The instant application is divided out of Indian Patent Application No.
1184/KOLNP/2003.
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 usually 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 pgAnL of estradiol and 30 pg/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
dyspareunia, 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 some of the estrogen preparations currently available
in the US and Europe. Listings of such preparations are available in such as the
Physicians' Desk Reference, The Orange Book, and the European equivalents thereof.
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Estrogen replacement therapies available in the United States and/or Europe

Generic Name Brand Name Strength
Oral estrogens
Conjugated equine
estrogens (natural) Premarin 0.3,0.625,0.9,1.25,2.5 mg
Conjugated estrogens
(synthetic) Cenestin 0.625,0.9 mg
Esterified estrogens (75-80%
estrone sulfate, 6-15% equilin
sulfate derived from plant sterols) Estratab 0.3, 0.625,1.25,2.5 mg
Estropipate (Piperazine
estrone sulfate) Ogen Ortho-Est 0.625,1.25,2.5 mg
Micronized estradiol Estrace 0.5,1.0,2.0 mg
Raloxifene (SERM) Evista 60 mg
Esterified estrogens and
methylestosterone Estratest
Estratest HS 1.25 mg esterified estrogen and
2.5 mg methylestosterone
0.625 mg esterified estrogen and
1.25 mg methylestosterone
Estradiol valerate
Estradiol
Estradiol
Estradiol
Piperazine esterone sulfate Climaval
Elleste Solo
Estrofem
Estrofem Forte
Harmogen 1 mg, 2 mg
1 mg, 2 mg
2mg
4mg
1.5 mg
Combination Estrone
Product: Estradiol
Estriol Hormonin 1.4 mg
0.6 mg
0.27 mg
Estradiol valerate
Estradiol Progynova
Zumenon 1 mg, 2 mg
1 mg, 2 mg
Transdermal estrogens
Estradiol Alora (twice wkly)
Climara (weekly)
Estraderm (2x wkly)
Fern Patch (wkly)
Vivelle (twice wkly) 0.025, 0.0375, 0.05, 0.075,
0.1 mg of estradiol released
daily (dose options for various
products)
Estradiol
Estradiol
Estradiol
Estradiol
Estradiol
Estradiol Dermestril
Estraderm
Evorel (Systen)
Fematrix
Menorest
Progynova TS
And TS Forte (Climara) 25, 50,100 ng
25,50, 100 g
25, 50, 75,100 ng
40, 80 ng
25, 37.5, 50, 75 Mg
50,100 ng
Vaginal estrogens
Conjugated equine estrogens
Dienestrol
Estradiol
Estropipate
Micronized estradiol Premarin vaginal cream
Ortho dienestrol cream
Estring
Ogen vaginal cream
Estrace vaginal cream 0.625 mg/g
0.1 mg/g
7.5 ng
1.5 mg/g
1.0 ma/g
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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. Listings of such preparations are available in such as the
Physicians' Desk Reference, The Orange Book, and the European equivalents thereof.
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Oral Combination HRT Products

Brand Name Estrogen/Progestin Strengths
Activelle Estradiol
Norethisterone acetate (NETA) 1 mg
0.5 mg
Climagest Estradiol valerate (Climaval)
Norethisterone (NET) 1 or 2 mg
1 mg days 17-28
Cyclo Progynova Estradiol valerate
Levonorgestrel 1 or 2 mg, days 1-21
250 or 500 ng, days 2-21
Elleste Duet Estradiol
Norethisterone acetate 1 or 2 mg
1 mg days 17-28
Femoston Estradiol
Dydrogesterone 1 or 2 mg
10 or 20 mg
Kliogest Estradiol
Norethisterone acetate 2mg
1 mg
Improvera Piperazine estrone sulfate
Medroxyprogesterone acetate
(MPA) 1.5 mg
10 mg, days 17-28
Nuvelle Estradiol valerate (Progynova)
Levonorgestrel 2mg
75 ng, days 17-28
Premphase Conjugated estrogens
MPA 0.625 mg
5.0 mg
Prempro Conjugated estrogens
MPA 0.625 mg
2.5 or 5.0 mg
Trisequens
And
Trisequens Forte Estradiol
Norethisterone 2 or 4 mg, days 1-22
1 mg, days 23-28
1 mg, days 13-22
Ortho-Prefest Estradiol
Nogestimate 1.0 mg, days 1-6
0.09 mg, days 4-6
Femhrt 1/5 Ethinyl estradiol
Norethindrone acetate 1.0 mg
5ng
Since it is possible that progestins ameliorate 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 vaginal 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, MPA 2.5 mg, levonorgesterel 0.25 mg, and
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dydrogesterone 5 mg have been used previously in continuous uninterrupted HRT
regimens.
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 conjugated
estrogens and MPA below that which has previously been demonstrated to be
effective. 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 a daily dosage of between
about 0.25 mg to about 0.1 mg conjugated estrogens (natural or synthetic) and a daily
dosage of between about 2.5 mg to about 0.5 mg medroxyprogesterone acetate
(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 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, conforming with the monograph for conjugated
estrogens in USP25) and CENESTIN (synthetic conjugated estrogens, A).
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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, vaginal and vulvar
atrophy, vasomotor instability, urinary incontinence, and increased risk of developing
osteoporosis, cardiovascular disease, and diseases related to the oxidative damage
from free radicals. 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
daily. The frequency is preferred to be once daily, but may be more than once daily,
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 30 days,
preferably 120 days, and most preferably as long term treatment, and possibly
indefinite, as one of the primary reasons for administering combinations of conjugated
estrogens and MPA is to treat or inhibit menopausal or postmenopausal disorders.
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 30 day preferred treatment period. It is anticipated that a
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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 is given every day
during the treatment period. 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.
It is preferred that the conjugated estrogens plus MPA combinations of this
invention are provided orally. The specific dosages of conjugated estrogens plus MPA
combinations of this invention that are disclosed herein are oral dosages.
In accordance with this invention, the continuously and uninterruptedly
providing of a combination of a daily dosage of from about 0.25 mg to about 0.1 mg
conjugated estrogens plus a daily dosage of from about 2.5 mg to about 0.5 mg of
medroxyprogesterone acetate is useful in treating or inhibiting menopausal or
postmenopausal disorders in perimenopausal, menopausal, or postmenopausal
women. 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, 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.
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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.
In the Physicians' Desk Reference, PREMARIN is described as containing
calcium phosphate tribasic, calcium sulfate, carnuaba wax, cellulose, glyceryl
momooleate, lactose, magneseum stearate, methyl cellulose, pharmaceutical glaze,
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polyethylene glycol, stearic acid, sucrose, and titanium dioxide as inactive ingredients.
This would be a typical formulation for PREMARIN.
CENESTIN is described as containing ethylcellulose, hydroxypropyl
methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol,
polysorbate 80, pregelatinized starch, titanium dioxide, and triethyl citrate as inactive
ingredients. This would be a typical formulation for CENESTIN. Formulations covering
CENESTIN are described in US Patent 5,908,638, which is hereby incorporated by
reference.
MPA is described as containing calcium stearate, corn starch, lactose, mineral
oil, sorbic acid, sucrose, talc as inactive ingredients. This would be a typical
formulaton for MPA.
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
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blend, granulation or multiparticulates containing the progestin and incorporated into
hard gelatin capsules.
Tablets of conjugated estrogens or MPA may also be cut in pieces, or crushed
and placed in capsules for administration of dosages that are not specifically
commercially available.
This invention also provides a pharmaceutical dose pack, containing any
number of daily pharmaceutical dosage units. Preferably, and conventionally, the
pack contains 28 tablets or multiples thereof. The pack should indicate
dosage units are to be taken consecutively on a daiiy basis untii 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.
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WE CLAIM:
1. A method of treating or inhibiting menopausal or postmenopausal disorders in
a perimenopausal, menopausal, or postmenopausal woman in need thereof, which
comprises orally providing to said woman continuously and uninterruptedly over the
treatment period, a combination of a daily dosage in an amount from about 0.25 mg to
about 0.1 mg conjugated estrogens and a daily dosage in an amount from about 2.5
mg to about 0.5 mg of medroxyprogesterone acetate.
2. The method according to claim 1, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
3. The method according to claim 2, wherein the daily dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
4. The method according to claim 3, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
5. The method according to claim 4, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
6. The method according to claim 1, wherein the conjugated estrogens is
synthetic conjugated estrogens, A.
7. A method of treating or inhibiting vasomotor symptoms in a perimenopausal,
menopausal, or postmenopausal woman in need thereof, which comprises orally
providing to said woman continuously and uninterruptedly over the treatment period, a
combination of a daily dosage in an amount from about 0.25 mg to about 0.1 mg
conjugated estrogens and a daily dosage in an amount from about 2.5 mg to about 0.5
mg of medroxyprogesterone acetate.
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8. The method according to claim 7, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
9. The method according to claim 8, wherein the daily dosage of conjugated
equine estrogens is between about 0.2 mg and about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
10. The method according to claim 9, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
11. The method according to claim 10, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
12. The method according to claim 7, wherein the vasomotor symptom is hot
flushes.
13. The method according to claim 7, wherein the conjugated estrogens is
synthetic conjugated estrogens, A.
14. A method of inhibiting or retarding bone demineralization or treating or
inhibiting osteoporosis in a perimenopausal, menopausal, or postmenopausah/voman
in need thereof, which comprises orally providing to said woman continuously and
uninterruptedly "over the treatment period, a combination of a daily dosage in an
amount from about 0.25 mg to about 0.1 mg conjugated estrogens and a daily dosage
in an amount from about 2.5 mg to about 0.5 mg of medroxyprogesterone acetate.
15. The method according to claim 14, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
16. The method according to claim 15, wherein the daily dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
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17. The method according to claim 16, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
18. The method according to claim 17, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
19. A method of treating or inhibiting vaginal or vulvar atrophy; atrophic vaginitis;
vagina! dryness; pruritus; dyspareunia; dysuria; frequent urination; urinary
incontinence; urinary tract infections in a perimenopausal, menopausal, or
postmenopausal woman in need thereof, which comprises orally providing to said
woman continuously and uninterruptedly over the treatment period, a combination of a
daily dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens
and a daily dosage in an amount from about 2.5 mg to about 0.5 mg of
medroxyprogesterone acetate.
20. The method according to claim 19, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
21. The method according to claim 20, wherein the daily dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
22. The method according to claim 21, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
23. The method according to claim 22, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
24. A method of lowering cholesterol, Lp(a), or LDL levels; inhibiting or treating
hypercholesteremia; hyperlipidemia; cardiovascular disease; atherosclerosis;
peripheral vascular disease; restenosis, vasospasm; or inhibiting vascular wall
damage from cellular events leading toward immune mediated vascular damage, in a
-15-

perimenopausal, menopausal, or postmenopausal woman in need thereof, which
comprises orally providing to said woman continuously and uninterruptedly over the
treatment period, a combination of a daily dosage in an amount from about 0.25 mg to
about 0.1 mg conjugated estrogens and a daily dosage in an amount fromabout 2.5
mg to about 0.5 mg of medroxyprogesterone acetate.
25. The method according to claim 24, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
26. The method according to ciaim 25, wherein the daily dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
27. The method according to claim 26, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
28. The method according to claim 27, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
29. A method of 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 in a perimenopausal, menopausal, or postmenopausal woman in need
thereof, which comprises orally providing to said woman continuously and
uninterruptedly over the treatment period, a combination of a daily dosage in an
amount from about 0.25 mg to about 0.1 mg conjugated estrogens and a daily dosage
in an amount from about 2.5 mg to about 0.5 mg of medroxyprogesterone acetate.
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30. The method according to claim 29, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
31. The method according to claim 30, wherein the daily dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
32. The method according to claim 31, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
33. The method according to claim 32, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
34. A method of treating or inhibiting dementias, neurodegenerative disorders, and
Alzheimer's disease; providing neuroprotection or cognition enhancement in a
perimenopausal, menopausal, or postmenopausal woman in need thereof, which
comprises orally providing to said woman continuously and uninterruptedly over the
treatment period, a combination of a daily dosage in an amount from about 0.25 mg to
about 0.1 mg conjugated estrogens and a daily dosage in an amount from about 2.5
mg to about 0.5 mg of medroxyprogesterone acetate.
35. The method according to claim 34, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
36. The method according to claim 35, wherein the daily dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
37. The method according to claim 36, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
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38. The method according to claim 37, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
39. A pharmaceutical composition for use in treating menopausal or
postmenopausal disorders, which comprises dosage in an amount from about 0.25 mg
to about 0.1 mg conjugated estrogens and a dosage in an amount from about 2.5 mg
to about 0.5 mg of medroxyprogesterone acetate, and a pharmaceutical carrier.
40. The composition according to claim 39, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
41. The composition according to claim 40, wherein the dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
42. The composition according to claim 41, wherein the dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
43. The composition according to claim 42, wherein the dosage of conjugated
equine estrogens, USP is about 0.2 mg and the dosage of medroxyprogesterone
acetate is about 1 mg.
44. A pharmaceutical dosage unit which comprises which comprises a dosage of
from about 0.25 mg to about 0.1 mg conjugated estrogens and a dosage of from about
2.5 mg to about 0.5 mg of medroxyprogesterone acetate, and a pharmaceutical
carrier.
45. The dosage unit according to claim 44, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
46. The dosage unit according to claim 45, wherein the medroxyprogesterone
acetate is micronized.
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47. The dosage unit according to claim 46, wherein the dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg..
48. The dosage unit according to claim 47, wherein the dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
49. The dosage unit according to claim 48, wherein the dosage of conjugated
equine estrogens,- USP is about 0.2 mg and the dosage of medroxyprogesterone
acetate is about 1 mg.
50. A method of minimizing or reducing levels of breast pain in a woman receiving
hormone replacement therapy, which comprises orally providing to said woman
continuously and uninterruptedly over the treatment period, a combination of a daily
dosage of from about 0.25 mg to about 0.1 mg conjugated estrogens and a daily
dosage of from about 2.5 mg to about 0.5 mg of medroxyprogesterone acetate.
51. The method according to claim 50, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
52. The method according to claim 51, wherein the daily dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
53. The method according to claim 52, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
54. The method according to claim 53, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
55. A method of minimizing spotting or breakthrough bleeding; or achieving
amenorrhea in a woman receiving hormone replacement therapy, which comprises
orally providing to said woman continuously and uninterruptedly over the treatment
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period, a combination of a daily dosage in an amount from about 0.25 mg to about 0.1
mg conjugated estrogens and a daily dosage in an amount from about 2.5 mg to about
0.5 mg of medroxyprogesterone acetate.
56. The method according to claim 55, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
57. The method according to claim 56, wherein the daily dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
58. The method according to claim 57, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
59. The method according to claim 58, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
60. A method of increasing bone mineral density in a perimenopausal,
menopausal, or postmenopausal woman in need thereof, which comprises orally
providing to said woman continuously and uninterruptedly over the treatment period, a
combination of a daily dosage in an amount from about 0.25 mg to about 0.1 mg
conjugated estrogens and a daily dosage in an amount from about 2.5 mg to about 0.5
mg of medroxyprogesterone acetate.
61. The method according to claim 60, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
62. The method according to claim 61, wherein the daily dosage of conjugated
equine estrogens is from about 0.2 mg to about 0.1 mg and the daily dosage of
medroxyprogesterone acetate is from about 1.5 mg to about 0.5 mg.
63. The method according to claim 62, wherein the daily dosage of
medroxyprogesterone acetate is from about 1 mg to about 0.5 mg.
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64. The method according to claim 63, wherein the daily dosage of conjugated
equine estrogens, USP is about 0.2 mg and the daily dosage of medroxyprogesterone
acetate is about 1 mg.
65. A pharmaceutical pack for use in the treatment of menopausal or
postmenopausal disorders comprising a plurality of pharmaceutical dosage units as
defined in any of claims 44 to 49 for continuous uninterrupted daily administration of a
daily dosage
66. Use of conjugated estrogens and medroxyprogesterone acetate in the
manufacture of a pharmaceutical composition as defined in any of claims 39 to 43 or
one or more pharmaceutical dosage units as defined in any of claims 44 to 49, for the
treatment of menopausal or post-menopausal disorders.
67. Use of conjugated estrogens and medroxyprogesterone acetate in the
manufacture of a pharmaceutical pack as defined in claim 65, for the treatment of
menopausal or post-menopausal disorders.
68. Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 66 or 67 for the treatment or inhibition of vasomotor symptoms in a
perimenopausal, menopausal or postmenopausal woman in need thereof.
69. Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 68 wherein the vasomotor symptom is hot flushes.
70. Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 66 or 67 for inhibiting or retarding bone demineralization or treating or inhibiting
osteoporosis in a perimenopausal, menopausal, or postmenopausal woman in need
thereof.
71. Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 66 or 67 for treating or inhibiting vaginal or vulvar atrophy; atrophic vaginitis;
vaginal dryness; pruritus; dyspareunia; dysuria; frequent urination; urinary
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incontinence; urinary tract infections in a perimenopausal, menopausal, or
postmenopausal woman in need thereof.
72. Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 66 or 67 for lowering cholesterol, Lp(a), or LDL levels; inhibiting or treating
hypercholesteremia; hyperlipidemia; cardiovascular disease; atherosclerosis;
peripheral vascular disease; restenosis, vasospasm; or inhibiting vascular wall
damage from cellular events leading toward immune mediated vascular damage, in a
perimenopausal, menopausal, or postmenopausal woman in need thereof
73. Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 66 or 67 for 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 in a perimenopausal, menopausal, or postmenopausal woman in need
thereof
74. Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 66 or 67 for treating or inhibiting dementias, neurodegenerative disorders, and
Alzheimer's disease; providing neuroprotection or cognition enhancement in a
perimenopausal, menopausal, or postmenopausal woman in need thereof
75 Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 66 or 67 for minimizing or reducing levels of breast pain in a woman receiving
hormone replacement therapy.
76. Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 66 or 67 for minimizing spotting or breakthrough bleeding; or achieving
amenorrhea in a woman receiving hormone replacement therapy
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77. Use of conjugated estrogens and medroxyprogesterone acetate according to
claim 66 or 67 for increasing bone mineral density in a perimenopausal, menopausal,
or postmenopausal woman in need thereof
Dated this 18th day of February, 2008.

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