This application is divided o,t of Indian Patent
Application No. 1208/KOLNP 72003
BACKGROUND
This invention relates to methods and pharmaceutical compositions for
providing estrogen replacement therapy in perimenopausal, menopausal, and
postmenopausal women through the continuous administration of conjugated
estrogens.
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 pg/mL 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.
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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 avaifable in the United States and/or Europe
Generic Name Brand Name Strength
Oral estrogensConjugated equineestrogens (natural) Premarin 0.3,0.625,0.9,1.25,2.5 mg
Conjugated estrogens(synthetic) Cenestin 0.625,0.9 mg
Esterffied estrogens (75-80%estrone sulfate, 6-15% equilinsulfate derived from plant sferols) Estratab 0.3, 0.625,1.25, 2.5 mg
Esfropipate (Piperazlneestrone sulfate) Ogen Ortho-Est 0,625,1.25,2.5 mg
MicronLzed estradfol Estrace 0.5,1.0,2.0 mg
Raloxifene (SERM) . Evista 60 mg
Esteriffed estrogens andmethylestosterone EstratestEstratestHS 1.25 mg esterifled estrogen and2.5 mg methylestosterone0.625 mg esterifled estrogen and1.25 mg methylestosterone
Estradiol valerateEstradiofEstradiolEstradiolPiperazine esterone sulfate ClimavalElleste SoloEstrofemEstrofem ForteHarmogen 1 mg, 2 mg1 mg, 2 mg2mg4mg1.5 mg
Combination EstroneProduct: EstradiolEstriol Hormonin 1.4 mg0.6 mg0.27 mg
Estradiol valerafeEstradiol ProgynovaZumenon 1 mg, 2 mg1 mg, 2mg
Transdermal estrogensEstradiol Alora (twice wkly)CJimara (weekly)Estraderm (2x wkly)Fern Patch (wkly)Vivelle (twice wkly) 0.025, 0.0375, 0.05,0.075,0.1 mg of estradiol releaseddaily (dose options for variousproducts)
EstradiolEstradiolEstradiolEstradiolEstradiolEsfradiol DermestrilEstradermEvorel (Systen)FematrbcMenorestProgynova TSAnd TS Forte (Climara) 25, 50,100 pg25,50,100 ug25,50, 75,100 ug40, 80ug25,37.5.50,75 ug50,100 ]ig
Vaginal estrogensConjugated equine estrogensDienestrolEstradiolEstropipateMicronized estradiol Premarin vaginal creamOrtho dienestrol creamEstringOgen vaginal creamEstrace vaginal cream 0.625 mg/g0.1 mg/g7.5 pg1.5 mg/g1.0 mg/g

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.
The addition of a progestin to ERT regimens, however, may ameliorate some
of the favorable estrogen effects on lipids and may potentially impair glucose
tolerance, it has desirably been an objective of HRT regimens to use the lowest
dosage of progestin that will minimize or eliminate endometrial hyperplasia. It is
therefore an object of this invention to provide low dosage ERT regimens that may-
minimize endometrial proliferation so that the need for concomitant progestin
administration is diminished. Accordingly, the ERT regimens covered by this invention
are particularly Useful in treating perimenopausal, menopausal, or postmenopausal
women when accompanied by adequate physician monitoring, and are also
particularly useful in treating subgroups of hysterectomized or progestin intolerant
women.
DESCRIPTION OF THE INVENTION
The purpose of this invention is to provide the significant benefits of a
commercially successful ERT product, such as PREMARIN (0.3 mg, 0.625 mg, 0.9
mg, 1.25 mg, or 2.5 mg conjugated equine estrogens, USP), while lowering the
dosage of conjugated estrogens 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 daily dosage in an amount from about
0.25 mg to about 0.1 mg conjugated estrogens (natural or synthetic). The dosage is
preferably provided as a pharmaceutical composition for use in treating menopausal or
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postmenopausa! disorders. This invention further provides a pharmaceutical pack
containing the daily dosage units of conjugated estrogen.
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).
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, 17a-
esiradiol, A8,9-dehydroestrone, 17b-dihydroequilin, 17b-estradiol, equilenin,
17a-dihydroequilenin, and 17|3-dihydroequilenin. 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
17a-dihydroequilin sulfate, sodium 17a-estradiol sulfate, sodium equilenin sulfate,
sodium 17a-dihydroequilenin sulfate, sodium equilin sulfate, sodium 17b-dihydro-
equilin sulfate, sodium 17b-estradiol sulfate, sodium 17a-dihydroequi!entn sulfate.
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CENESTIN is indicated in the treatment of moderate to severe vasomotor symptoms
associated with the menopause.
PREMARIN and CENESTIN are available from commercial sources (Wyeth-
Ayerst - PREMARIN; Duramed - CENESTIN).
It is preferred that the conjugated estrogen constituent is PREMARIN. It is
preferred that the dosage of PREMARIN is from about 0.25 mg per day to about 0.1
mg per day, and is more preferred that the dosage of PREMARIN is from about 0.2 mg
per day to about 0.1 mg per day, with a daily dosage of about 0.2 mg being specifically
preferred. It is also preferred that the ERT regimens described herein be administered
to hysterectomized women, or women with an uterus accompanied by careful
physician monitoring for endometrial hyperplasia.
If desired, the conjugated estrogen regimens of this invention can be
administered in conjunction with a progestin, particularly medroxyprogesterone acetate
(MPA, commercially available from Wyeth-Ayerst). When MPA is used as the
progestin, it is preferred that the daily dosage of MPA is 2.5 mg or less. Such
concomitant administration can be as a combination (as defined below), or that the
progestin can be provided for only part of the treatment period. For example,
PREMARIN may administered for 28-days per 28-day treatment period, and MPA may-
be administered on days 15-28 of the same 28-day treatment period.
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, 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.
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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 ERT regimens of this invention 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 ERT 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
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 ERT regimen 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 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.
The term "combination" means that the daily dosage of each of the
components of the combination is administered during the treatment day. The
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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.
In accordance with this invention, continuously and uninterruptedly providing a
daily dosage from about 0.25 mg to about 0.1 mg conjugated estrogens 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; hyperlipidemla; 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.
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Conjugated estrogens may be formulated neat or may be combined with one
or more pharmaceuticalfy acceptable carriers for administration. For example, solid
carriers include starch, lactose, dicalcium phosphate, microcrystaliine cellulose, *
sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols,
non-ionic surfactants and edible oils such as corn, 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, BUT 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,
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 trietbyl citrate as Inactive
ingredients. Formulations covering CENESTIN are described in US Patent 5,908,638,
which Is hereby Incorporated by reference. This would be a typical formulation for
CENESTIN.
Conjugated estrogens may be formulated in a core containing the conjugated
estrogens, and several components including alcohol, hydroxypropyl methyl cellulose,
lactose monohydrate, magnesium stearafe, and starch. The core can be covered with
' a coating made from components such as ethylcellulose, and triethyl citrate.
Conjugated estrogens can be incorporated in granules, spheroids or other
multiparficufafe forms, and, If necessary, coated to provide adequate stability.
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This invention also provides a pharmaceutical 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.
The ERT regimens described in this invention may also be administered as a
transdermal patch or as a vaginal cream. For example, PREMARIN vaginal cream
containing 0.625 mg conjugated equine estrogens, USP, is formulated to contain USP
in a nonliquefying base containing cetyl esters wax, cetyl alcohol, white wax, glyceryl
monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium
lauryl sulfate, glycerin, and mineral oil as excipients. ERT regimens covered by this
invention can be formulated similarly.
For the purposes of this disclosure, transdermal administrations are
understood to include all administrations across the surface of the body and the inner
linings of bodily passages including epithelial and mucosal tissues. Such
administrations may be carried out using the present compounds, or pharmaceutically
acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions,
and suppositories (rectal and vaginal).
Transdermal administration may be accomplished through the use of a
transdermal patch containing the active compound and a carrier that is inert to the
active compound, is non toxic to the skin, and allows delivery of the agent for systemic
absorption into the blood stream via the skin. The earner may take any number of
forms such as creams and ointments, pastes, gels, and occlusive devices. The
creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-
water or water-in-oil type. Pastes comprised of absorptive powders dispersed in
petroleum or hydrophilic petroleum containing the active ingredient may also be
suitable. A variety of occlusive devices may be used to release the active ingredient
into the blood stream such as a semi-permeable membrane covering a reservoir
containing the active ingredient with or without a carrier, or a matrix containing the
active ingredient. Other occlusive devices are known in the literature.
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WE CLAIM.;
1. A process of making a pharmaceutical composition, which comprises bringing
a dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens, into
association or combination with a pharmaceutical carrier.
2. The process according to claim 1, wherein the conjugated estrogens is
conjugated equine estrogens, USP. '
3. The process according to claim 2, wherein the dosage of conjugated equine
estrogens is from about 0.2 mg to about 0.1 mg.
4. The process according to claim 3, wherein the dosage of conjugated equine
estrogens, USP is about 0.2 mg.
5. A process of making a pharmaceutical dosage unit which comprises bringing a
dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens into
association or combination with a pharmaceutical carrier.
6. The process according to claim 5, wherein the conjugated estrogens is
conjugated equine estrogens, USP.
7. The process according to claim 6, wherein the dosage of conjugated equine
estrogens is from about 0.2 mg to about 0.1 mg.
8. The process according to claim 7, wherein the dosage of conjugated equine
estrogens, USP is about 0.2 mg.
9. A process of making a pharmaceutical pack which comprises bringing a
plurality of pharmaceutical dosage units each comprising about 0.25 mg to about 0-1
mg conjugated estrogens and a pharmaceutical carrier into a package for use for
continuous uninterrupted daily administration of a daily dosage.
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10. A process for making a pharmaceutical composition, substantially as herein
described.
11 .A process for making a pharmaceutical pack.substantially as herein
described.

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