Note: Descriptions are shown in the official language in which they were submitted.
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
TITLE
CONTRACEPTIVE REGIMEN INCLUDING REDUCED LEVEL OF ESTROGEN
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S. Provisional
Application No.
63/241,178, filed September 7, 2021 and U.S. Application No. 17/483,199, filed
September
23, 2021, which itself claims the benefit of U.S. Provisional Application No.
63/241,178.
The entirety of each of these prior applications is here incorporated by
reference herein.
FIELD OF THE INVENTION
[0002] This invention is related to regimens that include a progestogenic and
estrogenic
components that can be used for contraception and provide not only
significantly less
estrogen daily, but also significantly less overall estrogen in the regimen
without
compromising contraceptive efficacy, cycle control, or other desired benefits.
Moreover,
the invention provides for regimens that are effective for contraception while
reducing the
risk for osteoporosis. In addition, the regimens provided herein can be used
for the
treatment of one or more symptoms associated with endometriosis or fibroids.
Also
provided is a kit that may be used to practice the aforementioned inventive
regimens.
BACKGROUND OF THE INVENTION
[0003] Contraceptive compositions typically contain both estrogenic and
progestogenic
compounds and are known to be highly effective in controlling ovulation. The
progestogenic component of the composition is primarily responsible for the
contraceptive
efficacy of the composition, and the estrogenic component is employed to
reduce undesired
side effects, such as breakthrough bleeding, spotting, or bone loss.
[0004] Earlier forms of estrogenic/progestogenic contraceptive compositions
(monophasic
or multiphasic) contained a relatively high level of estrogenic component.
Over time
estrogenic/progestogenic contraceptive compositions have been disclosed where
the amount
of estrogen of such compositions has been lowered without reducing
contraceptive efficacy
and/or increasing undesired side effects. U.S. Patent No. 5,888,543, discloses
progestogen/estrogen combinations in a monophasic regimen (fixed dose in the
cycle) or as
biphasic or triphasic regimens (varied dose over the cycle).
1
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
[0005] U.S. Patent No. 4,962,098 discloses a triphasic method of contraception
using a
progestogen/estrogen combination in which the amount of estrogen is increased
stepwise
over the three phases. For all three phases the progestogen is 0.5 to 1.5 mg
of norethindrone
acetate, while about 10 to 30 mcg of ethinyl estradiol is used in the first
phase, about 20 to
40 mcg of ethinyl estradiol is used in the second phase and 30 to 50 mcg of
ethinyl estradiol
is employed in the third phase. Other multiphasic contraceptive compositions
have been
described in U.S. Patent Nos. 8,461,138 and 8,124,595.
[0006] Alternatively, another form of contraception, known as "mini-pills"
only contains
progestogen component in the absence of the estrogenic component. While this
may not
have certain drawbacks associated with estrogen exposure, it is known to
induce bone loss
and have less contraceptive efficacy than that of a combined
estrogenic/progestogenic
contraceptive composition.
SUMMARY OF THE INVENTION
[0007] The invention provides both cyclic and continuous methods of
contraception that
make it possible to significantly reduce not only the daily amount of estrogen
administered,
but also the overall amount of estrogen administered, while still achieving
desired
contraceptive efficacy and controlling undesired side effects. In addition,
the regimens
disclosed herein can be used for the treatment of one or more symptoms
associated with
endometriosis or fibroids.
[0008] This invention is related to a method of contraception for a female in
need thereof
In an embodiment, the method is a cyclic monophasic method and comprises the
step of:
administering, daily, about 1 mcg to less than about 5 mcg of an estrogen and
0.075 mg to
about 5 mg of a progestogen for about 20 to about 27 consecutive days of a 28-
day cycle.
The method comprises the step of administering, daily, a placebo for a
remainder of the 28-
day cycle.
[0009] In an embodiment, the method is a cyclic multiphasic method and
comprises the
steps of: administering, daily, about 1 mcg to less than about 5 mcg of an
estrogen and
0.075 mg to about 5 mg of a progestogen for about 20 to about 26 consecutive
days of a 28-
day cycle; and administering, daily, about 1 mcg to less than about 5 mcg of
the estrogen in
the absence of the progestogen for about 1 to about 6 consecutive days, of the
28-day cycle
following the preceding step. The method comprises the step of administering,
daily, a
placebo for a remainder of the 28-day cycle.
2
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
[0010] In an embodiment, the method is a cyclic monophasic method and
comprises the
step of: administering, daily, about 1 mcg to less than about 5 mcg of an
estrogen and 0.075
mg to about 5 mg of a progestogen for at least about 28 consecutive days up to
about 84
consecutive days of a cycle. The method comprises the step of administering,
daily, a
placebo for about 1 to 7 consecutive days of the cycle.
[0011] In an embodiment, the method is monophasic continuous method and
comprises the
step of administering, daily about 1 mcg to less than about 5 mcg of an
estrogen and 0.075
mg to about 5 mg of a progestogen.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The regimens disclosed herein can be used for contraception, which, in
addition to
providing desired contraceptive efficacy, can control undesired side effects
associated with
conventional contraceptive regimens. The regimens disclosed herein can also
provide
effective treatment or prevention of symptoms related to endometriosis or
fibroids, such as
pain and heavy bleeding. As a result, there is no need for a separate
treatment of these
symptoms, such as conventionally prescribed GnRH antagonists or agonists.
[0013] Conventional contraceptive regimens utilize relatively high amounts of
estrogen.
While these amounts are less than what they were even a few decades ago, they
are still
sufficiently high to have the potential to cause various adverse effects. From
among the
currently available combined estrogenic/progestogenic contraceptive regimens,
Lo
Loestrin0 has the lowest level of estrogen at 10 mcg of ethinyl estradiol per
day. However,
even this amount of estrogen can contribute to endometrial tissue stimulation
and may lead
to adverse effects including inflammation, severe pain, heavy or light
periods, aggravated
premenstrual syndrome, weight gain, noncancerous lumps in breasts, fibroids,
fatigue, low
sex drive, depression, or anxiety. Especially for females with endometriosis,
which is a
chronic disorder characterized by the implantation of endometrial glands and
stroma outside
the uterine cavity, these symptoms can be more severe and debilitating.
[0014] While there are different hypotheses regarding the pathogenesis of
endometriosis,
one conventional way to treat the symptoms of endometriosis is by
administering either
GnRH agonists or GnRH antagonists. For example, GnRH antagonists, such as
elagolix,
are typically prescribed for the management of moderate to severe pain
associated with
endometriosis in pre-menopausal females. However, these GnRH antagonists
reduce
endogenous sex hormones, such as estrogens, to post-menopausal levels. This
can lead to a
reduction in bone density, the occurrence of post-menopausal vasomotor
systems, such as
3
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
hot flashes or night sweats, and other urogenital symptoms. As a result,
combinations of an
estrogen and progestogen are often prescribed concomitantly with GnRH
antagonists to
treat the side effects of pharmacologically induced menopause, and since GnRH
antagonists
are not prescribed for contraception.
[0015] An alternative available contraceptive regimen is, for example, a so-
called "mini-
pill," which only includes a progestogenic component in order to avoid some of
the
drawbacks associated with estrogen exposure. For example, a mini-pill may be
prescribed
to females who are breast-feeding. Moreover, as females begin to get closer to
pen-
menopause or menopause, doctors may prescribe the mini-pill rather than a
conventional
contraceptive regimen, since conventional contraceptive regimens are not
recommended to
be prescribed with conditions such as high blood pressure, cardiovascular
issue, as well as
issues with mobility. However, the absence of estrogen altogether has its own
drawbacks
because an estrogenic component in a contraceptive can be helpful for
decreasing the
effects of bone loss, increasing stability to the endometrium, preventing
irregular shedding
and unwanted breakthrough bleeding as well as increasing the potency of the
progestogenic
component including in its antifertility effects.
[0016] In contrast, the present invention provides estrogenic/progestogenic
regimens that
use a significantly lower amount of estrogenic component than conventional
contraceptive
regimens, yet provide more benefits than the "mini-pill." Advantageously, as a
result of the
reduction in the overall level of estrogenic compound exposure over the
complete cycle, the
endometrial tissue stimulation can be reduced or minimized. Thus, the regimens
disclosed
herein can be used not only for contraception, but also to treat the symptoms
associated with
endometriosis and/or fibroids without the need for administering a
conventional treatment,
such as a GnRH antagonist or agonist. In addition, the overall significantly
reduced level of
estrogenic compound exposure only minimally contributes to bone loss and,
surprisingly,
may have little to no effect on suppression of lactation. Furthermore,
described herein are
regimens that allow for safe, effective and long-term use without a placebo,
which can
eliminate the withdrawal bleed, and allows for a female to remain on the same
regimen,
without needing to switch to, for example, a mini-pill, when closer in age to
peri-
menopause or menopause. The regimens disclosed herein are also safe and
effective for
females who may have cardiovascular issues and/or high blood pressure.
[0017] The designation "mcg" refers to micrograms and "mg" to milligrams.
[0018] The term "administration" refers to oral administration. That is, the
methods/regimens disclosed herein pertain to oral administrations.
4
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
[0019] The term "female in need thereof' refers to a female of child-bearing
age, and may
be experiencing one or more symptoms associated with endometriosis or
fibroids. For
example, the female in need thereof is a female who has started menstruation
and/or is
sexually active but is not yet in menopause. Thus, the female in need thereof
is pre-
menopausal or peri-menopausal, but not in menopause, such that the age range
may be
about 14 years old to about 55 years old, depending on the individual.
[0020] The term "continuous" refers to the uninterrupted time period of
hormone
administration in which there are no hormonal component-free intervals (i.e.,
placebo
periods). Thus, a continuous period, which may be up to about 40 years, does
not have a
time interval which induces a withdrawal bleed for the duration of the method.
[0021] The symptoms associated with endometriosis or fibroids include, for
example, pain,
menstrual symptoms, gastrointestinal symptoms, abdominal symptoms, and
infertility. Pain
associated with endometriosis can include, for example, lower abdominal pain,
lower back
pain, pelvic pain, rectal pain, and vaginal pain. Pain associated with
endometriosis can also
include, for example, pain during sexual intercourse, pain during defecation,
and pain
during urination. Menstrual symptoms associated with endometriosis can
include, for
example, abnormal menstruation, heavy menstruation, irregular menstruation,
prolonged
menstruation, painful menstruation, and spotting. Gastrointestinal symptoms
associated
with endometriosis include, for example, diarrhea, constipation, and nausea.
Abdominal
symptoms associated with endometriosis can include, for example, abdominal
fullness and
cramping. One of ordinary skill in the art would recognize that the amount of
pain the
female in need thereof experiences does not necessarily correlate with the
severity of
endometriosis. For example, on the one hand, the female in need thereof having
a moderate
or severe degree of endometriosis may experience minimal or no pain. On the
other hand,
the female in need thereof having a mild degree of endometriosis may
experience moderate
or severe pain or other aforementioned symptoms associated with endometriosis.
[0022] Endometriosis can be located in various parts of the female in need
thereof,
including, for example, ovaries, fallopian tubes, uterosacral ligaments,
posterior cul-de-sac
(space between the uterus and rectum), anterior cul-de-sac (space between the
uterus and
bladder), outer surface of the uterus, lining of the pelvic cavity,
intestines, rectum, bladder,
vagina, cervix, vulva, and abdominal surgery scars.
[0023] Estrogens which may be used in the present invention include, for
example, ethinyl
estradiol, 170-estradiol, 1713-estradiol-3-acetate, mestranol, conjugated
estrogens, USP and
estrone or salts thereof In an embodiment, the estrogen is ethinyl estradiol.
The amount of
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
estrogen used is described herein as that which is "equivalent" in estrogenic
potency to an
amount of ethinyl estradiol. The equivalent estrogenic potency of an estrogen
to ethinyl
estradiol may be readily determined by one of ordinary skill in the art.
[0024] Progestogens which may be used in the present invention include, for
example,
progesterone and its derivatives such as 17-hydroxy progesterone esters and 19-
nor-17-
hydroxy progesterone esters, 17-alpha-ethinyl testosterone, 17-alpha-ethiny1-
19-
nortestosterone (norethindrone) and derivatives thereof, norethindrone
acetate, norgestrel,
nogestamate, desogestrel and D-17-beta-acetoxy-17-beta-ethy1-17-alpha-ethinyl-
gon-4-en-
3-one oxime. Other exemplary progestogens include demegestone, drospirenone,
dydrogesterone, gestodene, medrogestone, medroxy progesterone and esters
thereof The
amount of progestogen used is described herein as that which is "equivalent"
in
progestogenic potency to an amount of norethindrone acetate. The equivalent
progestogenic
potency of a progestogen to norethindrone acetate may be readily determined by
one of
ordinary skill in the art.
[0025] In the regimens discloses herein, a placebo may be skipped altogether
so that neither
the active ingredients nor a placebo composition (e.g., a sugar tablet) is
administered. That
is, a reference to the administration of a placebo herein also encompasses
skipping
altogether the active ingredients and the placebo composition.
[0026] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for about 20 to about 27 consecutive
days of a 28-
day cycle; and (b) a placebo for the remainder of the 28-day cycle. The
administration
period for this monophasic cyclic contraceptive method is based on a 28-day
cycle. In an
embodiment, a new cycle begins following the completion of the preceding
cycle. For
example, a new 28-day cycle begins following the completion of the preceding
28-day
cycle. In an embodiment, the new cycle and the preceding cycle are identical
in the number
of days
[0027] In an embodiment, the estrogen is administered in a daily amount of
about 1.0 mcg
to less than about 5.0 mcg. In an embodiment, the estrogen is administered in
a daily
amount of about 2.0 mcg to about 4.0 mcg, or about 2.25 mcg to about 3.5 mcg,
or about
2.25 mcg to about 3.0 mcg. In an embodiment, the estrogen is administered in a
daily
amount of about 1 mcg, or about 1.1 mcg, or about 1.2 mcg, or about 1.3 mcg,
or about 1.4
mcg, or about 1.5 mcg, or about 1.6 mcg, or about 1.7 mcg, or about 1.8 mcg,
or about 1.9
6
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
mcg, or about 2.0 mcg, or about 2.1 mcg or about 2.2 mcg, or about 2.3 mcg, or
about 2.4
mcg, or about 2.5 mcg, or about 2.6 mcg, or about 2.7 mcg, or about 2.8 mcg,
or about 2.9
mcg, or about 3.0 mcg, or about 3.1 mcg or about 3.2 mcg, or about 3.3 mcg, or
about 3.4
mcg, or about 3.5 mcg, or about 3.6 mcg, or about 3.7 mcg, or about 3.8 mcg,
or about 3.9
mcg, or about 4.0 mcg or about 4.1 mcg, or about 4.2 mcg, or about 4.3 mcg, or
4.4 mcg, or
about 4.5 mcg, or any amount in between. In an embodiment, the estrogen is
administered
in a daily amount of 2.5 mcg.
[0028] In an embodiment, the progestogen is administered in a daily amount of
about 0.075
mg to about 5.0 mg, or about 0.3 mg to about 5.0 mg. In an embodiment, the
progestogen is
administered in a daily amount of about 0.075 mg to about 4.0 mg, or about
0.075 mg to
about 2.0 mg, or about 0.075 mg to about 1.0 mg, or about 0.075 mg to about
0.15 mg, or
about 0.4 mg to about 4.0 mg, or about 0.4 mg to about 3.0 mg, or about 0.5 mg
to about 2
mg. In an embodiment, the progestogen is administered in a daily amount of
about 0.075
mg, or about 0.1 mg, or about 0.15 mg, or about 0.2 mg, or about 0.25 mg, or
about 0.3 mg,
or about 0.4 mg, or about 0.5 mg, or about 0.6 mg, or about 0.7 mg, or about
0.8 mg, or
about 0.9 mg, or about 1.0 mg, or about 1.1 mg, or about 1.2 mg, or about 1.3
mg, or about
1.4 mg, or about 1.5 mg, or any amount in between. In an embodiment, the
progestogen is
administered in a daily amount of about 1.0 mg.
[0029] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for 27 consecutive days of a 28-day
cycle; and (b)
a placebo for the remaining 1 day of the 28-day cycle. In an embodiment, the
composition
comprises about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
embodiment, the composition comprises about 2.5 mcg of ethinyl estradiol and
about 1 mg
of norethindrone acetate. In an embodiment, the composition comprises about
2.5 mcg of an
estrogen and about 0.075 to about 0.15 mg of a progestogen. In an embodiment,
the
composition comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to
about 0.15
mg of a desogestrel.
[0030] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for 26 consecutive days of a 28-day
cycle; and (b)
a placebo for the remaining 2 days of the 28-day cycle. In an embodiment, the
composition
7
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
comprises about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
embodiment, the composition comprises about 2.5 mcg of ethinyl estradiol and
about 1 mg
of norethindrone acetate. In an embodiment, the composition comprises about
2.5 mcg of an
estrogen and about 0.075 to about 0.15 mg of a progestogen. In an embodiment,
the
composition comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to
about 0.15
mg of a desogestrel.
[0031] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for 25 consecutive days of a 28-day
cycle; and (b)
a placebo for the remaining 3 days of the 28-day cycle. In an embodiment, the
composition
comprises about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
embodiment, the composition comprises 2.5 mcg of ethinyl estradiol and 1 mg of
norethindrone acetate. In an embodiment, the composition comprises about 2.5
mcg of an
estrogen and about 0.075 to about 0.15 mg of a progestogen. In an embodiment,
the
composition comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to
about 0.15
mg of a desogestrel.
[0032] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for 24 consecutive days of a 28-day
cycle; and (b)
a placebo for the remaining 4 days of the 28-day cycle. In an embodiment, the
composition
comprises about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
embodiment, the composition comprises about 2.5 mcg of ethinyl estradiol and
about 1 mg
of norethindrone acetate. In an embodiment, the composition comprises about
2.5 mcg of an
estrogen and about 0.075 to about 0.15 mg of a progestogen. In an embodiment,
the
composition comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to
about 0.15
mg of a desogestrel.
[0033] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for 23 consecutive days of a 28-day
cycle; and (b)
a placebo for the remaining 5 days of the 28-day cycle. In an embodiment, the
composition
comprises about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
8
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
embodiment, the composition comprises 2.5 mcg of ethinyl estradiol and 1 mg of
norethindrone acetate. In an embodiment, the composition comprises about 2.5
mcg of an
estrogen and about 0.075 to about 0.15 mg of a progestogen. In an embodiment,
the
composition comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to
about 0.15
mg of a desogestrel.
[0034] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for 22 consecutive days of a 28-day
cycle; and (b)
a placebo for the remaining 6 days of the 28-day cycle. In an embodiment, the
composition
comprises about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
embodiment, the composition comprises about 2.5 mcg of ethinyl estradiol and
about 1 mg
of norethindrone acetate. In an embodiment, the composition comprises about
2.5 mcg of an
estrogen and about 0.075 to about 0.15 mg of a progestogen. In an embodiment,
the
composition comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to
about 0.15
mg of a desogestrel.
[0035] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for 21 consecutive days of a 28-day
cycle; and (b)
a placebo for the remaining 7 days of the 28-day cycle. In an embodiment, the
composition
comprises about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
embodiment, the composition comprises about 2.5 mcg of ethinyl estradiol and
about 1 mg
of norethindrone acetate. In an embodiment, the composition comprises about
2.5 mcg of an
estrogen and about 0.075 to about 0.15 mg of a progestogen. In an embodiment,
the
composition comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to
about 0.15
mg of a desogestrel.
[0036] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for 20 consecutive days of a 28-day
cycle; and (b)
a placebo for the remaining 8 days of the 28-day cycle. In an embodiment, the
composition
comprises about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
embodiment, the composition comprises about 2.5 mcg of ethinyl estradiol and
about 1 mg
9
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
of norethindrone acetate. In an embodiment, the composition comprises about
2.5 mcg of an
estrogen and about 0.075 to about 0.15 mg of a progestogen. In an embodiment,
the
composition comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to
about 0.15
mg of a desogestrel.
[0037] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for at least 28 consecutive days up to
about 84
consecutive days of a cycle; and (b) a placebo for about 1 to about 7 days
following step (a)
for the remainder of the cycle. The administration period for this cyclic
monophasic
regimen has an administration period of up to 91 days. In an embodiment, a new
cycle
begins following the completion of the preceding cycle. For example, a new 63-
day begins
following the completion of the preceding 63-day cycle. In an embodiment, the
new cycle
and the preceding cycle are identical in the number of days.
[0038] In an embodiment, the estrogen is administered in a daily amount of
about 1.0 mcg
to less than about 5.0 mcg. In an embodiment, the estrogen is administered in
a daily
amount of about 2.0 mcg to about 4.0 mcg, or about 2.25 mcg to about 3.5 mcg,
or about
2.25 mcg to about 3.0 mcg. In an embodiment, the estrogen is administered in a
daily
amount of about 1 mcg, or about 1.1 mcg, or about 1.2 mcg, or about 1.3 mcg,
or about 1.4
mcg, or about 1.5 mcg, or about 1.6 mcg, or about 1.7 mcg, or about 1.8 mcg,
or about 1.9
mcg, or about 2.0 mcg, or about 2.1 mcg or about 2.2 mcg, or about 2.3 mcg, or
about 2.4
mcg, or about 2.5 mcg, or about 2.6 mcg, or about 2.7 mcg, or about 2.8 mcg,
or about 2.9
mcg, or about 3.0 mcg, or about 3.1 mcg or about 3.2 mcg, or about 3.3 mcg, or
about 3.4
mcg, or about 3.5 mcg, or about 3.6 mcg, or about 3.7 mcg, or about 3.8 mcg,
or about 3.9
mcg, or about 4.0 mcg or about 4.1 mcg, or about 4.2 mcg, or about 4.3 mcg, or
4.4 mcg, or
about 4.5 mcg, or any amount in between. In an embodiment, the estrogen is
administered
in a daily amount of 2.5 mcg.
[0039] In an embodiment, the progestogen is administered in a daily amount of
about 0.075
mg to about 5.0 mg, or about 0.3 mg to about 5.0 mg. In an embodiment, the
progestogen is
administered in a daily amount of about 0.075 mg to about 4.0 mg, or about
0.075 mg to
about 2.0 mg, or about 0.075 mg to about 1.0 mg, or about 0.075 mg to about
0.15 mg, or
about 0.4 mg to about 4.0 mg, or about 0.4 mg to about 3.0 mg, or about 0.5 mg
to about 2
mg. In an embodiment, the progestogen is administered in a daily amount of
about 0.075
mg, or about 0.1 mg, or about 0.15 mg, or about 0.2 mg, or about 0.25 mg, or
about 0.3 mg,
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
or about 0.4 mg, or about 0.5 mg, or about 0.6 mg, or about 0.7 mg, or about
0.8 mg, or
about 0.9 mg, or about 1.0 mg, or about 1.1 mg, or about 1.2 mg, or about 1.3
mg, or about
1.4 mg, or about 1.5 mg, or any amount in between. In an embodiment, the
progestogen is
administered in a daily amount of about 1.0 mg.
[0040] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for at least 28 consecutive days, or
about 42 days,
or about 56 days, or about 63 days, up to about 84 consecutive days; and (b) a
placebo for
about 1 to about 7 days following step (a). In an embodiment, the composition
comprises
about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
embodiment, the
composition comprises about 2.5 mcg of ethinyl estradiol and about 1 mg of
norethindrone
acetate. In an embodiment, the composition comprises about 2.5 mcg of an
estrogen and
about 0.075 to about 0.15 mg of a progestogen. In an embodiment, the
composition
comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to about 0.15
mg of a
desogestrel.
[0041] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic multiphasic regimen which includes administering, daily, the following:
(a) phase I
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for any one of about 20 to about 26
consecutive
days of a 28-day cycle; (b) phase II composition comprising about 1 mcg to
less than about
mcg of the estrogen, without a progestogen, for about 1 to about 6 consecutive
days of the
28-day cycle following the administration of the phase I composition, such
that at least one
day remains in this 28-day cycle; and (c) a placebo for the remainder of the
28-day cycle.
[0042] In an embodiment, the phase I composition comprises about 2.5 mcg of an
estrogen
and about 1 mg of a progestogen. In an embodiment, the phase I composition
comprises
about 2.5 mcg of ethinyl estradiol and about 1 mg of norethindrone acetate. In
an
embodiment, the phase I composition comprises about 2.5 mcg of an estrogen and
about
0.075 to about 0.15 mg of a progestogen. In an embodiment, the phase I
composition
comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to about 0.15
mg of a
desogestrel.
[0043] In an embodiment, the phase II composition comprises about 2.5 mcg of
an
estrogen. In an embodiment, the phase II composition comprises about 2.5 mcg
of ethinyl
estradiol. The administration period for this multiphasic cyclic contraceptive
method is
11
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
based on a 28-day cycle. In an embodiment, a new cycle begins following the
completion
of the preceding cycle. For example, a new 28-day cycle begins following the
completion
of the preceding 28-day cycle. In an embodiment, the new cycle and the
preceding cycle
are identical in the number of days.
[0044] In an embodiment, the estrogen in each of phases I and II is
administered in a daily
amount of about 1.0 mcg to less than about 5.0 mcg. In an embodiment, the
estrogen in
each of phases I and II is administered in a daily amount of about 2.0 mcg to
about 4.0 mcg,
or about 2.25 mcg to about 3.5 mcg, or about 2.25 mcg to about 3.0 mcg. In an
embodiment, the estrogen in each of phases I and II is administered in a daily
amount of
about 1 mcg, or about 1.1 mcg, or about 1.2 mcg, or about 1.3 mcg, or about
1.4 mcg, or
about 1.5 mcg, or about 1.6 mcg, or about 1.7 mcg, or about 1.8 mcg, or about
1.9 mcg, or
about 2.0 mcg, or about 2.1 mcg or about 2.2 mcg, or about 2.3 mcg, or about
2.4 mcg, or
about 2.5 mcg, or about 2.6 mcg, or about 2.7 mcg, or about 2.8 mcg, or about
2.9 mcg, or
about 3.0 mcg, or about 3.1 mcg or about 3.2 mcg, or about 3.3 mcg, or about
3.4 mcg, or
about 3.5 mcg, or about 3.6 mcg, or about 3.7 mcg, or about 3.8 mcg, or about
3.9 mcg, or
about 4.0 mcg or about 4.1 mcg, or about 4.2 mcg, or about 4.3 mcg, or 4.4
mcg, or about
4.5 mcg, or any amount in between. In an embodiment, the estrogen in each of
phases I and
II is administered in a daily amount of 2.5 mcg.
[0045] In an embodiment, the progestogen in phase I is administered in a daily
amount of
about 0.075 mg to about 5.0 mg, or about 0.3 mg to about 5.0 mg. In an
embodiment, the
progestogen in phase I is administered in a daily amount of about 0.075 mg to
about 4.0 mg,
or about 0.075 mg to about 2.0 mg, or about 0.075 mg to about 1.0 mg, or about
0.075 mg
to about 0.15 mg, or about 0.4 mg to about 4.0 mg, or about 0.4 mg to about
3.0 mg, or
about 0.5 mg to about 2 mg. In an embodiment, the progestogen in phase I is
administered
in a daily amount of about 0.075 mg, or about 0.1 mg, or about 0.15 mg, or
about 0.2 mg, or
about 0.25 mg, or about 0.3 mg, or about 0.4 mg, or about 0.5 mg, or about 0.6
mg, or about
0.7 mg, or about 0.8 mg, or about 0.9 mg, or about 1.0 mg, or about 1.1 mg, or
about 1.2
mg, or about 1.3 mg, or about 1.4 mg, or about 1.5 mg, or any amount in
between. In an
embodiment, the progestogen in phase I is administered in a daily amount of
about 1.0 mg.
In an embodiment, no progestogen is administered in phase II.
[0046] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic multiphasic regimen which includes administering, daily, the following
compositions: (a) phase I composition for 24 consecutive days of a 28-day
cycle comprising
about 1 mcg to less than about 5 mcg of an estrogen and about 0.075 mg to
about 5 mg of a
12
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
progestogen; (b) phase II composition for 2 consecutive days of the 28-day
cycle following
the administration of the phase I composition, comprising about 1 mcg to less
than about 5
mcg of the estrogen without a progestogen; and (c) a placebo for 2 consecutive
days of the
28-day cycle following the administration of the phase II composition. In an
embodiment,
the phase I composition comprises about 2.5 mcg of an estrogen and about 1 mg
of a
progestogen. In an embodiment, the phase I composition comprises about 2.5 mcg
of
ethinyl estradiol and about 1 mg of norethindrone acetate. In an embodiment,
the phase I
composition comprises about 2.5 mcg of an estrogen and about 0.075 to about
0.15 mg of a
progestogen. In an embodiment, the phase I composition comprises about 2.5 mcg
of an
ethinyl estradiol and about 0.075 to about 0.15 mg of a desogestrel. In an
embodiment, the
phase II composition comprises about 2.5 mcg of an estrogen. In an embodiment,
the phase
II composition comprises about 2.5 mcg of ethinyl estradiol.
[0047] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic multiphasic regimen which includes administering, daily, the following
compositions: (a) phase I composition for 24 consecutive days of a 28-day
cycle comprising
about 1 mcg to less than about 5 mcg of an estrogen and about 0.075 mg to
about 5 mg of a
progestogen; (b) phase II composition for 3 consecutive days of the 28-day
cycle following
the administration of the phase I composition, comprising about 1 mcg to less
than about 5
mcg of the estrogen without a progestogen; and (c) a placebo for 1 day of the
28-day cycle
following the administration of the phase II composition. In an embodiment,
the phase I
composition comprises about 2.5 mcg of an estrogen and about 1 mg of a
progestogen. In
an embodiment, the phase I composition comprises about 2.5 mcg of ethinyl
estradiol and
about 1 mg of norethindrone acetate. In an embodiment, the phase I composition
comprises
about 2.5 mcg of an estrogen and about 0.075 to about 0.15 mg of a
progestogen. In an
embodiment, the phase I composition comprises about 2.5 mcg of an ethinyl
estradiol and
about 0.075 to about 0.15 mg of a desogestrel. In an embodiment, the phase II
composition
comprises about 2.5 mcg of an estrogen. In an embodiment, the phase II
composition
comprises about 2.5 mcg of ethinyl estradiol.
[0048] In an embodiment, the method of contraception for a female in need
thereof is a
cyclic multiphasic regimen which includes administering, daily, the following
compositions: (a) phase I composition for 24 consecutive days of a 28-day
cycle comprising
about 1 mcg to less than about 5 mcg of an estrogen and about 0.075 mg to
about 5 mg of a
progestogen; (b) phase II composition for 1 day of the 28-day cycle following
the
administration of the phase I composition, comprising about 1 mcg to less than
about 5 mcg
13
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
of the estrogen without a progestogen; and (c) a placebo for 3 consecutive
days of the 28-
day cycle following the administration of the phase II composition, comprising
a. In an
embodiment, the phase I composition comprises about 2.5 mcg of an estrogen and
about 1
mg of a progestogen. In an embodiment, the phase I composition comprises about
2.5 mcg
of ethinyl estradiol and about 1 mg of norethindrone acetate. In an
embodiment, the phase I
composition comprises about 2.5 mcg of an estrogen and about 0.075 to about
0.15 mg of a
progestogen. In an embodiment, the phase I composition comprises about 2.5 mcg
of an
ethinyl estradiol and about 0.075 to about 0.15 mg of a desogestrel. In an
embodiment, the
phase II composition comprises about 2.5 mcg of an estrogen. In an embodiment,
the phase
II composition comprises about 2.5 mcg of ethinyl estradiol.
[0049] In an embodiment, the method of contraception for a female in need
thereof, is a
monophasic continuous regimen which includes administering, daily, the
following: (a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen.
[0050] In an embodiment, the estrogen is administered in a daily amount of
about 1.0 mcg
to less than about 5.0 mcg. In an embodiment, the estrogen is administered in
a daily
amount of about 2.0 mcg to about 4.0 mcg, or about 2.25 mcg to about 3.5 mcg,
or about
2.25 mcg to about 3.0 mcg. In an embodiment, the estrogen is administered in a
daily
amount of about 1 mcg, or about 1.1 mcg, or about 1.2 mcg, or about 1.3 mcg,
or about 1.4
mcg, or about 1.5 mcg, or about 1.6 mcg, or about 1.7 mcg, or about 1.8 mcg,
or about 1.9
mcg, or about 2.0 mcg, or about 2.1 mcg or about 2.2 mcg, or about 2.3 mcg, or
about 2.4
mcg, or about 2.5 mcg, or about 2.6 mcg, or about 2.7 mcg, or about 2.8 mcg,
or about 2.9
mcg, or about 3.0 mcg, or about 3.1 mcg or about 3.2 mcg, or about 3.3 mcg, or
about 3.4
mcg, or about 3.5 mcg, or about 3.6 mcg, or about 3.7 mcg, or about 3.8 mcg,
or about 3.9
mcg, or about 4.0 mcg or about 4.1 mcg, or about 4.2 mcg, or about 4.3 mcg, or
4.4 mcg, or
about 4.5 mcg, or any amount in between. In an embodiment, the estrogen is
administered
in a daily amount of 2.5 mcg.
[0051] In an embodiment, the progestogen is administered in a daily amount of
about 0.075
mg to about 5.0 mg, or about 0.3 mg to about 5 mg. In an embodiment, the
progestogen is
administered in a daily amount of about 0.075 mg to about 4.0 mg, or about
0.075 mg to
about 2.0 mg, or about 0.075 mg to about 1.0 mg, or about 0.075 mg to about
0.15 mg, or
about 0.4 mg to about 4.0 mg, or about 0.4 mg to about 3.0 mg, or about 0.5 mg
to about 2
mg. In an embodiment, the progestogen is administered in a daily amount of
about 0.075
mg, or about 0.1 mg, or about 0.15 mg, or about 0.2 mg, or about 0.25 mg, or
about 0.3 mg,
14
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
or about 0.4 mg, or about 0.5 mg, or about 0.6 mg, or about 0.7 mg, or about
0.8 mg, or
about 0.9 mg, or about 1.0 mg, or about 1.1 mg, or about 1.2 mg, or about 1.3
mg, or about
1.4 mg, or about 1.5 mg, or any amount in between. In an embodiment, the
progestogen is
administered in a daily amount of about 1.0 mg.
[0052] In an embodiment, the estrogen and the progestogen can be in a combined
single
dosage form or a separate dosage form. In an embodiment, the dosage form can
be a solid
dosage form, a liquid dosage form, or a semisolid dosage form. In an
embodiment, the
dosage form can include, for example, a pill, an orally disintegrating tablet,
a chewable
tablet, a swallowing tablet, a capsule, a caplet, a drink, a syrup, a gel, or
a strip.
[0053] In an embodiment, the dosage form is a vaginal ring or a patch, such
that the vaginal
ring or patch can be removed during any period where the active ingredient(s)
are not
administered in the methods disclosed herein. For example, in a continuous
regimen, a
patch or ring can be removed after a defined period (e.g., 90 days) and
another ring or patch
can be applied right away so as to provide uninterrupted administration of the
active
ingredient(s).
[0054] In an embodiment, the contraception method includes a kit comprising a
package
containing daily dosages of the estrogen with or without the progestogen, and
the optional
placebo, as described herein.
[0055] In an embodiment, the package may contain daily dosages of: (a) a
composition
comprising about 1 mcg to less than about 5 mcg of an estrogen and 0.075 mg to
about 5
mg of a progestogen for about 20 to about 27 consecutive days of a 28-day
cycle (e.g.,
about 20 to about 27 tablets, each including the aforementioned amounts of the
estrogen and
the progestogen, in, for example, a blister pack); and (b) a placebo (e.g.,
placebo tablet(s) in,
for example, the blister pack, or, alternatively, empty blister(s) in the
blister pack) for the
remainder of the 28-day cycle. In an embodiment, the composition comprises
about 2.5
mcg of an estrogen and about 1 mg of a progestogen. In an embodiment, the
composition
comprises about 2.5 mcg of ethinyl estradiol and about 1 mg of norethindrone
acetate. In an
embodiment, the composition comprises about 2.5 mcg of an estrogen and about
0.075 to
about 0.15 mg of a progestogen. In an embodiment, the composition comprises
about 2.5
mcg of an ethinyl estradiol and about 0.075 to about 0.15 mg of a desogestrel.
[0056] In an embodiment, the kit further comprises instructions for
administering the daily
dosages according to the method of contraception for a female in need thereof,
being a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
0.075 mg to about 5 mg of a progestogen for about 20 to about 27 consecutive
days of a 28-
day cycle; and (b) a placebo for the remainder of the 28-day cycle.
[0057] In an embodiment, the package may contain daily dosages of: (a) a
composition
comprising about 1 mcg to less than about 5 mcg of an estrogen and 0.075 mg to
about 5
mg of a progestogen for about 28 consecutive days up to 84 consecutive days
(e.g., up to 84
tablets, each including the aforementioned amounts of the estrogen and the
progestogen, in,
for example, a blister pack, or multiple blister packs); and (b) a placebo
(e.g., placebo
tablet(s) in, for example, the blister pack, or, alternatively, empty
blister(s) in the blister
pack) for the up to 7 days. In an embodiment, the composition comprises about
2.5 mcg of
an estrogen and about 1 mg of a progestogen. In an embodiment, the composition
comprises about 2.5 mcg of ethinyl estradiol and about 1 mg of norethindrone
acetate. In an
embodiment, the composition comprises about 2.5 mcg of an estrogen and about
0.075 to
about 0.15 mg of a progestogen. In an embodiment, the composition comprises
about 2.5
mcg of an ethinyl estradiol and about 0.075 to about 0.15 mg of a desogestrel.
[0058] In an embodiment, the kit further comprises instructions for
administering the daily
dosages according to the method of contraception for a female in need thereof,
being a
cyclic monophasic regimen which includes administering, daily, the following:
(a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen for at least 28 consecutive days up to
about 84
consecutive days of a cycle; and (b) a placebo for about 1 to about 7 days
following step (a)
for the remainder of the cycle.
[0059] In an embodiment, the package may contain daily dosages of: (a) phase I
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
0.075 mg
to about 5 mg of a progestogen for about 20 to about 26 consecutive days of a
28-day cycle
(e.g., about 20 to about 26 tablets, each including the aforementioned amounts
of the
estrogen and the progestogen, in, for example, a blister pack); (b) phase II
composition
comprising about 1 mcg to less than about 5 mcg of the estrogen, without a
progestogen, for
about 1 to about 6 consecutive days of the 28-day cycle following the
administration of the
phase I composition, such that at least one day remains in this 28-day cycle
(e.g., about 1 to
6 tablets, each including the aforementioned amount of the estrogen and no
progestogen, in,
for example, the blister pack); and (c) a placebo (e.g., placebo tablet(s),
or, alternatively,
empty blister(s) in the blister pack) for the remainder of the 28-day cycle.
In an
embodiment, the phase I composition comprises about 2.5 mcg of an estrogen and
about 1
mg of a progestogen. In an embodiment, the phase I composition comprises about
2.5 mcg
16
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
of ethinyl estradiol and about 1 mg of norethindrone acetate. In an
embodiment, the phase I
composition comprises about 2.5 mcg of an estrogen and about 0.075 to about
0.15 mg of a
progestogen. In an embodiment, the phase I composition comprises about 2.5 mcg
of an
ethinyl estradiol and about 0.075 to about 0.15 mg of a desogestrel. In an
embodiment, the
phase II composition comprises about 2.5 mcg of an estrogen. In an embodiment,
the phase
II composition comprises about 2.5 mcg of ethinyl estradiol.
[0060] In an embodiment, the kit further comprises instructions for
administering the daily
dosages according to the method of contraception for a female in need thereof,
being a
cyclic multiphasic regimen which includes administering, daily, the following
compositions: (a) phase I composition comprising about 1 mcg to less than
about 5 mcg of
an estrogen and about 0.075 mg to about 5 mg of a progestogen for about 20 to
about 26
consecutive days of a 28-day cycle; (b) phase II composition comprising about
1 mcg to
less than about 5 mcg of the estrogen in the absence of the progestogen for
about 1 to about
6 consecutive days of the 28-day cycle following the administration of the
phase I
composition,; and (c) a placebo for the remainder of the 28-day cycle
following the
administration of the phase II composition.
[0061] In an embodiment, the package may contain daily dosages of: (a) a
composition
comprising about 1 mcg to less than about 5 mcg of an estrogen and about 0.075
mg to
about 5 mg of a progestogen for a continuous regimen. In an embodiment, the
composition
comprises about 2.5 mcg of an estrogen and about 1 mg of a progestogen. In an
embodiment, the composition comprises about 2.5 mcg of ethinyl estradiol and
about 1 mg
of norethindrone acetate. In an embodiment, the composition comprises about
2.5 mcg of an
estrogen and about 0.075 to about 0.15 mg of a progestogen. In an embodiment,
the
composition comprises about 2.5 mcg of an ethinyl estradiol and about 0.075 to
about 0.15
mg of a desogestrel.
[0062] In an embodiment, the kit further comprises instructions for
administering the daily
dosages according to the method of contraception for a female in need thereof,
being a
monophasic continuous regimen which includes administering, daily, the
following: (a) a
composition comprising about 1 mcg to less than about 5 mcg of an estrogen and
about
0.075 mg to about 5 mg of a progestogen.
[0063] While the methods/regimens as disclosed herein are practiced by
administration of
the compositions in a numeric sequence with the estrogen/progestin containing
composition(s) being used first, optionally, the estrogen only composition(s)
or the optional
placebo being used thereafter as discussed above, if packaging and/or other
requirements
17
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
dictate, the method and kit described herein can be employed as part of a
larger scheme for
contraception, or treatment of gynecological disorders. Reasonable variations,
such as those
which would occur to one of ordinary skill in the art, can be made herein
without departing
from the scope of the invention. For example, variations in time and dosage
can be
tolerated when medical considerations so dictate.
EXAMPLES
[0064] Specific embodiments will now be demonstrated by reference to the
following
examples. It should be understood that these examples are disclosed solely by
way of
illustrating the invention and should not be taken in any way to limit the
scope of the
present invention.
EXAMPLE 1
[0065] The compositions employed in accordance with the invention will have
the
administration times and drug contents set forth in the following table.
[0066] Table 1
Norethindrone Ethinyl Estradiol
Phase Days acetate (NA) (EE)
(mg/day) (mcg/day)
24 1.0 2.5
4 0 (placebo) 0 (placebo)
[0067] The norethindrone acetate (NA) and ethinyl estradiol (EE) are well
known and
readily available.
EXAMPLE 2
[0068] The compositions employed in accordance with the invention will have
the
administration times and drug contents set forth in the following table.
[0069] Table 2
Norethindrone Ethinyl Estradiol
Phase Days acetate (NA) (EE)
(mg/day) (mcg/day)
21 1.0 2.5
7 0 (placebo) 0 (placebo)
[0070] The norethindrone acetate (NA) and ethinyl estradiol (EE) are well
known and
readily available.
18
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
EXAMPLE 3
[0071] The compositions employed in accordance with the invention will have
the
administration times and drug contents set forth in the following table.
[0072] Table 3
Norethindrone Ethinyl Estradiol
Phase Days acetate (NA) (EE)
(mg/day) (mcg/day)
27 1.0 2.5
1 0 (placebo) 0 (placebo)
[0073] The norethindrone acetate (NA) and ethinyl estradiol (EE) are well
known and
readily available.
EXAMPLE 4
[0074] The compositions employed in accordance with the invention will have
the
administration times and drug contents set forth in the following table.
[0075] Table 4
Norethindrone Ethinyl Estradiol
Phase Days acetate (NA) (EE)
(mg/day) (mcg/day)
24 1.0 2.5
II 2 0 2.5
2 0 (placebo) 0 (placebo)
[0076] The norethindrone acetate (NA) and ethinyl estradiol (EE) are well
known and
readily available. In an embodiment, each of the phase I composition and phase
II
compositions are administered as oral dosage forms. In an embodiment, phase I
composition is administered as a vaginal ring or a patch and the phase II
composition is
administered as an oral dosage form.
EXAMPLE 5
[0077] The compositions employed in accordance with the invention will have
the
administration times and drug contents set forth in the following table.
19
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
[0078] Table 5
Norethindrone Ethinyl Estradiol
Phase Days acetate (NA) (EE)
(mg/day) (mcg/day)
24 1.0 2.5
JJ 3 0 2.5
1 0 (placebo) 0 (placebo)
[0079] The norethindrone acetate (NA) and ethinyl estradiol (EE) are well
known and
readily available.
EXAMPLE 6
[0080] The compositions employed in accordance with the invention will have
the
administration times and drug contents set forth in the following table.
[0081] Table 6
Norethindrone Ethinyl Estradiol
Phase Days acetate (NA) (EE)
(mg/day) (mcg/day)
24 1.0 2.5
II 1 0 2.5
3 0 (placebo) 0 (placebo)
[0082] The norethindrone acetate (NA) and ethinyl estradiol (EE) are well
known and
readily available.
EXAMPLE 7
[0083] The compositions employed in accordance with the invention will have
the
administration times and drug contents set forth in the following table.
[0084] Table 7
Norethindrone Ethinyl Estradiol
Phase Days acetate (NA) (EE)
(mg/day) (mcg/day)
42 1.0 2.5
7 0 (placebo) 0 (placebo)
[0085] The norethindrone acetate (NA) and ethinyl estradiol (EE) are well
known and
readily available.
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
EXAMPLE 8
[0086] The compositions employed in accordance with the invention will have
the
administration times and drug contents set forth in the following table.
[0087] Table 8
Norethindrone Ethinyl Estradiol
Phase Days acetate (NA) (EE)
(mg/day) (mcg/day)
63 1.0 2.5
7 0 (placebo) 0 (placebo)
[0088] The norethindrone acetate (NA) and ethinyl estradiol (EE) are well
known and
readily available.
EXAMPLE 9
[0089] The compositions employed in accordance with the invention will have
the
administration times and drug contents set forth in the following table.
[0090] Table 9
Norethindrone Ethinyl Estradiol
Phase Days acetate (NA) (EE)
(mg/day) (mcg/day)
Continuous
1.0 2.5
without a placebo
[0091] The norethindrone acetate (NA) and ethinyl estradiol (EE) are well
known and
readily available. For example, continuous regimen can be administered for up
to 40 years.
[0092] In an embodiment, the regimens in the above Examples are administered
daily via
oral dosage forms. In an embodiment, norethindrone acetate (NA) and/or ethinyl
estradiol
(EE) in the Examples are administered via a vaginal ring or a patch.
[0093] For instance, in a multiphasic regimen, phase I is administered via a
vaginal ring or
a patch and phase II is administered via an oral dosage form. Alternatively,
each phase is
administered via a vaginal ring or a patch.
[0094] In an embodiment, if a vaginal ring is used, the vaginal ring may be
removed after a
certain period of time (e.g., 30 days or 90 days) followed by immediately
inserting a new
vaginal ring. In an embodiment, if a patch is used, the patch may be removed
after a certain
period of time (e.g., 30 days or 90 days) followed by immediately applying a
new patch.
21
CA 03234836 2024-04-08
WO 2023/037264
PCT/IB2022/058420
[0095] It should be noted that the tables are presented for illustrative
purposes only. The
substitution of functionally equivalent amounts and kinds of reagent(s) in
these schemes is
contemplated.
22
