Note: Descriptions are shown in the official language in which they were submitted.
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ORAL CONTRACEPTIVE PREPARATION HAVING A FIRST PHASE COI~RISING
PROGESTllV/ESTROGEN AND A
SECOND PHASE COMPRISING PROGESTIN
BACKGROUND OF THE INVENTION
The vast majority of oral contraceptives consist of a combination of a
progestin
and estrogen that are administered concurrently for 21 days followed either by
a 7 day
pill free interval or by the administration of a placebo for 7 days in each 28
day cycle.
The most important aspects of a successful oral contraceptive product are
effective
contraception, good cycle control (absence of spotting and breakthrough
bleeding and
occurrence of withdrawal bleeding), and minimal side effects. Combination oral
contraceptives have traditionally acted by suppression of gonadotropins. In
addition, it
appears that the progestin component is primarily responsible for
contraceptive e~cacy
through inhibition of ovulation, and other peripheral effects which include
changes in
the cervical mucus (which increase the difficulty of sperm entry into the
uterus) and the
endometrium (which reduce the likelihood of implantation). The estrogenic
component
intensifies the anovulatory effect of the progestin, and is also important for
maintaining
cycle control.
Since the introduction of oral contraceptives (OCs) over a quarter-century
ago,
research has been directed toward developing preparations that minimize the
potential
for side effects while maintaining efficacy and normal menstrual patterns. The
first-
generation OCs contained more progestin and estrogen than was necessary to
prevent
conception. Adverse hemostatic and metabolic changes, clinical problems, and
side
effects were associated with these high-dose preparations. In 1978, the World
Health
Organization (WHO) recommended that the focus of OC research should be the
development of products containing the lowest possible dose levels of estrogen
and
progestin.
The first reductions in steroid content in a combination pill were focused on
estrogen because it, rather than progestin, was thought to be related to the
most serious
side effects. Reduction in progestin content followed, as evidence mounted
that
lowering progestin intake might lower the risk of cardiovascular complications
such as
stroke and ischemic heart disease. [Kay CR, Am J Obstet Gynecol 142:762
(1982)].
However, this evidence was not as clear as that implicating estrogen in
thromboembolic
disorders. [Inman WHW, Br Med J 2:203 ( 1970); Stolley PD, Am J Epidemiol
102:197 (1975)]. The need for a balance between estrogens and progestins to
nunimize
adverse effects on carbohydrate metabolism and on lipid and lipoprotein levels
was also
recognized. [Bradley DD, N Engl J Med 299:17 (1978); Wynn V, Lancet 1:1045
( 1979)]. Researchers then found that the synergistic action between progestin
and
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estrogen in a balanced ratio successfully inhibited ovulation at low levels of
both
components.
Research into low-dose progestins was advanced significantly by the
development of norgestrel (Ng) and levonorgestrel (LNg). LevonorgestreI is the
biologically active moiety of racemic norgestrel. It is strongly
progestational, has no
inherent estrogenic activity, is antiestrogenic, and possesses good biologic
activity.
The contraceptive effects of levonorgestrel are manifested throughout the
hypothalamic-
pituitary-gonadal-target organ axis.
Ethinyl estradiol (EE) is the estrogen most frequently used in combination
OCs.
In attempts to fulfill the WHO objective, the dosage of EE in marketed OC
formulations
has been steadily reduced from that found in earlier OCs. Thromboembolic
mortality
decreased when the amount of synthetic estrogen in OC formulations was reduced
from
100 ilg to 50 ug. Subsequently, a significant reduction in fatal myocardial
infarctions
was reported for women using OCs with 30 llg of EE rather than 50 Irg of EE.
[Meade
TW, Br Med J 280:1157 (1980)].
In keeping with the goal of reducing the total steroidal dosage, while
maintaining contraceptive efficacy, good cycle control, and minimizing side
effects,
numerous regimens have been developed in which the progestin/estrogen
combination
is administered either as a fixed dosage combination (monophasic) or as
biphasic or
triphasic regimens in which the dosage of the combination is varied either
once or twice
throughout the menstrual cycle. In these regimens, the progestin/estrogen
combination
is typically administered for 21 days followed by either a 7-day pill free
period or the
administration of a non-contraceptive placebo (or iron supplement) for 7 days.
In these
regimens, 3-ketodesogestrel (3-KDSG), desogestrel (DSG), levonorgestrel (LNg),
gestodene (GTD), norgestrel (NG), and norethindrone (NE) are typically used as
the
progestin while ethinyl estradiol (EE); 17(3-estradiol, and mestranol are
typically the
estrogenic components.
Several examples of attempts at reducing the total steroidal dosage by using
bridged or 24-day regimens are provided below.
De Jager (European Patent Application 368,373 A) discloses 22-30 day bridged
regimens consisting of the administration of 20-22 (preferrably 21 ) days of a
progestin/estrogen combination followed by 2-10 (preferrably 7) days of a
progestin.
Specifically disclosed regimens include (a) a combination of 150 p.g DSG and
2.0 mg
17(3-estradiol for 21 days, followed by 30 pg desogestrel for 7 days; (b) a
combination
of 150 pg DSG and 30 pg EE for 21 days, followed by 30 p.g desogestrel for 7
days;
(c) a combination of 50 pg DSG and 3 mg 17(3-estradiol for 7 days, followed by
a
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combination of 150 pg DSG and 2 mg 17(3-estradiol for 14 days, followed by 30
~,g
DSG for 7 days; (d) a combination of 50 pg DSG and 35 pg EE for 7 days,
followed
by a combination of 150 ~.g DSG and 30 ~.g EE for 14 days, followed by 30 ~g
DSG
for 7 days; (e) a combination of 50 ~g DSG and 3 mg 17j3-estradiol for 7 days,
followed by a combination of 100 ~.g DSG and 2 mg 17(3-estradiol for 7 days,
followed by a combination of 150 ~.g DSG and 1.5 mg 17[3-estradiol for 7 days,
followed by 30 ~.g DSG for 7 days; (fj a combination of 50 p.g DSG and 3 mg
17~i-
estradiol for 7 days, followed by a combination of 100 ~.g DSG and 2 mg 17~i-
estradiol
for 7 days, followed by a combination of 150 pg DSG and 1.5 mg 17~i-estradiol
for 8
days, followed by 30 pg DSG for 6 days; (g) a combination of 50 pg LNG and 2
mg
17~i-estradiol for 11 days, followed by a combination of 150 pg LNG and 2 mg
17(3-
estradiol for 11 days, followed by 125 ~.g LNg for 2 days; and (h) a
combination of 50
pg LNG and 2 mg 17(3-estradiol for 6 days, followed by a combination of 75 ~.g
LNG
and 2.5 mg 17~i-estradiol for 5 days, followed by a combination of 125 ug LNG
and
2 mg 17~i-estradiol for 10 days, followed by 70 ~.g LNg for 2 days, followed
by SO ~g
LNg for 2 days.
Endrikat (PCT Publication WO 97/23228) discloses bridged regimens
consisting of the squential administration of an ovulation inhibiting dose of
a progestin
for at least 28 days and a natural estrogen during the last 5-10 days of the
at least 28 day
sequential administration. A preferred contraceptive kit consists of 28 daily
dosage
units with a first phase having 18-23 daily dosage units of a progestin and a
second
phase having 5-10 daily dosage units of a prigestin in combination with a
natural
estrogen. Specific disclosed regimens include: (a) administration of 100 ug
LNg for
28 days, with 2.5 mg 17~-estradiol concomitantly adminsistered for the last 10
days of
the 28-day administration; (b) administration of 100 llg LNg for 28 days, with
2.5 mg
17(i-estradiol concomitantly adminsistered for the last 8 days of the 28-day
administration; (c) administration of 100 p.g LNg for 56 days, with 2.5 mg
17/3-
estradiol concomitantly adminsistered for the last 10 days of the 56-day
administration;
(d) administration of 100 ~,g LNg for 84 days, with 2.5 mg 17~i-estradiol
concomitantly
adminsistered for the last 10 days of the 84-day administration; and
equivalent regimens
using 75 ~.g GTD as the progestin.
Erlich (German Patent DE 4,104,385 C1 and U.S. Patent 5,280,023) discloses
sequential contraceptive regimens consisting of the administration of an
estrogen which
effects a disturbance of follicle stimulation, followed by the administration
of a
combination of a progestin/estrogen in a dose at least adequate to inhibit
ovulation.
The regimen is administered for a total of 28 days per cycle. It is preferred
that the
estrogen is administered for 5-14 days per cycle and the progestin/estrogen
combination
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is administered for 23-14 days per cycle, so that the total administration is
for 28 days
per cycle. Specific regimens include (a) 4 mg estradiol for 7 days followed by
21 days
of the combination of 1 mg norethisterone acetate and 4 mg estradiol; (b) 2 mg
estradiol
valerate for 7 days followed by 21 days of the combination of 2 mg
chlormadinone
acetate and 4 mg estradiol valerate; and (c) 20 p.g EE followed by 18 days of
the
combination of 150 p,g LNg and 20 p.g EE. Regimen (c) in Erlich provides a
total
steroidal load of 2.7 mg of LNg and 560 pg EE per 28 day cycle.
Lachnit (PCT Publication WO 95/26730) discloses bridged regimens consisting
of the administration of a combination of a progestin/estrogen combination (50
- 125 p.g
LNg and 10 - 40 p,g EE) for the first 23-24 days of the menstrual cycle
followed by the
administration of an estrogen (2 - 40 pg EE) for 4-10 days for a total
administration of
at least 28 days per cycle. The use of 100 - 300 p,g drospirenone and 10 - 40
p.g EE as
the 23-24 day progestin/estrogen combination is disclosed. Lachnit also
discloses a
triphasic plus bridging regimen (4-9 days, 4-9 days, 9-13 days, and 28 days
for the
three phases and estrogen phase, respectively) in which a combination of 50
p,g LNg
and 20 p,g EE are administered in the first phase, a combination of 75 ~tg LNg
and 25
pg EE are administered in the second phase, a combination of 100 p.g LNg and
20 ~tg
EE are administered in the third phase, and 10 pg EE is administered in the
estrogen
phase. Other progestins disclosed include GTD, DSG, 3-KDSG, DRSP, cyproterone
acetate, norgestimate, and norethisterone.
Moore (DE 4313926 A1) discloses bridged triphasic regimens consisting of the
administration of a combination of 10 - 50 p,g LNg and 5 - 20 ~tg EE from days
1-7 of
the menstrual cycle; of 50 - 75 pg LNg and 5 - 20 p.g EE from days 8-14 of the
menstrual cycle; of 75 - 125 p,g LNg and 5 - 20 pg EE from days 15-21 Qf the
menstrual cycle; and 5 - 20 pg EE from days 22-28 of the menstrual cycle.
Spona (U.S. Patent 5,583,129 and PCT Publication W0 95/17194) discloses
contraceptive regimens which consist of the administration of a combinaton of
a
progestin (50 - 75 ~g GTD, 75 - 125 p.g LNg, 60 - 150 ~tg DSG, 60 - 150 pg 3-
KDSG, 100 - 300 p,g DRSP, 100 - 200 ~tg cyproterone acetate, 200 - 300 ~,g
norgestimate, or >350 - 750 ~.g norethisterone) and an estrogen ( 15 - 20 p,g
EE or 2 - 6
mg I7~3-estradiol) for 23-24 days per cycle.
Upton (EP Patent Specification 253,b07 B 1 ) teaches the use of low dose
progestin/estrogen combinations for combined hormone replacement therapy and
contraception in climacteric women. Climacteric women are defined in Upton as
pre-
menopausal women around 40 years of age whose hormone levels are waning. The
climacteric woman still ovulates (albeit may have irregular ovulation), but
she still
experiences many of the symptoms of the hypoestrogenic menopausal woman, such
as
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insomnia, hot flushes, and irritability. Upton teaches the administration of a
23-26 day
monophasic regimen of progestin/estrogen followed by a pill free or placebo
interval of
2-5 days; with 24 days of progestin/estrogen administration followed by a 4-
day pill
free or placebo administration being preferred. Upton teaches the use of a
progestin
selected from 25 - 100 p,g LNg, 10 - 70 p,g GTD, 25 - 100 ~.g DSG, 25 - 100 ~g
3-
KDSG, and 85 - 350 p.g NE used in combination with an estrogen selected from
500 -
2000 p.g 17~i-estradiol, 8 - 30 pg EE, and 15 - 60 pg mestranol. Based on
relative
potencies, Upton teaches that a dose of 75 p,g LNg is equivalent to 35 p.g of
GTD, 75
p,g of 3-KDSG or DSG, and 250 p,g NE and that a dose of 1000 p,g of 17(3-
estradiol is
equivalent to a dose of 15 p,g EE and 30 p,g mestranol. Upton also teaches
that NG
may be substituted for LNg, but at twice the dose.
Bergink (U.S. Patent 5,262,408) discloses a 24 day triphasic combination
regimen in which the first 7-9 day phase consists of the administration of a
progestin at
a daily dosage equivalent to 100 p.g DSG and an estrogen at a daily dosage
equivalent to
25 p.g EE, the second 7-9 day phase consists of the administration of a
progestin at a
daily dosage equivalent to 125 p,g DSG and an estrogen at a daily dosage
equivalent to
p,g EE, and the third 7-9 day phase consists of the administration of a
progestin at a
daily dosage equivalent to SO p,g DSG and an estrogen at a daily dosage
equivalent to
20 p.g EE. It is preferred that the three phases be 8 days each. Following the
24 day
20 contraceptive steroid administration, a placebo may be administered for 4
days, the 4
day interval may be pill free, or a progestin at a dosage equivalent to 25-35
p.g DSG
may be administered.
DESCRIPTION OF THE INVENTION
This invention provides a progestin bridged combination progestin/estrogen
oral
contraceptive regimen for females of child-bearing age that provides effective
contraception, good cycle control, and minimal side effects while greatly
reducing the
total contraceptive steroid administered per 28-day cycle. To achieve the
substantial
reduction in the total contraceptive steroid administered per cycle while
maintaining
good cycle control, the low dose progestin/estrogen combination is
administered for 23-
25-days per cycle followed by the administration of a progestin for the
remaining 3-5
days of the cycle. Administration of the contraceptive progestin/estrogen
combination
is begun on the first day of menses (day 1 ), and continued for 23-25
consecutive days.
Following the 23-25-day administration period, a progestin is administered for
3-5 days
to assist in maintaining good cycle control. The total administration during
each cycle is
28 days.
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More particularly, this invention provides a method of contraception which
comprises administering to a female of child bearing age a combination of a
progestin
at a daily dosage equivalent in progestational activity to 40-150 p.g
levonorgestrel and
an estrogen at a daily dosage equivalent in estrogenic activity to 10-20 p,g
ethinyl
estradiol for 23-25 days beginning on day 1 of the menstrual cycle. Following
the 23-
25-day period, a progestin at a daily dosage equivalent to 10-100 p,g
levonorgestrel is
administered for 3-5 days. The total administration during each cycle is 28
days.
Preferred progestins include, but are not limited to levonorgestrel,
norgestrel,
desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone
acetate,
norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and
drospirenone. It is more preferred that the progestin is levonorgestrel. When
levonorgestrel is used as the progestin during the first 23-25 days of the
cycle, it is
preferred that the daily dosage of levonorgestrel is 30-150 p,g, with 50-100
~g being
more preferred, and 90 ~g being most preferred. When levonorgestrel is used as
the
progestin during the last 3-5 days of the cycle, it is preferred that the
daily dosage be
10-100 pg, with 20-50 ~g levonorgestrel being more preferred, and 37.5 ug most
preferred. Preferred dosages of the preferred progestins are provided in the
table
below.
PREFERRED DAILY DOSAGE
RANGES
Pr i First 23-25 CycleLast 3-5 ~rcle Davs
Dad
Levonorgestrel 30-150 pg I O-100 p.g
Norgestrel 60-300 pg 20-200 pg
Desogestrel 45-225 ~.g 15- I 50 ~.g
3-Ketodesogestrel 45-225 ~.g 15-150 ~,g
Norethindrone 200 pg - 1 mg 65-650 ~.g
Norethisterone Acetate 200 ~,g - 1 mg 65-650 pg
Gestodene 20-115 ~.g 7.5-75 p.g
Norgestimate 75-375 ~.g 25-250 pg
Osaterone 250 p.g - 2.5 100 ~.g - 1.5 mg
mg
Trimegestone 75-375 ~,g 25-250 p.g
Dienogest 500 pg - 3.75 100 ~g - 2.5 mg
mg
Drospirenone 500 p.g - 3.75 100 p.g - 2.5 mg
mg
Cyproterone Acetate 450 p.g - 2.5 150 ~.g - 1.5 mg
mg
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Preferred estrogens include, but are not limited to ethinyl estradiol; 17~i-
estradiol; conjugated estrogens, USP; estrone or a salt thereof; and
mestranol; with
ethinyl estradiol being more preferred. When ethinyl estradiol is used as the
estrogen
the preferred daily dosage is 10-20 ~tg, with 15 ~tg being more preferred.
When 17(3-
estradiol is used as the estrogen, it is preferred that the daily dosage of
17[3-estradiol is
1-3 p,g. Preferred salts of estrone include, but are not limited to the sodium
and
piperate salt. When conjugated estrogens, USP are used as the estrogen, it is
preferred
that the daily dosage is 0.3-5 mg, with a daily dose of 1.25 mg conjugated
estrogens,
USP being equivalent to a daily dose of 15 p,g ethinyl estradiol.
It is preferred that the progestin/estrogen combination be administered for 24
days beginning on day 1 of the menstrual cycle, and following this 24-day
period, it is
preferred that the progestin be administered for 4 days.
The following daily dosages of a combination of levonorgestrel and ethinyl
estradiol are preferred for contraception when administered for 23-25
consecutive days
beginning on the first day of menses, followed by the administration of
levonorgestrel
for 3-5 days. The total administration during each cycle is 28 days.
PREFERRED DAILY DOSAGES
First 23-25 Cycle Days Last 3-5 C,
cl~~
Regimen Levonorge_strelEthinvl EstradiolLevonor eg strel
A 100 p,g 15 ~g 20-50 pg
B 90 pg 15 ~.g 20-50 p,g
C 75 pg 15 p.g 20-50 p,g
D 60 ~,g 15 pg 20-50 p,g
E 50 p.g 15 p.g 20-50 p,g
F 40 p,g 15 p,g 20-50 p,g
G 100 p.g 10 p,g 10-40 ~,g
H 90 p,g 10 p,g 10-40 ~,g
I 75 p,g 10 ~,g 10-40 p,g
J 60 p,g 10 p.g 10-40 p.g
K 50 ~,g 10 ~,g 10-40 pg
L 40 ~g 10 ~.g 10-40 ~.g
The following daily dosages of a combination of levonorgestrel and ethinyl
estradiol are more preferred for contraception when administered for 24
consecutive
days beginning on the first day of menses, followed by the administration of
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_g_
levonorgestrel for 4 days. The total administration during each cycle is 28
days. Of the
regimens listed below, Regimens M-O are more preferred, with Regimen N being
most
preferred.
S MORE PREFERRED DAILY DOSAGES
First 24 Cy cle Davs Last 4 C~ cl~
a Days
Regimen LevonorgestrelEthinX,l EstradiolLevonorgestrel
M 75 p,g 15 p.g 37.5 p.g
N 90 p,g 15 p.g 37.5 p,g
O 100 p,g 15 pg 37.5 pg
P 50 p,g 10 pg 25 pg
Q 60 p.g 15 p,g 37.5 ~,g
R 75 pg 10 p.g 25 p.g
S 40 p.g 15 p,g 37.5 pg
For administration during the first 23-25 days of the menstrual cycle, it is
preferred that the combination progestin/estrogen contraceptive be
administered in unit
dosage form i.e., tablet or pill, with each unit providing the entire daily
dosage. It is
preferred that the progestin and estrogen are admixed together in the same
dosage unit.
Such dosage units can be prepared by conventional methodology that is well
known to
one skilled in the art. In each dosage unit, the contraceptively active
progestin and
estrogen are combined with excipients, vehicles, pharmaceutically acceptable
carriers,
and colorants. For example, the following illustrates an acceptable
composition of a
contraceptive progestin/estrogen combination of this invention.
EXAMPLE 1
Levonorgestrel, 75 p,g
Ethinyl estradiol, 15 ~.g
Microcrystaline Cellulose
Lactose, NF, Spray Dried
Polacrillin Potassium, NF
Magnesium Stearate
Opadry Pink
Polyethylene Glycol, 1500, Flakes
Water, Purified, USP
Wax E (Pharma)
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For administration during the last 3-5 days of the menstrual cycle, it is
preferred
that the progestin be administered in unit dosage form i.e., tablet or pill,
with each unit
providing the entire daily dosage. Such dosage units can be prepared by
conventional
methodology that is well known to one skilled in the art. In each dosage unit,
the
estrogen is combined with excipients, vehicles, phanmaceutically acceptable
carriers,
and colorants. For example, the following illustrates an acceptable estrogen
composition of this invention.
EXAMPLE 2
Levonorgestrel, 37.5 p.g
Microcrystaline Cellulose
Lactose, NF, Spray Dried
Polacrillin Potassium, NF
Magnesium Stearate
GP~Y Pink
Polyethylene Glycol, 1500, Flakes
Water, Purified, USP
Wax E (Pharma)
This invention also provides a contraceptive kit adapted for daily oral
administration which comprises a total of 28 separate dosage units. In this
kit, 23-25
dosage units each consisting of a combination of progestin at a daily dosage
equivalent
in progestational activity to 30-150 pg levonorgestrel and an estrogen at a
daily dosage
equivalent to 10-20 p,g ethinyl estradiol. The remaining 3-5 dosage units
contain an
progestin at a daily dosage equivalent to 10-100 ~,g levonorgestrel. The daily
dosage
arrangements are preferably arranged in a blister pack or in a dial pack type
tablet
dispenser. Specific referred progestins and estrogens and the specifically
preferred
dosages of each combination dosage unit are described above.
