysmenorrhea/pelycalgia (40%), serious withdrawal bleeding (36%), the headache (35%) relevant with menstruation, facility (13%), acne (10%) and other (15%) relevant with menstruation.
About 70% begins to adopt the patient's persistent period that prolongs the OC scheme above 2 years.In the middle of them, about 50% adopts the prolongation scheme of the active pills of taking 13 weeks or longer time, and 88% employing is lower than 4 days the pill that cuts out.
In contrast to this, 25% patient stops using OC because of following one or more reasons at last: side effect (23%), wish to become pregnant (23%), medical condition (12%), uterectomy (12%) and other (30%).Modal side effect is break-through bleeding or petechial hemorrhage (=60% or former prolongation patient sum 3.5%) in this group.
In the patient of the OC scheme that begins to prolong, only 6 percent return standard 21+7 scheme mainly due to side effect (60%).In this group modal side effect be break-through bleeding or petechial hemorrhage (35% or prolong the cycle patient's sum 1.2%).
In the prolongation cycle regimen of attempting the hemorrhage method of application controls, amount to only 4.7% hemorrhage end of patient because of disliking.

Claims (71)

1, a kind of estrogen method of contraception, its be included in the ethinylestradiol of single-phase in first short period of described women's Len req, successive administration 5 to＜30 μ g amount or be equivalent to 5 to＜30 μ g ethinylestradiol amounts to described women other synthesize or the active ingredient of the progestogen of natural estrogen and contraception amount, described then women began the described active ingredient of interruption of the administration 1 to 6 day, and had no progeny in wherein said and have at least a persistent period to be at least the most short-period first further administration cycle.
2, the method for claim 1, the cycle of wherein said women's Len req is unacceptable hemorrhage up to described women takes place.
3, method as claimed in claim 1 or 2, wherein the preparation of administration is monophasic in the described further administration cycle, and the amount of ethinylestradiol or other are synthetic or identical in the amount of natural estrogen and progestogen and described first short period.
4, method as claimed in claim 1 or 2, wherein said estrogen is ethinylestradiol.
5, method as claimed in claim 1 or 2, wherein said estrogen is estradiol.
6, method as claimed in claim 1 or 2, wherein said progestogen are drospirenone, dienogest, levonorgestrel, gestodene, desogestrel, 3-keto-desogestrel, norethindrone acetate, norgestimate, norelstromin, trimegestone or cyproterone acetate.
7, method as claimed in claim 6, wherein said progestogen are drospirenone or dienogest.
8, method as claimed in claim 6, wherein said progestogen are levonorgestrels.
9, method as claimed in claim 4, wherein the every day of ethinylestradiol, amount was 10 to 25 μ g.
10, method as claimed in claim 9, wherein the every day of ethinylestradiol, amount was 20 μ g.
11, method as claimed in claim 7, wherein the every day of drospirenone amount between 1.0 and 4.0mg between.
12, method as claimed in claim 11, wherein the every day of drospirenone amount between 2.5 and 3.5mg between.
13, method as claimed in claim 12, wherein the every day of drospirenone, amount was 3mg.
14, method as claimed in claim 7, wherein the every day of dienogest amount between 0.5 and 3.0mg between.
15, method as claimed in claim 14, wherein the every day of dienogest amount between 1.0 and 2.5mg between.
16, method as claimed in claim 15, wherein the every day of dienogest, amount was 2mg.
17, method as claimed in claim 8, wherein the every day of levonorgestrel, amount was 100 μ g.
18, method as claimed in claim 17, wherein the every day of ethinylestradiol, amount was 20 μ g.
19, method as claimed in claim 1 or 2, the wherein said first short period is 7 to 59 days.
20, method as claimed in claim 19, the wherein said first short period is 14 to 35 days.
21, method as claimed in claim 20, the wherein said first short period is 21 to 28 days.
22, method as claimed in claim 21, the wherein said first short period is 21 to 24 days.
23, method as claimed in claim 1 or 2, it is 4 or 3 days that wherein said active ingredient interrupts.
24, method as claimed in claim 1 or 2 is wherein at active ingredient intercourse administration placebo.
25, method as claimed in claim 1 or 2 is wherein at not administration of active ingredient intercourse placebo.
26, method as claimed in claim 1 or 2, at least one in wherein said at least one further administration cycle is 77 to 91 days.
27, method as claimed in claim 26, one of wherein said further administration cycle is 77 to 91 days.
28, method as claimed in claim 27, the further administration cycle after the interruption after the wherein said first short period is 84 days.
29, method as claimed in claim 1 or 2, at least one in wherein said at least one further administration cycle is 112 to 126 days.
30, method as claimed in claim 29, one of wherein said further administration cycle is from 112 to 126 days.
31, method as claimed in claim 30, the further administration cycle after the interruption after the wherein said first short period is 120 days.
32, method as claimed in claim 1 or 2, at least one in wherein said at least one further administration cycle is 175 to 189 days.
33, method as claimed in claim 32, one of wherein said at least one further administration cycle is 175 to 189 days.
34, method as claimed in claim 33, the further administration cycle after the interruption after the wherein said first short period is 182 days.
35, method as claimed in claim 1 or 2, at least one in wherein said at least one further administration cycle is 336 to 364 days.
36, method as claimed in claim 35, one of wherein said further administration cycle is 336 to 364 days.
37, method as claimed in claim 36, the further administration cycle after the interruption after the wherein said first short period is 360 days.
38, method as claimed in claim 1 or 2, wherein said monophasic preparation is with oral dosage unit form administration every day.
39, method as claimed in claim 1 or 2, wherein said unacceptable hemorrhage through being observed the break-through bleeding that needs the healthy prevention.
40, method as claimed in claim 1 or 2, wherein said unacceptable hemorrhage through being observed the petechial hemorrhage that does not need the healthy prevention.
41,, wherein said unacceptable hemorrhage through being observed petechial hemorrhage and the break-through bleeding that needs the healthy prevention as claim 1 and 2 described methods.
42, a kind of method that oral contraception is provided to the women by the drug administration oral administration contraceptive, described oral contraceptive contains estrogen and progestogen, measure wherein estrogenic every day is the ethinylestradiol of 15 to 25 μ g or the estrogen that is equivalent to 15 to 25 μ g ethinylestradiols, and amount was 1 to 4mg drospirenone or was equivalent to 1 progestogen to the 4mg drospirenone every day of progestogen, described method was characterised in that in first 14 to the 35 days by a definite date cycle takes oral contraceptive, in the second period that schedules to last 1-6 days, do not take oral contraceptive, and selecting by described women afterwards, but take described oral contraceptive at least with in same the 3rd the long cycle in described first cycle.
43, method as claimed in claim 42, measure wherein said estrogenic every day is 20 μ g ethinylestradiols.
44, method as claimed in claim 42, amount every day of wherein said progestogen is drospirenones of 3mg.
45, method as claimed in claim 42, the wherein said first cycle is 24 days.
46, method as claimed in claim 42, wherein said second period are 4 days.
47, method as claimed in claim 42, wherein said women is chosen in when break-through bleeding takes place and stops the first cycle.
48, method as claimed in claim 42, wherein said estrogenic every day, amount was 20 μ g ethinylestradiols, and amount every day of progestogen is 3mg drospirenones, and the first cycle is that 24 days and second period are 4 days.
49, method as claimed in claim 42, wherein said estrogenic every day, amount was 20 μ g ethinylestradiols, amount every day of progestogen is 3mg drospirenones, stops the first cycle and second period is 4 days when break-through bleeding takes place.
50, as the application in the syndrome before treating menstrual period of the described method of one of claim 1 to 49.
51, as the application of the described method of one of claim 1 to 49 in treatment PMDD.
52, as the application of the described method of one of claim 1 to 49 in the treatment endometriosis.
53, as the application of the described method of one of claim 1 to 49 in the treatment dysmenorrhea.
54, as the application of the described method of one of claim 1 to 49 in the treatment acne.
55, as the application of the described method of one of claim 1 to 49 in treatment PCOS.
56, a kind of medicated bag, it comprises:
A) ethinylestradiol of 5 to＜30 μ g amount or be equivalent to other estrogen of amount of 5 to＜30 μ g ethinylestradiols and the monophasic preparation of the progestogen of contraception amount,
B) in the described preparation number of individual dose unit through selecting realizing as the described hormonal contraceptive methods of one of claim 11, and
C) illustrate how in described estrogen contraceptive device, use as one of claim 1-49 as described in patient's description of monophasic preparation.
57, medicated bag as claimed in claim 56, wherein said estrogen is ethinylestradiol.
58, medicated bag as claimed in claim 56, wherein said estrogen is estradiol.
59, medicated bag as claimed in claim 56, wherein said progestogen are drospirenone, dienogest, levonorgestrel, gestodene, desogestrel, 3-keto-desogestrel, norethindrone acetate, norgestimate, norelstromin, trimegestone or cyproterone acetate.
60, medicated bag as claimed in claim 59, wherein said progestogen are drospirenone or dienogest.
61, medicated bag as claimed in claim 59, wherein said progestogen are levonorgestrels.
62, medicated bag as claimed in claim 47, wherein the every day of ethinylestradiol, amount was 10 to 25 μ g.
63, medicated bag as claimed in claim 62, wherein the every day of ethinylestradiol, amount was 20 μ g.
64, medicated bag as claimed in claim 60, wherein the every day of drospirenone amount between 1.0 and 4.0mg between.
65, as the described medicated bag of claim 64, wherein the every day of drospirenone amount between 2.5 and 3.5mg between.
66, as the described medicated bag of claim 65, wherein the every day of drospirenone, amount was 3mg.
67, medicated bag as claimed in claim 60, wherein the every day of dienogest amount between 0.5 and 3.0mg between.
68, as the described medicated bag of claim 67, wherein the every day of dienogest amount between 1.0 and 2.5mg between.
69, as the described medicated bag of claim 68, wherein the every day of dienogest, amount was 2mg.
70, medicated bag as claimed in claim 61, wherein the every day of levonorgestrel, amount was 100 μ g.
71, as the described medicated bag of claim 70, wherein the every day of ethinylestradiol, amount was 20 μ g.
CNA200580013899XA 2004-04-30 2005-04-29 Management of breakthrough bleeding in extended hormonal contraceptive regimens Pending CN1950092A (en)

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Publication number Priority date Publication date Assignee Title
CN108025014A (en) * 2015-06-23 2018-05-11 莱昂实验室制药股份有限公司 The contraceptive based on Drospirenone for overweight female patient

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US6787531B1 (en) * 1999-08-31 2004-09-07 Schering Ag Pharmaceutical composition for use as a contraceptive

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108025014A (en) * 2015-06-23 2018-05-11 莱昂实验室制药股份有限公司 The contraceptive based on Drospirenone for overweight female patient
CN108025014B (en) * 2015-06-23 2021-10-22 莱昂实验室制药股份有限公司 Drospirenone-based contraceptive for overweight female patients

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