A PHARMACEUTICAL COMPOSITION, A PHARMACEUTICAL DOSAGE UNIT
AND A PHARMACEUTICAL PATCH THEREOF
BACKGROUND
This invention relates to methods and pharmaceutical compositions for
providing hormone replacement therapy in perimenopausal, menopausal, and
postmenopausal women through the continuous administration of combinations of
conjugated estrogens and medroxyprogesterone acetate.
Menopause is generally defined as the last natural menstrual period and is
characterized by the cessation of ovarian function, leading to the substantial
diminution of circulating estrogen in the bloodstream. Menopause is usually
identified, in retrospect, after 12 months of amenorrhea. It is not a sudden event, but
is often preceded by a time of irregular menstrual cycles prior to eventual cessation of
menses. Following the cessation of menstruation, the decline in endogenous estrogen
concentrations is typically rapid. There is a decrease in serum estrogens from
circulating levels ranging from 40-250 pg/mL of estradiol and 40-170 pg/mL of
estrone during ovulatory cycles to less than 15 pg/mL of estradiol and 30pg/mL of
estrone in postmenopausal women.
As these estrogens decline during the time preceding (perimenopause) and
following the menopause (postmenopause), various physiological changes may result,
including vulvar and vaginal atrophy causing vaginal dryness, pruritus and
dyspareuma, and vasomotor instability manifested as hot flushes. Other menopausal
disturbances may include depression, insomnia, and nervousness. The long-term
physiologic effects of postmenopausal estrogen deprivation may result in significant
morbidity and mortality due to increase in the risk factors for cardiovascular disease
and osteoporosis. Menopausal changes in blood lipid levels, a major component of
the pathogenesis of coronary heart disease (CHD), may be precursors to increased
incidence of ischemic heart disease, atherosclerosis, and other cardiovascular disease.
A rapid decrease in bone mass of both cortical (spine) and trabecular (hip) bone can

be seen immediately after the menopause, with a total bone mass loss of 1% to 5% per
year, continuing for 10 to 15 years.
Estrogen replacement therapy (ERT) is beneficial for symptomatic relief of
hot flushes and genital atrophy and for prevention of postmenopausal osteoporosis.
ERT has been recognized as an advantageous treatment for relief of vasomotor
symptoms. There is no acceptable alternative to estrogen treatment for the atrophic
changes in the vagina; estrogen therapy increases the vaginal mucosa and decreases
vaginal dryness. Long term ERT is the key to preventing osteoporosis because it
decreases bone loss, reduces spine and hip fracture, and prevents loss of height. In
addition, ERT has been shown to be effective in increasing high density lipoprotein-
cholesterol (HDL-C) and in reducing low density lipoprotein cholesterol (LDL-C),
affording possible protection against CHD. ERT also can provide antioxidant
protection against free radical mediated disorders or disease states. Estrogens have
also been reported to confer neuroprotection, and inhibit neurodegenerative disorders,
such as Alzheimer's disease (see U.S. Patent 5,554,601, which is hereby incorporated
by reference). The following table contains a list of estrogen preparations currently
available.



To minimize the occurrence of estrogen-related side effects and to maximize
the benefit-risk ratio, the lowest dose effective in relief of symptoms and prevention
of osteoporosis should be used. Although ERT reduces the relative risk (RR) for
ischemic heart disease (RR, 0.50) and osteoporosis (RR, 0.40), the relative risk of
endometrial cancer for postmenopausal women with a uterus may be increased.
There are extensive clinical data showing that the relative risk of endometrial cancer
can be reduced by the addition of a progestin, either sequentially or continuously.
The addition of a progestin to estrogen therapy prevents estrogen-induced endometrial
proliferation. Continuous combined hormone replacement therapy (HRT), with
appropriate doses of daily estrogen and progestin, has been shown to be effective in
relieving vaginal atrophy and vasomotor symptoms, preventing postmenopausal

osteoporosis, and reducing the risk of endometrial cancer by prevention of
endometrial hyperplasia. The following table contains a list of some currently
available oral combination HRT products.

Since it is possible that progestins ameliorate of the favorable estrogen effects
on lipids and may potentially impair of glucose tolerance, it is desirable, and an
objective to find the lowest dose estrogen plus progestin HRT product, which also

minimizes or eliminates endometrial hyperplasia. In addition, a major factor affecting
a woman's decision to start and to continue taking HRT is vagina] bleeding, and many
women would prefer a bleed-free product. Therefore, another objective is to provide
the lowest effective dose which provides an acceptable bleeding pattern. Doses as
low as NETA 0.5 mg, NET 0.35 mg, medroxyprogesterone acetate (MPA) 2.5 mg,
levonorgesterel 0.25 mg, and dydrogesterone 5 mg have been used previously in
continuous uninterrupted HRT regimens.
Thus, according to the present invention there is provided a pharmaceutical
pack comprising daily dosage units comprising a combination of conjugated estrogens
and a daily dosage of about 1.5 mg of medroxyprogesterone acetate, and further
provided is the use of conjugated estrogens and medroxyprogesterone acetate in the
manufacture of such pharmaceutical packs for the treatment or inhibition of
menopausal or postmenopausal disorders in a perimenopausal, menopausal, or
postmenopausal woman in need thereof.
ACCOMPANYING
BRIEF DESCRIPTION OF THFJDRAWINGS
FIG. 1 shows the mean number of hot flushes per day in patients receiving
PREMARIN plus MPA combinations or placebo.
FIG. 2 shows the mean severity of hot flushes in patients receiving
PREMARIN plus MPA combinations or placebo.
FIG. 3 shows the percentage of patients with amenorrhea in patients receiving
PREMARIN plus MPA combinations or placebo.
DESCRIPTION OF THE INVENTION
The purpose of this invention is to provide the significant benefits of a
commercially successful HRT product, such as PREMPRO (0.625 mg conjugated
equine estrogens, USP plus 2.5 mg MPA), while lowering the dosage of MPA below
that which has previously been demonstrated to be effective, and preferably also
lowering the dosage of the conjugated estrogens. This invention provides a method of
treating or inhibiting menopausal or postmenopausal disorders in a perimenopausal,
menopausal, or postmenopausal woman in need thereof, which comprises providing
to said woman, continuously and uninterruptedly over the treatment period, a
combination of conjugated estrogens (natural or synthetic) and a daily dosage of

about 1.5 mg MPA. The dosage is preferably provided as a pharmaceutical
composition for use in treating menopausal or postmenopausal disorders which
comprises a combination of conjugated estrogens and a dosage of about 1.5 mg MPA.
This invention further provides a pharmaceutical pack containing the daily dosage
units of conjugated estrogen and MPA for continuous daily administration.
Conjugated estrogens refer to estrogenic steroidal substances in which one or
more functional groups (typically hydroxyl groups) on the steroid exists as a
conjugate (typically a sulfate or glucuronide). The conjugated estrogens may be a
single conjugated estrogen, or may consist of mixtures of various conjugated
estrogens. Numerous conjugated estrogens are described in the literature or are
commercially available that are capable of being formulated for use in this invention
either as a unitary estrogen, or may be mixed together with other synthetic and/or
natural estrogens.
Conjugated estrogens may also contain other steroidal or non-steroidal
compounds, which may, or may not, contribute to the overall biological effect. Such
compounds include, but are not limited to, unconjugated estrogens, androstanes, and
pregnanes. Preferred conjugated estrogens for use in this invention are PREMARIN
(conjugated equine estrogens, USP) and CENESTIN (synthetic conjugated estrogens,
A).
PREMARIN (conjugated estrogens tablets, USP) for oral administration
contains a mixture of estrogens obtained exclusively from natural sources, occurring
as the sodium salts of water-soluble estrogen sulfates blended to represent the average
composition of material derived from pregnant mares' urine. It is a mixture of sodium
estrone sulfate and sodium equilin sulfate, and at least the following 8 concomitant
components, also as sodium sulfate conjugates: 17a-dihydroequilin, 17α-estradiol,
A8,9-dehydroestrone, 17β-dihydroequilin, 17β-estradiol, equilenin,
17α-dihydroequilenin, and 17β-dihydroequilenin. The make up of PREMARIN of
PREMARIN is currently being analyzed, and other components are in the process of
being identified and characterized. PREMARIN is indicated in the treatment of
moderate to severe vasomotor symptoms associated with the menopause; treatment of
vulvar and vaginal atrophy; and prevention of osteoporosis, as well as other
indications approved for estrogen products.

CENESTIN (synthetic conjugated estrogens, A) tablets for oral administration
contain a blend of 9 synthetic estrogenic substances: sodium estrone sulfate, sodium
17o>dihydroequilin sulfate, sodium 17α-estradiol sulfate, sodium equilenin sulfate,
sodium 17α-dihydroequilenin sulfate, sodium equilin sulfate, sodium 17β-
dihydroequilin sulfate, sodium 17β-estradiol sulfate, sodium 17a-dihydroequilenin
sulfate. CENESTIN is indicated in the treatment of moderate to severe vasomotor
symptoms associated with the menopause.
PREMARIN, CENESTIN, and medroxyprogesterone acetate are all available
from commercial sources (Wyeth-Ayerst - PREMARIN and medroxyprogesterone
acetate; Duramed - CENESTIN). The dosage of MPA is about 1.5 mg per day. It is
preferred that the conjugated estrogen constituent is PREMARIN. It is preferred that
the dosage of PREMARIN is about 0.625 mg per day or less, and is more preferred
that the dosage of PREMARIN is either about 0.45 mg per day or about 0.30 mg per
day.
As used in accordance with this invention, the term "menopausal or
postmenopausal disorder" refers to conditions, disorders, or disease states that are at
least partially caused by the decreased estrogen production occurring during the
perimenopausal, menopausal, or post-menopausal stages of a woman's life. Such
disorders typically include, but are not limited to, one or more of:
• vasomotor instability, vasomotor symptoms such as hot flushes;
• bone demineralization causing reduced bone mineral density, increased risk of
developing osteoporosis;
• vaginal or vulvar atrophy; atrophic vaginitis; vaginal dryness; pruritus;
dyspareunia; dysuria;
• frequent urination; urinary incontinence; urinary tract infections,
• raised cholesterol, triglycerides, Lp(a), or LDL levels; hypercholesteremia;
hyperlipidemia;
• cardiovascular disease; atherosclerosis; peripheral vascular disease; restenosis,
vasospasm; vascular wall damage from cellular events leading toward immune
mediated vascular damage;
• free radical involvement in the development of cancers, central nervous system
disorders, Alzheimer's disease, bone disease, aging, inflammatory disorders,
peripheral vascular disease, rheumatoid arthritis, autoimmune diseases, respiratory
distress, emphysema, prevention of reperfusion injury, viral hepatitis, chronic

active hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus,
amyotrophic lateral sclerosis, aging effects, adult respiratory distress syndrome,
central nervous system trauma and stroke, or injury during reperfusion
procedures;
dementias, neurodegenerative disorders, and Alzheimer's disease.
As used herein, menopausal also includes conditions of decreased estrogen
production that may be surgically, chemically, or be caused by a disease state which
leads to premature diminution or cessation of ovarian function.
The term "daily" means that the dosage is to be administered at least once a
day. The frequency of administration is preferred to be once a day, but may be more
than once a day, provided that any specified daily dosage is not exceeded.
The term "combination" of conjugated estrogens and MPA means that the
daily dosage of each of the components of the combination is administered during the
treatment day. The components of the combination are preferably administered at the
same time; either as a unitary dosage form containing both components, or as separate
dosage units; the components of the combination can be administered at different
times during the day, provided that the desired daily dosage is achieved.
The term "continuous and uninterrupted" means that there is no break in the
treatment regimen, during the treatment period. Thus, "continuous, uninterrupted
administration" of a combination, means that the combination is administered at least
once daily during the entire treatment period. It is expected that the treatment period
for the combination of conjugated estrogens and MPA will be for at least 28 days,
preferably 30 days and preferably for long term treatment, possibly an indefinite
period, as one of the primary reasons for administering combinations of conjugated
estrogens and MPA is to treat or inhibit menopausal or postmenopausal disorders. It
is preferred that the treatment is provided for at least 120 days, preferably 180 days,
and most preferably as an indefinite treatment. Pharmaceutical packs suitably contain
sufficient daily dosage units appropriate to the treatment period or in amounts which
facilitate the patient's compliance with the regimen. For example, the pharmaceutical
pack may contain from 28 to 180 daily dosage units, for example from 30 to 120 daily
dosage units. Pharmacaceutical packs containing large numbers of dosage units may
be further sub-packaged, for example, in 28 day periods, or 30 day periods.
Treatment periods also may vary depending on the symptoms to be treated. For
example, for the treatment of vasomotor symptoms, it is preferred that the treatment
may last from one month to several years, depending on the severity and duration of
the symptoms. Physician evaluation along with patient interaction will assist the

determination of the duration of treatment. For the treatment or inhibition of
osteoporosis, it is preferred that the treatment period could last from six months to a
number of years, or indefinitely.
This invention, also covers short term treatments or treatments of a finite term,
that may be less than the 28 or 30 day preferred treatment period. It is anticipated that
a patient may miss, or forget to take, one or a few dosages during the course of a
treatment regimen, however, such patient is still considered to be receiving
continuous, uninterrupted administration.
The term "fixed daily dosage" means that the same dosage amount is given
every day during the treatment period. It is preferred that the MPA is given in a fixed
daily dosage of about 1.5 mg, with an appropriate dose of conjugated estrogens,
preferably equivalent to about 0.45 mg or about 0.30 mg PREMARIN. One aspect of
this invention also covers situations in which a fixed daily dosage of the conjugated
estrogens plus MPA combination is not given every day during the treatment period.
For example, the dosage of a patient may need to be adjusted (either up or down), to
achieve the desired effect during the middle of a treatment period.
The term "providing," with respect to providing a dosage of one or both of the
components of this invention, means either directly administering such a component
of this invention, or administering a prodrug, derivative, or analog which will form
the equivalent amount of the component within the body.
The daily dosage unit is preferably provided in a form for oral administration
containing both the conjugated estrogens and the MPA.
The ability of the conjugated estrogens plus MPA combinations of this
invention to treat or inhibit menopausal or postmenopausal disorders was confirmed
in a double blind clinical study of postmenopausal women using combinations of
PREMARIN plus MPA, or placebo. In this study, patients received continuous and
uninterrupted treatment for 13 cycles (1 year). The relief of vasomotor symptoms,
prevention of endometrial hyperplasia, and effects on lipids, vaginal bleeding were
measured throughout the study. Additionally, the effect on bone mineral density was
evaluated in patients who received continuous and uninterrupted treatment for up to
26 cycles (2 years).
Vasomotor instability is a menopausal or postmenopausal disorder which is
often manifested as hot flushes. In the clinical study described above, relief of
vasomotor symptoms was analyzed in a subset of patients who experienced at least an

average of 7-8 moderate-to-severe hot flushes per day during the 7-day period just
prior to the initiation of treatment in this study. The results obtained are summarized
in the tables below. The first table shows the mean number of flushes, and the second
table shows the mean daily severity of the flushes. These results are also shown in
FIGS. 1 and 2.

As shown in both tables and Figures, all dosages of PREMARIN plus MPA
reduced the number and severity of hot flushes experienced by the women in this
clinical study compared with women taking placebo. All differences from placebo
were significant (p < 0.05) by weeks 3-4. It was unexpected, however, that the lower
dosages of PREMARIN (0.45 and 0.3 mg) and MPA (1.5 mg), would rapidly reduce
the number and severity of hot flushes to the same extent as the higher dose
combination containing 0.625 mg PREMARIN plus 2.5 mg MPA.
Vaginal atrophy is a common menopausal or postmenopausal disorder leading
to vaginal dryness, pruritus, and dyspareunia. Vagina] atrophy results from a

sloughing of vaginal epithelial cells which are not replaced, leading to a thinning of
the vaginal lining. The effects of the lower dose conjugated estrogen plus MPA
regimens on vaginal atrophy were evaluated by comparing the vaginal maturation
index of superficial cells at baseline, and after cycles 6 and 13 of treatment. The
vaginal maturation index is a measure of the number of superficial vaginal epithelial
cells. An increase (positive number) in the vaginal maturation index indicates a
reversal (successful treatment) of vaginal atrophy. The following table summarizes
the results obtained.

These data show that all the evaluated dosages of conjugated estrogens plus
MPA provided significant (p < 0.001) improvement in the vaginal maturation index
versus placebo, demonstrating their ability to successfully treat or inhibit vaginal
atrophy. It is notable that the lower dosages of conjugated estrogens plus MPA were
as equally as effective as the 0.625 mg PREMARIN plus 2.5 mg MPA dosage in
facilitating the growth of the vaginal superficial cells.
As HRT using estrogens alone has been shown to increase the relative risk of
endometrial hyperplasia in postmenopausal women with a uterus, the incidence of
endometrial hyperplasia was evaluated in the clinical study for patients treated with
PREMARIN plus MPA treated groups and placebo. Two independent pathologists
evaluated endometrial biopsies in a blinded fashion. A patient was considered to have
endometrial hyperplasia if both of the primary pathologists agreed on the diagnosis.
If they disagreed, a third pathologist was consulted, and the diagnosis of hyperplasia
was based on the diagnosis of the majority. The following table summarizes the
results obtained after 13 cycles of treatment.


These results showed that that the use of conjugated equine estrogens/MPA at
a dosage of 0.625/2.5 mg/day effectively prevented the development of endometrial
hyperplasia. The results also show the unexpected result that lowering the dosage of
MPA to 1.5 mg/day in PREMARIN plus MPA combinations, also continued to
effectively inhibit the development of endometrial hyperplasia. The difference
between the results obtained in the 1.5 mg MPA treatment groups and 2.5 mg MPA
treatment groups was not statistically significant.
In providing an HRT regimen that will be acceptable to menopausal, and
particularly postmenopausal women, it is highly desirable that the regimen produce a
high rate of amenorrhea, as most of these women prefer a product which does not
cause spotting or breakthrough bleeding. The following table shows the percent of
women experiencing amenorrheic cycles at during cycles 1, 3, 6, 9, and 13.

The results show that greater than 90 percent of women receiving placebo
were amenorrheic throughout the study. While the percent of amenorrheic women
receiving daily dosages of 0.625 mg PREMARIN plus 2.5 mg MPA is satisfactory, as
measured by the commercial success of PREMPRO (0.625 mg conjugated equine

estrogens plus 2.5 mg MPA), lowering the dosages of PREMARIN to either 0.45 mg
or 0.3 mg and MPA to 1.5 mg, produced an equal, if not significantly better (0.3 mg
PREMARIN plus 1.5 mg MPA) percent of women achieving amenorrhea, while still
maintaining the other benefits of HRT. Additionally, as shown in the above table, and
in FIG. 3, a higher percentage of amenorrhea was achieved more rapidly with the
lower dose combinations.
It is well known that the addition of progestins to ERT regimens may
ameliorate some of the beneficial cardioprotective effects conferred by the estrogen,
or even produce deleterious effects on the lipid levels. In this study total cholesterol
(TC), HDL, HDL2, and LDL levels were measured. There was a general dose-
response trend between treatment groups, that showed more favorable lipid profiles
with higher doses of PREMARIN and lower doses of MPA. Patients receiving 0.625
mg PREMARIN + 2.5 mg MPA had slight reductions in TC, significant increases in
HDL and HDL2, and significant decreases in levels of LDL. The 0.45 mg
PREMARIN plus 1.5 mg MPA dosage produced a similar favorable profile (but of
less magnitude) to 0.625 mg PREMARIN + 2.5 mg MPA treated women. Women
treated with 0.3 mg PREMARIN plus 1.5 mg MPA had a less favorable lipid profile
(TC, HDL, HDL2 and LDL), than women treated, with 0.625 mg PREMARIN plus
2.5 mg MPA, however, this profile was still better than those receiving placebo.
During the study, adverse events were recorded and analyzed. Treatment
emergent adverse events were consistent with those seen with hormone therapy. With
the exception of breast pain, the side effect profile was comparable between the
PREMARIN plus MPA treatment groups. Women receiving the daily dosage of 0.3
mg PREMARIN plus 1.5 mg MPA experienced significantly less breast pain than the
women taking 0.625 mg PREMARIN plus 2.5 mg MPA.
In summary the results of the clinical study demonstrated that conjugated
estrogen HRT regimens containing dosages of 1.5 mg/day of MPA were equally
effective in treating menopausal or postmenopausal disorders as the regimens
containing the higher dose of 2.5 mg MPA (0.625 mg PREMARIN plus 2.5 mg MPA,
in particular). Higher rates of amenorrhea were also achieved more rapidly.

Additionally, less breast tenderness was observed in women taking 0.3 mg
PREMARIN plus 1.5 mg MPA, than in women taking the commercially available
0.625 mg PREMARIN plus 2.5 mg MPA combination.
It is well known that a rapid decrease in bone mass of both cortical (spine) and
trabecular (hip) bone can be seen immediately after the menopause, with a total bone
mass loss of 1% to 5% per year, continuing for 10 to 15 years. In the clinical study
described above, bone mineral density (BMD) was determined using dual energy
x-ray absorptiometry (DEXA) measurements of the lumbar spine (L2-L4), femoral
neck, trochanter, and total body. BMD measurements were made at least twice pre-
study (7-14 days apart but not to exceed 3 weeks), during cycles 6, 13, 19, and twice
during cycle 26 (7-14 days apart but not to exceed 3 weeks). The final visit results
(cycle 26) are summarized in the table below.

The results showed that all dosages of PREMARIN plus MPA significantly
increased the BMD versus baseline and placebo in the lumbar spine, femoral neck,
trochanter, and total body demonstrating that combinations of conjugated estrogens
plus MPA inhibited or retarded bone demineralization. These data also show that
combinations of conjugated estrogens plus MPA actually increased the bone mineral
density relative to pre-study baseline levels, and also relative to patients receiving
placebo.

Based on the results observed in the clinical study described above, it has been
found that the continuous and uninterrupted administration of a combination
conjugated estrogens plus a dosage of about mg per of medroxyprogesterone acetate
is useful in treating or inhibiting menopausal or postmenopausal disorders in
perimenopausal, menopausal, or postmenopausal women (most particularly the latter).
More particularly, the combinations described herein are useful in treating or
inhibiting vaginal or vulvar atrophy; atrophic vaginitis; vaginal dryness; pruritus;
dyspareunia; dysuria; frequent urination; urinary incontinence; urinary tract
infections; vasomotor symptoms, including hot flushes, myalgia, arthralgia, insomnia,
irritability, and the like; inhibiting or retarding bone demineralization; increasing bone
mineral density; and treating or inhibiting osteoporosis.
The combinations of this invention also exert a cardioprotective effect in
perimenopausal, menopausal, and postmenopausal women, and are therefore useful in
lowering cholesterol, triglycerides, Lp(a), and LDL levels; inhibiting or treating
hypercholesteremia; hyperlipidemia; cardiovascular disease; atherosclerosis;
peripheral vascular disease; restenosis, and vasospasm; and inhibiting vascular wall
damage from cellular events leading toward immune mediated vascular damage.
The combinations of this invention are antioxidants, and are therefore useful
in inhibiting disorders or disease states which involve free radicals. More
particularly, the combinations of this invention are useful in treating or inhibiting free
radical involvement in the development of cancers, central nervous system disorders,
Alzheimer's disease, bone disease, aging, inflammatory disorders, peripheral vascular
disease, rheumatoid arthritis, autoimmune diseases, respiratory distress, emphysema,
prevention of reperfusion injury, viral hepatitis, chronic active hepatitis, tuberculosis,
psoriasis, systemic lupus erythematosus, amyotrophic lateral sclerosis, aging effects,
adult respiratory distress syndrome, central nervous system trauma and stroke, or
injury during reperfusion procedures.
The combinations of this invention are useful in treating or inhibiting
dementias, neurodegenerative disorders, and Alzheimer's disease; providing
neuroprotection or cognition enhancement.

The conjugated estrogens and medroxyprogesterone acetate described in this
invention can be either formulated as separate tablets or as a unitary combination
tablet.
Either of the components or the combination may be formulated neat or may
be combined with one or more pharmaceutically acceptable carriers for
administration. For example, solid carriers include starch, lactose, dicalcium
phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers
include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such
as com, peanut and sesame oils, as are appropriate to the nature of the active
ingredient and the particular form of administration desired. Adjuvants customarily
employed in the preparation of pharmaceutical compositions may be advantageously
included, such as flavoring agents, coloring agents, preserving agents, and
antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of
preparation and administration are solid compositions, particularly tablets and hard-
filled or liquid-filled capsules. Oral administration of the compounds is preferred.
Conjugated estrogens and MPA can be formulated in a number of ways to
provide a single combination dosage form. Conjugated estrogens can be incorporated
within the core of a compressed tablet and the progestin can be placed in an
overcoating consisting of a compressed, Film or sugar coat, as described in U.S.
Patent 5,547,948, which is hereby incorporated by reference. The tablets described in
U.S. Patent 5,547,948 are suitable for formulation of the conjugated estrogens and
MPA described in this invention as a unitary tablet. U.S. Patent 5,908,638, which is
hereby incorporated by reference, also describes combination tablets which are
suitable for formulation of the conjugated estrogens and MPA described in this
invention as a unitary tablet.
Conjugated estrogens may be formulated in a core containing the conjugated
estrogens, and several components including alcohol, hydroxypropyl methyl
cellulose, lactose monohydrate, magnesium stearate, and starch. The core can be
covered with a coating made from components such as ethylcellulose, and triethyl
citrate.

Both components can be incorporated in the compressed tablet core or in a
tablet coating formulated to maintain drug stability and provide adequate oral
bioavailability. For example, the progestin can be micronized.
Conjugated estrogens can be incorporated in granules, spheroids or other
multiparticulate forms, and, if necessary, coated to provide adequate stability. These
multiparticulates can be combined, in the appropriate proportions, with a powder
blend, granulation or multiparticulates containing the progestin and incorporated into
hard gelatin capsules.
This invention also provides a pharmaceutical does pack, containing any
number of daily pharmaceutical dosage units. Preferably, and conventionally, the
pack contains 28 tablets or multiples thereof. The pack should indicate that the
dosage units are to be taken consecutively on a daily basis until the treatment period
has ended, or until the pack has been completed. The next pack should be started on
the next consecutive day. For combinations containing a unitary dosage tablet
containing both conjugated estrogens and MPA, it is preferable that the pack contain
one tablet corresponding to each day of administration. For combinations containing
separate dosage units of conjugated estrogens and MPA, it is preferable that each one
tablet of each correspond to each given day's administration, as indicated on the pill
pack.

WE CLAIM:
1. A pharmaceutical composition which comprises conjugated estrogens, a dosage
of 1.5 mg medroxyprogesterone acetate, and a pharmaceutical carrier.
2. The composition as claimed in claim 1, wherein the conjugated estrogens is
synthetic conjugated estrogens, A.
3. The composition as claimed in claim 1 to 2, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
4. The composition as claimed in any of the preceding claims, wherein the daily
dosage of conjugated estrogens is between 0.625 mg and 0.3 mg.
5. The composition as claimed in any of the preceding claims, wherein the daily
dosage of conjugated estrogens is between 0.45 mg and 0.3 mg.
6. The composition as claimed in any of the preceding claims, wherein the daily
dosage of conjugated estrogens is 0.45mg.
7. The composition as claimed in any of the preceding claims, wherein the daily
dosage of conjugated estrogens, is 0.3 mg.
8. The composition as claimed in any preceding claim, in which the
medroxyprogesterone acetate is micronized.

9. The composition as claimed in any preceding claim which contains 0.45 mg of
conjugated equine estrogens and 1.5 mg of medroxyprogesterone acetate.
10. The composition as claimed in any preceding claim which contains 0.3 mg of
conjugated equine estrogens and 1.5 mg of medroxyprogesterone acetate.

This invention relates to methods and pharmaceutical compositions for providing hormone replacement therapy in perimenopausal, menopausal, and postmenopausal women through the continuous administration of combinations of conjugated estrogens and medroxyprogesterone acetate.