Note: Descriptions are shown in the official language in which they were submitted.
CA 02596416 2007-08-21
P/1890-
- 1 -
ULTRA LOW DOSE ORAL CONTRACEPTIVES WITH LESS
MENSTRUL BLEEDING AND SIISTAINED EFFICACY
BACKGROUND OF THE INVENTION
The ovarian/menstrual cycle is a complex event
characterized by an estrogen rich follicular phase and,
after ovulation, a progesterone rich luteal phase. Each
has a duration of approximately 14 days resulting in an
intermenstrual interval of about 28 days. The
endometrial tissue responds to the changes in hormonal
milieu.
The onset of menstruation is the beginning of a
new menstrual cycle and is counted as day 1. During a
span of about 5 to 7 days, the superficial layers of the
endometrium, which grew and developed during the
antecedent ovarian/menstrual cycle, are sloughed because
demise of the corpus luteum in the non-fertile menstrual
cycle is associated with a loss of progesterone
secretion. ovarian follicular maturation occurs
progressively resulting in a rise in the circulating
levels of estrogen, which in turn leads to new
endometrial proliferation.
The dominant ovarian follicle undergoes
ovulation at mid-cycle, generally between menstrual cycle
SPSC1201939
CA 02596416 2007-08-21
- 2 -
days 12 to 16 and is converted from a predominantly
estrogen source to a predominantly progesterone source
(the corpus luteum). The increasing level of
progesterone in the blood converts the proliferative
endometrium to a secretory phase in which the tissue
proliferation has promptly abated, leading to the
formation of endometrial glands or organs. When the
ovulated oocyte is viably fertilized and continues its
progressive embryonic cleavage, the secretory endometrium
and the conceptus can interact to bring about
implantation (nidation), beginning about 6 to 8 days
after fertilization.
If an ongoing pregnancy is to be established
via implantation, the embryo will attach and burrow into
the secretory endometrium and begin to produce human
chorionic gonadotropin (HCG). The HCG in turn stimulates
extended corpus luteum function, i.e. the progesterone
production remains elevated, and menses does not occur in
the fertile menstrual cycle. Pregnancy is then
established.
In the non-fertile menstrual cycle, the waning
level of progesterone in the blood causes the endometrial
tissue to be sloughed. This starts a subsequent
menstrual cycle.
SPEC\201939
CA 02596416 2007-08-21
- 3 -
Because endometrial proliferation serves to
prepare the uterus for an impending pregnancy,
manipulation of hormones and of the uterine environment
can provide contraception. For example, estrogens are
known to decrease follicle stimulating hormone secretion
by feedback inhibition. Under certain circumstances,
estrogens can also inhibit luteinizing hormone secretion,
once again by negative feedback. Under normal
circumstances, the spike of circulating estrogen found
just prior to ovulation induces the surge of gonadotropic
hormones that occurs just prior to and resulting in
ovulation. High doses of estrogen immediately post-
coitally also can prevent conception probably due to
interference with implantation.
Progestins can also provide contraception.
Endogenous progesterone after estrogen is responsible for
the progestational changes of the endometrium and the
cyclic changes of cells and tissue in the cervix and the
vagina. Administration of progestin makes the cervical
mucus thick, tenacious and cellular which is believed to
impede spermatozoal transport. Administration of
progestin also inhibits luteinizing hormone secretion and
blocks ovulation in humans.
SPEC1201939
CA 02596416 2007-08-21
- 4 -
The most prevalent form of oral contraception
is a pill that combines both an estrogen and a progestin,
a so-called combined oral contraceptive preparation.
Alternatively, there are contraceptive
preparations that comprise progestin only. However, the
progestin-only preparations have a more varied spectrum
of side effects than do the combined preparations,
especially more breakthrough bleeding. As a result, the
combined preparations are the preferred oral
contraceptives in use today (Sheth et al., Contraception
25:243, 1982).
Whereas the conventional 21 day pill packs with
a 7 day "pill free" or placebo interval worked well when
oral contraceptives were of higher dosage, as the doses
have come down, for both the estrogen and progestin
components, bleeding problems have increased in
frequency, especially in the early months of oral
contraceptive use, but even persistently so in some
patients.
Since the advent of combined estrogen-progestin
medications as oral contraceptives, there has been a
steady downward adjustment of the daily estrogen dosage.
Concurrently, where exposure to the progestin component
has also been lowered, reduced androgenicity has remained
an ongoing priority. Together these adaptions in
SPEC\201939
CA 02596416 2007-08-21
- 5 -
formulation have been presented in a variety of regimens,
both monophasic and multiphasic. Each have their own
advantages and disadvantages. All-in-all, today's oral
contraceptives are much safer with regard to the
incidence and severity of estrogen-linked clotting
disorders as well as the suggested cumulative impact of
more "lipid friendly" progestins that maintain the
potentially advantageous high density lipoprotein
cholesterol levels in circulation.
U.S. Patent 4,390,531 teaches a triphasic
regimen in which each phase uses about 20-40 mcg ethinyl
estradiol, phases 1 and 3 use 0.3-0.8 norethindrone and
phase 2 doubles the amount of the norethindrone. These
three phases consume 21 days of a 28 day cycle. European
published application 0 226 279 states that this regimen
is associated with a high incidence of breakthrough
bleeding and substitutes a three phase oral contraceptive
regimen using a relatively low amount of ethinyl
estradiol (10-50 Mg) and a relatively high amount of
norethindrone acetate (0.5-1.5 mg) in each phase provided
that the amount of estrogen in any two phases is never
the same. A "rest" phase of about 7 days is used in this
regimen.
U.S. Patent 5,098,714 teaches an osmotic, oral
dosage form. One "pill" is administered per day but the
SPEC\201939
CA 02596416 2007-08-21
- 6 -
administration is, in effect, polyphasic. The dosage
form is constructed such that it provides an initial
pulse delivery of estrogen and progestin followed by
prolonged delivery of estrogen.
European published patent application 0 253 607
describes a monophasic contraceptive preparation
containing units having 0.008-0.03 mg of ethinyl
estradiol and 0.025-0.1 mg of desogestrel (or equivalent)
and a regimen where the preparation is administered over
a 23-25 day period, preferably 24 days, followed by a 2-5
day pill-free period. The object of this regimen is to
provide hormonal replacement therapy and contraceptive
protection for the pre-menopausal woman in need thereof
by supplying a low dose of an estrogen combined with a
"very low dose of a progestogen."
In 1989, the accumulating data from the
evolution of oral contraceptive pill formulations
containing only 20-35 g of estrogen per day spurred the
Food and Drug Administration's Fertility and Maternal
Health Drugs Advisory Committee to recommend indication
of low dose oral contraceptives for healthy, non-smoking
women even during the perimenopausal years, such as, for
instance, ages 35-50. In Japan, oral contraceptives are
being evaluated for safety and efficacy, as well as
social acceptability, for the first time.
SPEC\201939
CA 02596416 2007-08-21
- 7 -
U.S. patent number 5,552,394 describes a method
of female contraception which is characterized by a
reduced incidence of breakthrough bleeding after the
first cycle involves monophasicly administering a
combination of estrogen and progestin for 23-25
consecutive days of a 28 day cycle in which the daily
amounts of estrogen and progestin are equivalent to about
5-35 mcg of ethinyl estradiol and about 0.025 to 10 mg of
norethindrone acetate, respectively and in which the
weight ratio of estrogen to progestin is at least 1:45
calculated as ethinyl estradiol to norethindrone acetate.
In establishing a estrogen-progestin regimen
for oral contraceptives, two principal issues must be
confronted. First, efficacy must be maintained and
second, there must be avoidance of further erosion in the
control of endometrial bleeding. In general, even the
lowest dose oral contraceptive products commercially
available have demonstrated efficacy but the overall
instances of bleeding control problems has increased as
the doses were reduced, as manifest both in breakthrough
bleeding (untimely flow or spotting) or withdrawal
amenorrhea during the "pill free" week (expected menses).
It is the object of the present invention to
provide a new estrogen-progestin combination and/or
regimen for oral contraceptive use which maintains the
SP8C1201939
CA 02596416 2007-08-21
- 8 -
efficacy and provides enhanced control of endometrial
bleeding. The regimen enhances compliance by involving
fewer stop/start transitions per year and also results in
less blood loss in patients with anemia. Having fewer
menstrual intervals can enhance lifestyles and
convenience. This and other objects of the invention
will become apparent to those skilled in the art from the
following detailed description.
SUMMARY OF THE INVENTION
This invention relates to a method of female
contraception which is characterized by a reduced number
of withdrawal menses per year. More particularly, it
relates to a method of female contraception which
involves administering, preferably monophasicly, a
combination of estrogen and progestin for 60-110
consecutive days followed by 3-10 days of no
administration, in which the daily amounts of the
estrogen and progestin are equivalent to about 5-35 mcg
of ethinyl estradiol and about 0.025-10 mg of
norethindrone acetate, respectively.
SPM201939
CA 02596416 2007-08-21
- 9 -
DESCRIPTION OF INVENTION
In accordance with the present invention, a
women in need of contraception is administered a combined
dosage form of estrogen and progestin, preferably
monophasicly, for 60 to 110 consecutive days, preferably
about 80-90 days, followed by an administration free
interval of 3 to 10 days, preferably about 5-8 days, in
which the daily amounts of estrogen and progestin are
equivalent to about 5-35 mcg of ethinyl estradiol and
about 0.025 to 10 mg of norethindrone acetate,
respectively. On a schedule of 84 days administration
followed by 7 pill free days, there are only four
treatment and menstrual cycles per year.
The preferred estrogen and progestins are
ethinyl estradiol and norethindrone acetate although
other estrogens and progestins can be employed. The
weight ratio of these two active ingredients is at least
1:45 and preferably at least 1:50. The preferable amount
of ethinyl estradiol is about 10-20 mcg and the
preferable amount of the norethindrone acetate is about
0.25-1.5 mg. Other estrogens vary in potency from
ethinyl estradiol. For example, 30 mcg of ethinyl
estradiol is roughly equivalent to 60 mcg of mestranol or
2,000 mg of 17 fl-estradiol. Likewise, other progestins
vary in potency from norethindrone acetate. Thus, 3.5 mg
SPEC\201939
CA 02596416 2007-08-21
- 10 -
of norethindrone acetate is roughly equivalent to 1 mg of
levonorgestrel or desogestrel and 3-ketodesogestrel and
about 0.7 mg of gestodene. The values given above are
for the ethinyl estradiol and the norethindrone acetate
and if a different estrogen or progestin is employed, an
adjustment in the amount based on the relative potency
should be made. The correlations in potency between the
various estrogens and progestins are known.
Other useable estrogens include the esters of
estradiol, estrone and ethinyl estradiol such as the
acetate, sulfate, valerate or benzoate, conjugated equine
estrogens, agnostic anti-estrogens, and selective
estrogen receptor modulators. The estrogen is
administered in the conventional manner by any route
where it is active, for instance orally or transdermally.
Most estrogens are orally active and that route of
administration is therefore preferred. Accordingly,
administration forms can be tablets, dragees, capsules or
pills which contain the estrogen (and preferably the
progestin) and a suitable pharmaceutically acceptable
carrier.
Pharmaceutical formulations containing the
progestin and a suitable carrier can be solid dosage
forms which includes tablets, capsules, cachets, pellets,
pills, powders or granules; topical dosage forms which
SPEC1201939
CA 02596416 2007-08-21
- 11 -
includes solutions, powders, fluid emulsions, fluid
suspensions, semi-solids, ointments, pastes, creams, gels
or jellies, foams and controlled release depot entities;
and parenteral dosage forms which includes solutions,
suspensions, emulsions or dry powder comprising an
effective amount of progestin as taught in this
invention. It is known in the art that the active
ingredient, the progestin, can be contained in such
formulations in addition to pharmaceutically acceptable
diluents, fillers, disintegrants, binders, lubricants,
surfactants, hydrophobic vehicles, water soluble
vehicles, emulsifiers, buffers, humectants, moisturizers,
solubilizers, preservatives and the like. The means and
methods for administration are known in the art and an
artisan can refer to various pharmacologic references for
guidance. For example, "Modern Pharmaceutics", Banker &
Rhodes, Marcel Dekker, Inc. 1979; "Goodman & Gilman,s The
Pharmaceutical Basis of Therapeutics", 6th Edition,
MacMillan Publishing Co., New York 1980 can be consulted.
The pharmaceutical formulations may be provided
in kit form containing at least about 60, and preferably
at least about 84 tablets, and up to 110 tablets,
intended for ingestion on successive days. Preferably
administration is daily for at least 60 days using
SPBC\201939
CA 02596416 2007-08-21
- 12 -
tablets containing the both the estrogen and the
progestin and then for at least 3 days with placebo.
In order to further illustrate the present
invention, specific examples are set forth below. It
will be appreciated, however, that these examples are
illustrative only and are not intended to limit the scope
of the invention.
SPEC1201939
CA 02596416 2007-08-21
- 13 -
EXAMPLE 1
A study is carried out at a fully accredited
animal research facility which complies through its
animal care and use committee with the review standards
set forth in the National Institute of Health's "Guide
for Care and Use of Laboratory Animals", the Public
Health Services' "Principles for the Care and Use of
Laboratory Animals", and the United States Department of
Agriculture's Implementation Regulations of the 1985
Amendments for the Animal Welfare Act.
Ten adult female cynomolgus monkeys (macaca
fasicularis) having regular presumably ovulatory
menstrual cycles (28.9 3.1 days for the month prior to
study entry) are selected. Their duration of spontaneous
menses is 3.4 1.4 days. Mean body weight of the
monkeys is 4.9 1.1 kg (X SEM). They are housed
individually in a controlled environment (12 hours of
light and 23 C). Their diet is a commercial primate food
(Purina, St. Louis, MO) with water ad libitum.
The monkeys are divided at random into two
groups (N=5 each). The studies begin with spontaneous
menstruation in a pretreatment control cycle. At the
onset of the next spontaneous menses, alternatively, they
are assigned to receive on cycle day one an ultra low
SPEC120l939
CA 02596416 2007-08-21
- 14 -
dose oral contraceptive for either 60 consecutive days,
followed by 3 non-treatment days or 84 consecutive days,
followed by a 7 non-treatment days. These regimens are
continued through three treatment cycles. The study
concludes with each group of primates being followed
during a post-treatment spontaneous ovarian menstrual
cycle.
Femoral blood is collected daily and the serum
frozen for subsequent RIA of estradiol, progesterone, FSH
and LH in the pretreatment and post-treatment cycles and
every 3rd day during all three treatment cycles, except
daily through the "pill free" interval. Bleeding
profiles are kept by daily vaginal swabs, indicating
spontaneous menstruation, withdrawal bleeding,
breakthrough bleeding, or withdrawal amenorrhea.
Breakthrough bleeding is defined as detectable blood in
the vagina outside of the first 8 days after the last
dose of oral contraceptive or the onset of spontaneous
menses in non-treatment cycles.
Since the objective is to test an ultra low
dose oral contraceptive, the medication is adjusted to
fit the smaller (than human) body weight of these
laboratory primates. The dose of ethinyl estradiol is
1.2 g/day, while the dose of norethindrone acetate is
0.06 mg/day. This "in-house" reformulation is achieved
SPEC\201939
CA 02596416 2007-08-21
- 15 -
by grinding to powder a commercially available monophasic
pill (Loestrin 1/20, Parke Davis, Morris Plains, NJ),
which originally contained 1 mg of norethindrone acetate
and 20 g of ethinyl estradiol per tablet, contained in a
conventional 21 day pack along with 7 iron-containing
placebos.
In terms of comparison to human dose
equivalents, the daily dose received by the monkeys (with
a monkey's body weight about 5 kg and a woman's at 50 kg)
is about 12 g of ethinyl estradiol and 0.6 mg of
norethindrone acetate. Thus, this ultra low dose oral
contraceptive formulation presented a 40% reduction in
daily estrogen-progestin exposure as compared to one of
the lowest estrogen dose combination oral contraceptives
commercially available today in America or Europe.
Taking into account that when a continuous 84 day ultra
low dose regimen plus a 7 dy pill free interval was used,
versus the traditional 21 + 7 day protocol, that there
would be 63 more doses on an annualized basis, still the
exposure to medication was reduced by more than 26%
yearly, compared to the commercial product Loestrin 1/20.
SPF.C1201939
CA 02596416 2007-08-21
- 16 -
EBAMPLE3 ~ - 5
The example 1 procedure is repeated using the
following combinations of,estrogen and progestin:
Example Estrogen Progestin Treatment
Days
2 mestranol levo- 84
norgestrel
3 17-beta- 3-keto- 110
estradiol desogestrel
4 ethinyl desogestrel 80
estradiol
5 mestranol gestodone 60
Application of the compounds, compositions and
methods of the present invention for the medical or
pharmaceutical uses described can be accomplished by any
clinical, medical, and pharmaceutical methods and
techniques as are presently or prospectively known to
those skilled in the art. It will therefore be
appreciated that the various embodiments which have been
described above are intended to illustrate the invention
SP8C1201939
CA 02596416 2007-08-21
- 17 -
and various changes and modifications can be made in the
inventive method without departing from the spirit and
scope thereof.
SPM201939
