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Classifications

• • 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
  • A61K31/565—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

Definitions

• This invention relates to a method of hormonal treatment for menopausal (including perimenopausal and post-menopausal) disorders in women, and particularly to a treatment involving the continuous administration of a progestogen in conjunction with an estrogen.
• the invention further relates to a pharmaceutical composition comprising selected dosage units of progestogen and estrogen.
• the invention is concerned with a regimen comprising the continuous administration of progestogen in conjunction with the cyclical administration of estrogen and to a multi-preparation pack containing selected dosage units of progestogen and estrogen and particularly adapted to such regimen.
• Perimenopausal i.e. over approximately forty years of age
• menopausal and post-menopausal women frequently experience a large variety of conditions and disorders which have been attributed to estrogen deprivation due to ovarian failure.
• the duration of these disorders can be extremely variable, and include hot flushes which can be devastating in some women and very mild in others. Dryness of the vagina associated with susceptibility to minor infections, and frequently associated with discomfort during intercourse, is another symptom which may be directly related to the decrease is estrogen availability.
• 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 dl-norgestrel (or laevo-norgestrel), a favourable effect upon blood lipids is also 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 . .along.!. .Iadd.alone .Iaddend.or estrogen plus a progestogen.
• Estrogen . .along.!. .Iadd.alone.Iaddend. 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 . .along.!. .Iadd.alone.Iaddend. 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 . .along.!. .Iadd.alone.Iaddend.
• 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 Gynaecology, 17, 397-412, 1961).
• Still another routine for estrogen administration would involve a formulation such as those found in birth control pills which contain relatively small doses of estrogen over the full 20-21 day treatment cycle, plus very substantial doses of potent progestogens over the same period of time.
• This routine not only produces withdrawal bleeding on each cycle, but is further unacceptable because such formulations have been shown to carry an increased risk of developing arterial complications such as stroke or myocardial infaraction in older women about the age of 35-40. This is especially true if the individual is a smoker of cigarettes (Plunkett, Am. J. Obs/Gyn. 142, 6, 747-751, 1982).
• Therapeutic regimens employing a progestogen along require relatively large doses in order to control hot flushes. Moreover, use of a progestogen alone does not prevent atrophy of the vaginal mucosa, although it may help to prevent osteoporosis. However, a progestogen administered in large doses, together with large amounts of a synthetic estrogen, induces changes in blood lipids which may promote arteriosclerotic changes and have been implicated in the appearance of strokes and myocardial infarction among women taking oral contraceptives in their later reproductive years, (Plunkett, supra).
• the present invention provides a novel therapeutic method and composition involving the use of low dosage levels of estrogens and progestogens, which method is designed to avoid or minimize bleeding and prevent overstimulation of the lining of the uterus while producing favourable changes in blood lipids.
• the method involves continuous and uninterrupted administration of very small doses of a progestogen along with administration of an estrogen, the latter being cyclical, where required (for example, with perimenopausal women).
• the method specifically provides for treatment of menopausal or post-menopausal disorders in a women comprising either:
• perimenopausal refers to women of approximately forty years of age and older, who have not yet definitely arrived at menopause but who are experiencing symptoms associated with menopause.
• continuous as applied in the specification and the claims to "administration” means that the frequency of administration is at least once daily. Thus, administration, e.g. every other day or once every third day, is not “continuous” for purposes of this invention. Note, however, that the frequency of administration may be greater than once daily and still be “continuous”, e.g. twice or even three times daily so long as the dosage level as specified herein is not exceeded.
• the term "dosage level" means the total amount of estrogen or progestogen administered per day.
• the "continuous administration" of a progestogen to a women at a “dosage level" of 75 micrograms means that the women receives a total of 75 micrograms of progestogen on a daily basis, whether the progestogen is administered as a single 75 microgram dose or, e.g. three separate 25 microgram doses.
• the most conventional means of continuously administering an estrogen or progestogen is as a single daily oral dose at the prescribed dosage level. Parenteral modes of administration, which provide a slow release of the progestogen, could be substituted for the oral route.
• the invention realizes the objects of providing a therapeutic method allowing for the administration of an estrogen, controlling hot flushes, restoring the vaginal mucosa to a healthier state, preventing the development of the dimineralization of bones as well as preventing changes in lipids which predispose to cardiovascular disease, over long periods of treatment, which method does not, however, initiate bleeding or increase the risk of endometrial carcinoma.
• the invention provides a pharmaceutical composition for hormonal treatment of menopausal or post-menopausal disorders in a woman, which comprises a dosage unit of a progestogen and a dosage unit of an estrogen for continuous administration wherein the units comprise a progestogen in the range of 0.025 to 30 mg and an estrogen in the range of 0.005 to 2.5 mg together with a pharmaceutically acceptable inert carrier.
• the actual unit dosages are selected according to conventionally known methods, e.g. body weight of patient and biological activity of the hormones, with the ultimate goal of producing the desired result with the minimum quantities of hormones.
• the interruption of the estrogen administration is required in perimenopausal women to maintain normal periods and may be required in certain jurisdictions due to health concerns--particularly overstimulation of the lining of the uterus to cause a pre-malignant condition.
• the absence of estrogen for a short period allows the lining of the uterus to be sloughed and any pre-malignancy thus avoided.
• the inventors believe that even with continuous administration of estrogen, the presence of progestogen will give rise to sufficient atrification of the uterus that no such condition would be likely to occur.
• a further and important object of the invention is to provide the means whereby a woman may receive the proper quantities and dosage units of the progestogen and estrogen for adherence to the prescribed regimen wherein the dosage of estrogen is cyclically administered.
• Such means takes the form of a multi-preparation pack, which facilitates administration by a nurse or physical in appropriate circumstances or, more usually, self-administration by the woman.
• the multi-preparation pack contains sufficient dosage units of progestogen and estrogen for continuous administration of both said progestogen and said estrogen for a period of from about 20 to 120 days plus an additional number of dosage units of progestogen for administration for an additional period of time of from about 3 to about 7 days during which administration of said estrogen is terminated.
• the estrogen used in the present disclosure may be those which are orally active and are suitable for oral contraception and selected from natural estrogens such as estradiol, estradiol-17 ⁇ , estradiol valerate, conjugated equine estrogens, piperazine estrone sulphate, estrone, estriol, estriol succinate and polyestriol phosphate, or from synthetic estrogens such as ethinyl estradiol, quinestranol and mestranol.
• natural estrogens such as estradiol, estradiol-17 ⁇ , estradiol valerate, conjugated equine estrogens, piperazine estrone sulphate, estrone, estriol, estriol succinate and polyestriol phosphate
• synthetic estrogens such as ethinyl estradiol, quinestranol and mestranol.
• the natural estrogens are preferred.
• the progestogen is again selected from those which are orally active and suitable for oral contraceptives and may be, . .foro.!. .Iadd.for .Iaddend.example, dl-norgestrel, laevo-norgestrel, norethindrone (norethisterone), norethindrone acetate, ethynodiol diacetate, medroxyprogesterone acetate, cyproterone acetate or norethynodrel.
• Tables 1A and 1B are listed preferred unit dosages, minimum unit dosages and maximum unit dosages for the estrogens and progestogens useful in this invention.
• the quantities are determined by the biological activities of the particular substances as obtained commercially from sources that normally supply them in micronized form.
• estriol preparations marked with an asterisk have lower preference than estradiols or estrones because they fail to spare bone in post-menopausal women.
• estradiols or estrones could be combined with natural or synthetic estrogens for the purpose of the invention.
• chlormadinone acetate and megestrol are useful in the context of this invention, it has been speculated that these progestogens may pre-dispose breast tumors, although no clinical proof exists to that effect. However, unless and until such suspicions are proven to be without foundation, these compounds are clearly of lower preference.
• the estrogen/progestogen combinations may be administered non-orally by implants or intramuscular injections.
• the required dosages are based upon somewhat lower daily dosage levels that those required for the orally administered estrogens and progestogens, for the simple reason that the former are directly released into the bloodstream with consequently greater activity than the same compounds when orally ingested.
• Estradiol, estradiol valerate and estradiol 17- ⁇ are suitable candidates for estrogen implants, in maximum and minimum amounts of 100 mg and 20 mg, with 100 mg preferred. These quantities will be suitable for slow-release implants intended for replacement every 3 to 12 months.
• Suitable progestogen implants and intramuscular injections are set forth in Table 1C.
• dl-Norgestrel laevo norgestrel (the common name for d-13 ⁇ -ethyl-17 ⁇ -ethinyl-17 ⁇ -hydroxygon-4-en-3-one), norethindrone (common name for 17-hydroxy-19-nor-17 ⁇ -pregn-4-en-20-yn-3-one), ethynodiol diacetate (common name for 19-nor-17 ⁇ -pregn-4-en-20-yne-3 ⁇ , 17-diol diacetate), norethindrone acetate, and cyproterone acetate may also be administered by injection. It will be readily appreciated by those skilled in the art thay any other synthetic progestogen which is orally active or effective for use in conjunction with contraception is also suitable for use in this invention.
• any of the suitable estrogens and progestogens may be combined with one another in the quantities recited to give estrogen/progestogen combinations within the purview of the invention.
• Especially preferred combinations are those containing the estradiols or conjugated equine estrogens and the norgestrels norethindrones, or medroxyprogesterones.
• especially preferred combinations are:
• the comparison of the invention is usually administered orally in admixture with a pharmaceutically acceptable inert carrier.
• the estrogen and progestogen can be compounded in any pharmaceutically acceptable inert (non-toxic) form.
• the packaging can be any system convenient for proper delivery.
• the pharmaceutical carrier can be of any of the conventionally employed carriers, for example pharmaceutically grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum cellulose, glucose, sucrose, magnesium carbonate, and similar substances.
• the compositions may be formulated into solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations, etc.
• One of the unique aspects of this invention is the adaptation of the multi-preparation pact to the continuous uninterrupted administration of a progestogen and an estrogen is administered in a cyclic fashion.
• the duration of the estrogen cycle can be very variable, with continuous administration ranging between 20 and 120 days followed by a break (i.e. interruption) in estrogen administration ranging anywhere from about 3 to about 7 days. However, if the estrogen is discontinued for a period longer than 5 days, recurrence of hot flushes is most likely to occur, in a number of patients.
• the multi-pack dispensing system may be accommodated by conventional packaging equipment, e.g. transparent strip foil packages continuously arranged in daily dosages or other conventional means in the art.
• the pack would conveniently comprise a transparent strip foil package with the combined unit daily dosages arranged continuously with, for example, up to a total of 120 such dosages, the 3 to 7 unit dosages of progestogen being located at the end of the combined daily unit dosages whereby they would be taken at the end of the series.
• Treatment comprised administering each hormone and the combination as follows: (1) estrogen alone for two months; (2) progestogen alone for two months; (3) combination therapy using (1) and (2) for six months. Each period of administering a hormone of the combination was followed by a one month period of placebo (substance with no endocrine activity) administration.
• the estrogen was micronized 17 ⁇ -estradiol administered at a daily dosage level of 1 milligram, while the progestogen was dl-norgestrel administered at a dosage level of 75 micrograms.
• the combination therapy has been associated with no evidence whatsoever of endometrial hyperplasia (over-stimulation of the lining of the uterus).
• laevo-norgestral may be used as an alternative to dl-norgtestrol. Since the dl-norgestrol consists of equal parts of the dextro (inactive) and laevo (active) forms, only half the quantity of laevo-norgestrol is used with the same effect. Thus, if laevo-norgestrol is substituted for dl-norgestrol in the foregoing examples, the laevo-norgestrol dosage level is 37.5 micrograms.
• estrogen replacement therapy to prevent the early appearance of bone demineralization (osteorosis), elevation of cholesterol and triglycerides and to control sever hot flushes and vaginal atrophy. If patients such as these are treated with estrogen alone, they frequently develop recurrence of pain symptoms due to residual endometriosis being restimulated by the administered estrogen.
• the inventors' combination therapy tends to promote atrophy of the lining of the uterus (endometrium) no matter whether it is located normally within the uterus or in the endometriotic tissue in the pelvis, it is found that these patients tolerate the treatment very well and do not have a recurrence or reactive of their endometriosis. Furthermore, even small doses of estrogen in combination with the continuous progestogen routine is sufficient to control the severe hot flushes which such patients experience.
• this invention permits control of menopausal disorders including hot flushes and vaginal atrophy along with many of the subjective symptoms. Further, given that both components of the combination therapy are considered to be effective in retarding osteoporosis, long term therapy to prevent this disabling disease should be effective.
• the risk of developing endometrial (uterine) cancer from the combination therapy should, at a minimum, be reduced to the normal incidence of the general population as opposed to the increased risk which has in fact been demonstrated to occur using estrogen-only treatment.
• the inventors have in fact developed some evidence suggestive that the combination therapy reduces the risk of premalignant endometrial changes, which may reduce the risk of developing endometrial cancer.
• the reduction in bleeding or spotting in patients taking the combination therapy makes it much more desirable relative to known treatments, particularly to older women.
• the tablet set herein is used to control menopausal symptoms. It is not a birth control pill and cannot be relied upon to prevent pregnancy.
• Oral contraceptives should not be taken at the same time as these tablets and, if necessary, you should therefore ask your doctor about alternative means of mechanical protection.
• the foregoing instructions may be printed as a leaflet, and the package instruction modified as follows:
• FIGS. 1 and 2 of the drawings A multi-preparation pack suitable for administration of tablets in accordance with the regimen described above is illustrated in FIGS. 1 and 2 of the drawings.
• a bubble pack 10 (which may be folded along the line 10a) is sold in a protective sleeve 11, upon the rear of which are printed the directions for use and salient facts concerning the tablets, as indicated at 12 in the drawing.
• the bubble pack When removed from the protective sleeve by the consumer, the bubble pack contains as many tablets as the number of days which the pack is intended to cover (in this example, one hundred and twenty days).
• the individual bubble segments may be numbered from one to one hundred and twenty but it is important that the last few segments, which contains the progestogen-only tablets, be clearly distinguished from the remainder of these segments.
• the segments 13 containing the first one hundred and thirteen tablets are a light colour (for example, white) whilst the last seven segments 14, containing the progestogen-only tablets are a dark colour (red, for example).
• the consumer will take the combination tablets for the first one hundred and thirteen days and the progestogen tablets for the last seven days. Thereafter, a new package would be opened, whereby the cycle is repeated.

Abstract

Description

              TABLE 1A
______________________________________
ESTROGENS
                     Dosage    (mg/day)
             Preferred
                     Minimum   Maximum
______________________________________
Natural estrogens (steroids)
Estradiol      1         0.500     2
Estradiol-17β
               1         0.500     2
Estradiol valerate
               1         0.500     2
Conjugated equine estrogens
               0.600     0.300     2.5
Estrene        0.600     0.300     2.5
Piperazine estrone sulphate
               0.500     0.250     2.5
(estropipate)
Estriol*       0.100     0.050     0.500
Estriol succinate*
               0.100     0.050     0.500
Polyestriol phosphate*
               0.100     0.050     0.500
Synthetic estrogens (steroids)
Ethinyl estradiol
               0.010     0.005     0.020
Mestranol      0.015     0.005     0.040
. .Quinestranol.!. .Iadd.Quinestrol.Iaddend.
               0.010     0.005     0.030
______________________________________

______________________________________
Stilboestrol    0.100      0.020  2
Stilboestrol dipropionate
                0.100      0.020  2
Diethylstilboestrol
                1          0.400  2.5
Chlorotrianiscos
                2          1      2.5
Benzoestrol     2          0.5    2.5
Dienoestrol     0.500      0.200  2.5
Hexoestrol      0.500      0.200  2.5
Methallenoestril
                1          0.500  2.5
______________________________________

              TABLE 1B
______________________________________
PROGESTOGENS
                      Dosage   (mg/day)
              Preferred
                      Minimum  Maximum
______________________________________
Laevo-norgestrel
                0.050     0.025    0.075
dl-norgestrel   0.100     0.050    0.150
Norethindrone (norethisterone)
                0.30      0.15     1.0
Norethindrone (norethisterone)
                0.20      0.10     1.0
acetate
Dydrogesterone  10        5        30
Medroxyprogesterone acetate
                2.5       1        15.
Norethynodrel   1         0.200    5
Allylestrenol   2         1        30
Lynoestrenol    0.200     0.100    2
Quingestanol acetate
                0.200     0.050    1
Medrogestone    2         1        10
Norgestrienone  0.050     0.020    0.200
Dimethisterone  1         0.500    15
Ethisterone     2.5       1        25
Cyproterone acetate
                0.500     0.100    10
Chlormadinone acetate
                0.300     0.100    1
Megestrol acetate
                1         0.100    10
______________________________________

              TABLE 1C
______________________________________
                      Total Quantity (mg)
                        Pre-   Min-   Max-
               Period   ferred imum   imum
______________________________________
Progestogen implants
Loevonorgestrel   every 2-5 yr.
                            50     25   100
dl-norgestrel    every 2-5 yr.
                            100    50   200
Norgestrienone   every 1-2 yr.
                            100    25   200
Norethindrone acetate
                  every 2-4 mon.
                            100    25   200
Intramuscular progestogen depots
Medroxyprogesterone acetate
                  every 3 mon.
                            150    50   500
Norethindrone enanthate
                  every 3 mon.
                            50     20   400
Gestrocol hexanoate
                  every 3 mon.
                            100    50   400
Algestone acetophenide
                 monthly    50     20   300
Hydroxyprogesterone hexanoate
                 weekly     100    50   250
Hydroxyprogesterone caproate
                 bi-weekly  100    50   250
______________________________________

Claims (14)

______________________________________
                 Dosage   (mg/day)
                 Minimum  Maximum
______________________________________
Laeve-norgestrel   about 0.025
                              about 0.075
dl-norgestrel      about 0.050
                              about 0.150
Norethindrone (norethisterone)
                   about 0.15 about 1.0
Norethindrone (norethisterone)
                   about 0.10 about 1.0
acetate
Ethynodiol diacetate
                   about 0.10 about 1.0
Dydrogesterone     about 5    about 30
Medroxyprogesterone acetate
                   about 1    abou 15
Norethynodrel      about 0.203
                              about 5
Allylestrenol      about 1    about 10
Lynoestrenol       about 0.300
                              about 2
Quingestanol acetate
                   about 0.050
                              about 1
Medrogestone       about 1    about 10
Norgestrienone     about 0.020
                              about 0.200
Dimethisterone     about 0.500
                              about 15
Ethisterone        about 1    about 25
Cyproterone acetate
                   about 0.300
                              about 10.Iadd...Iaddend.
______________________________________

______________________________________
                Dosage   (mg/day)
                Minimum  Maximum
______________________________________
Estradiol         about 0.500
                             about 2
Estradiol-17β
                  about 0.500
                             about 2
Estradiol valerate
                  about 0.500
                             about 2
Conjugated equine estrogens
                  about 0.300
                             about 2.5
Estrone           about 0.300
                             about 2.5
Piperazine estrone sulphate
                  about 0.250
                             about 2.5
(estropipate)
Ethinyl estrodiol about 0.005
                             about 0.020
Mestranol         about 0.005
                             about 0.030
. .Quinestranol.!. .Iadd.Quinestrol.Iaddend.
                  about 0.005
                             about 0.020.Iadd...Iaddend.
______________________________________

______________________________________
                     Dosage (mg/day)
______________________________________
Estradiol              about 1
Estradiol-17β     about 1
Estradiol valerate     about 1
Conjugated equine estrogens
                       about 0.600
Estrone                about 0.600
Piperazine estrone sulphate (estropipate)
                       about 0.500
Ethinyl estradiol      about 0.010
Mestranol              about 0.015
. .Quinestranol.!. .Iadd.Quinestrol.Iaddend.
                       about 0.010.Iadd...Iaddend.
______________________________________

______________________________________
                     Dosage (mg/day)
______________________________________
Laevo-norgestrel       about 0.050
dl-norgestrel          about 0.100
Norethindrone (norethisterone)
                       about 0.30
Norethindrone (norethisterone)
                       abour 0.30
Ethynodiol diacetate   about 0.30
Dydrogestrone          about 10
Medroxyprogesterone acetate
                       about 2.5
Norethynodrel          about 1
Allylestrenol          about 2
Lynoestrenol           about 0.200
Quingestanol acetate   about 0.200
Medrogestone           about 2
Norgestrienone         about 0.050
Dimethisterone         about 1
Ethisterone            about 2.5.Iadd...Iaddend.
______________________________________

______________________________________
              .Iadd.Dosage(mg/day)
                         Dosage (mg/day)
              Minimum    Maximum
______________________________________
Laevo-norgestrel
                about 0.025  about 0.075
dl-norgestrel   about 0.050  about 0.150
Ethynodiol diacetate
                about 0.10   about 1.0
Dydrogesterone  about 5      about 30
Medroxyprogesterone acetate
                about 1      about 15
Norethynodrel   about 0.200  about 5
Allylestrenol   about 1      about 10
Lynoestrenol    about 0.100  about 2
Quingestanol acetate
                about 0.050  about 1
Medrogestone    about 1      about 10
Norgestrienone  about 0.020  about 0.200
Dimethisterone  about 0.500  about 15
Ethisterone     about 1      about 25
Cyproterone acetate
                about 0.100  about 10..Iaddend.
______________________________________

______________________________________
              .Iadd.Dosage(mg/day)
                         Dosage (mg/day)
              Minimum    Maximum
______________________________________
Laevo-norgestrel
                about 0.025  about 0.050
dl-norgestrel   about 0.050  about 0.100
Ethynodiol diacetate
                about 0.10   about 0.30
Dydrogesterone  about 5      about 10
Medroxyprogesterone acetate
                about 1      about 2.5
Norethynodrel   about 0.200  about 1
Allylestrenol   about 1      about 2
Lynoestrenol    about 0.100  about 0.200
Quingestanol acetate
                about 0.050  about 0.200
Medrogestone    about 1      about 2
Norgestrienone  about 0.020  about 0.050
Dimethisterone  about 0.500  about 1
Ethisterone     about 1      about 2.5
Cyproterone acetate
                about 0.100  about 0.500..Iaddend.
______________________________________

______________________________________
              .Iadd.Dosage(mg/day)
                         Dosage (mg/day)
              Minimum    Maximum
______________________________________
Estradiol       about 0.500  about 2
Estradiol-17β
                about 0.500  about 2
Estradiol valerate
                about 0.500  about 2
Conjugated equine estrogens
                about 0.300  about 2.5
Estrone         about 0.300  about 2.5
Piperazine estrone sulphate
                about 0.250  about 2.5
(estropipate)
Ethinyl estrodiol
                about 0.005  about 0.020
Mestranol       about 0.005  about 0.040
Quinestrol      about 0.005  about 0.030..Iaddend.
______________________________________

______________________________________
              .Iadd.Dosage(mg/day)
                         Dosage (mg/day)
              Minimum    Maximum
______________________________________
Estradiol       about 0.500  about 1
Estradiol-17β
                about 0.500  about 1
Estradiol valerate
                about 0.500  about 1
Conjugated equine estrogens
                about 0.300  about 0.600
Estrone         about 0.300  about 0.600
Piperazine estrone sulphate
                about 0.250  about 0.500
(estropipate)
Ethinyl estrodiol
                about 0.005  about 0.010
Mestranol       about 0.005  about 0.015
Quinestrol      about 0.005  about 0.010..Iaddend.tz,1/32

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Citations (8)

• 1984
  • 1984-07-27 US US06/635,236 patent/US4826831A/en not_active Ceased
  • 1984-07-31 CA CA000460073A patent/CA1240927A/en not_active Expired
  • 1984-07-31 IL IL72556A patent/IL72556A/en not_active IP Right Cessation
  • 1984-07-31 NZ NZ209066A patent/NZ209066A/en unknown
  • 1984-08-02 DE DE10199010C patent/DE10199010I2/en active Active
  • 1984-08-02 EP EP84305260A patent/EP0136011B2/en not_active Expired - Lifetime
  • 1984-08-02 DE DE10199001C patent/DE10199001I2/en active Active
  • 1984-08-02 DE DE3486442T patent/DE3486442T3/en not_active Expired - Lifetime
  • 1984-08-02 DE DE1997175086 patent/DE19775086I2/en active Active
  • 1984-08-02 DE DE10075037C patent/DE10075037I2/en active Active
  • 1984-08-02 AT AT84305260T patent/ATE147987T1/en active
  • 1984-08-03 DK DK198403770A patent/DK165390C/en active Protection Beyond IP Right Term
  • 1984-08-03 PH PH31063A patent/PH24052A/en unknown
• 1992
  • 1992-06-29 MX MX9203720A patent/MX9203720A/en active IP Right Grant
• 1995
  • 1995-10-13 US US08/542,941 patent/USRE36247E/en not_active Expired - Lifetime
• 1997
  • 1997-07-21 LU LU90107C patent/LU90107I2/en unknown
  • 1997-07-22 NL NL970026C patent/NL970026I1/en unknown
  • 1997-10-22 NL NL970037C patent/NL970037I2/en unknown
• 1998
  • 1998-11-20 NL NL980038C patent/NL980038I2/en unknown
• 1999
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