AU2008200820A1 - Estrogen replacement therapy - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: 00 00 O O (N 00q Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Wyeth Actual Inventor(s): James Harrison Pickar Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: ESTROGEN REPLACEMENT THERAPY Our Ref: 823311 POF Code: 460048/460161 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- 6oa-- 00 ESTROGEN REPLACEMENT THERAPY C BACKGROUND C The present application is a divisional application from Australian Patent Application No. 2002338277, the entire disclosure of which is incorporated herein by reference.

00 This invention relates to methods and pharmaceutical compositions for providing estrogen replacement therapy in perimenopausal, menopausal, and 00 10 postmenopausal women through the continuous administration of conjugated estrogens.

c 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 CN 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 O 5 the vagina; estrogen therapy increases the vaginal mucosa and decreases vaginal 00 dryness. Long term ERT is the key to preventing osteoporosis because it decreases 0bone loss, reduces spine and hip fracture, and prevents loss of height. In addition, 00 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 r 10 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.

Estrogen replacement therapies available in the United States and/or Europe Gereric Name Brand Name Strength Oral estrogens Conjugated equine estrogens (natural) Conjugated estrogens (synthetic) Esterified estrogens (75-80% estrone sulfate, 6-15% equilin sulfate derived from plant sterols) Estropipate (Piperazine estrone sulfate) Premarin Cenestin Micronized estradiol RaIoxifene (SERM) Est3rified estrogens and methylestosterone Est-adiol valerate Estradlol Estradiol Estradlol Pip erazine esterone sulfate Combination Estrone Product: Estradiol Estdol Estradlol valerate Estradiol Transdermal estrogens Estradiol Estratab Ogen Ortho-Est Estrace Evista Estratest Estratest HS Climaval Elleste Solo Estrofem Estrofemn Forte Harmogen Hormonin Progynova Zumenon Alora (twice wk~y) Climara (weekly) Estraderm (2x wkly) Fern Patch (wNkly) Vivelle (twice wkly) Dermestrl Estraderm Evorel (Systen) Fematrix Menorest Progynova TS And TS Forte (Climara) Premarin vaginal cream Ortho dienestrol cream Estring Ogen vaginal cream Estrace vaginal cream 0.3, 0.625, 0.9, 1.25, 2.5 mg 0.625, 0.9 mg 0.3, 0.625, 1.25, 2.5 mg 0.625,1.25, 2.5 mg 0.5, 1.0, 2.0 mg 60 mg 1.25 mg esterifled estrogen and 2.5 mg methylestosterone 0.625 mg esterified estrogen and 1.25 mg methylestosterone 1 mg, 2 mg 1 mg, 2 mg 2 mg 4 mg 1.5 mg 1.4 mg 0.6 mg 0.27 mg 1 mg, 2 mg 1 mg, 2 mg 0.025, 0.0375, 0.05, 0.075, 0.1 mg of estradlol released daily (dose options for various products) Estradlol Estradlol Estradlol Estradiol Estradlol Esiradlol 25, 50, 100 gg 25, 50, 100 pg 25, 50, 75, 100 1 pg 40, 80 pg 25, 37.5, 50, 75 gg 50, 100 g Vaginal estrogens Conjugated equine estrogens Dienestrol Estradiol Estropipate Micronized estradiol 0.625 mg/g 0.1 mg/g 7.5 i.Lg 1.5 mg/g 1.0 mglg 00 To minimize the occurrence of estrogen-related side effects and to maximise Sthe benefit-risk ratio, the lowest dose effective in relief of symptoms and prevention of Sosteoporosis should be used. Although ERT reduces the relative risk (RR) for CT 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 progestin, either sequentially or continuously. The oO addition of a progestin to estrogen therapy prevents estrogen-induced endometrial proliferation.

O 10 The addition of a progestin to ERT regimens, however, may ameliorate some Sof the favourable estrogen effects on lipids and may potentially impair glucose C 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 aspect 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.

Throughout the description and claims of this specification, use of the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

DESCRIPTION OF THE INVENTION An aspect 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 W:\ManlaFIlESAU Prosk703275\Dwis1naA7l3275 1 4 5 damsv 182O doc 4 00 0 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 S0.25 mg to about 0.1 mg conjugated estrogens (natural or synthetic). The dosage is C preferably provided as a pharmaceutical composition for use in treating menopausal 5 or postmenopausal disorders. This invention further provides a pharmaceutical pack containing the daily dosage units of conjugated estrogen.

A further aspect of the invention is a method of treating or inhibiting vasomotor 00 symptoms in a perimenopausal, menopausal or postmenopausal woman in need thereof, which comprises orally providing to said woman continuously and 0O 10 uninterruptedly over the treatment period, a daily dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens.

c A further aspect of the invention is a method of inhibiting or retarding bone demineralization or treating or inhibiting osteoporosis 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 daily dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens.

A further aspect of the invention is a method of treating or inhibiting vaginal or vulvar atrophy; atrophic vaginitis; vaginal 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 daily dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens.

A further aspect of the invention is 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 perimenopausal, menopausal or postmenopausal woman in need thereof, which comprises orally 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.

A further aspect of the invention is 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 W.Wnta\FIESMAU PmsN7O3275\D isionR7O3275 pI 45 Cdst 182.08doc 00 injury during reperfusion procedures in a perimenopausal, menopausal or C postmenopausal woman in need thereof, which comprises orally providing to said Swoman continuously and uninterruptedly over the treatment period, a daily dosage in T an amount from about 0.25 mg to about 0.1 mg conjugated estrogens.

A further aspect of the invention is 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 00 in need thereof, which comprises orally providing to said woman continuously and uninterruptedly over the treatment period, a daily dosage in an amount from about 10 0.25 to about 0.1 mg conjugated estrogens.

00 SA further aspect of the invention is 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 daily dosage in an amount from about 0.25 to about 0.1 mg conjugated estrogens.

A further aspect of the invention is 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 period, a daily dosage in an amount from about 0.25 mg to about 0.1 mg.

A further aspect of the invention is 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 daily dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens.

A further aspect of the invention is a pharmaceutical composition for use in treatir.g menopausal or postmenopausal disorders, which comprises dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens, and a pharmaceutical carrier.

A further aspect of the invention is a pharmaceutical dosage unit which comprises conjugated estrogens, a dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens and a pharmaceutical carrier.

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 sulphate or glucoronide). 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 W:WanrFILES)AU Pos\703275\Disonf703275 pl 4 5 caims div 18 208 doc 00 0 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 Sestrogens.

L Conjugated estrogens may also contain other steroidal or non-steroidal 5 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 00 (conjugated equine estrogens, USP, conforming with the monograph for conjugated estrogens in USP25) and CENESTIN (synthetic conjugated estrogens, A).

"0 10 PREMARIN (conjugated estrogens tablets, USP) for oral administration Scontains 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 estrogen sulphate and sodium equilin sulphate, and at least the following 8 concomitant components, also as sodium sulphate conjugates: 17a-dihydroequilin, 17ac-estradiol, A8,9-dehydroesterone, 17p-dihydroequilin, 17p-estradiol, equilenin, 17ca-dihydroequilenin, and 17p-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 sulphate, sodium 17a-dihydroequilin sulphate, sodium 17a-3stradiol sulphate, sodium equilenin sulphate, sodium 17a-dihydroequilenin sulphate, sodium equilin sulphate, sodium 17p-dihydroequilin sulphate, sodium 17p-estradiol sulphate, sodium 17adihydroequilenin sulphate.

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J CENESTIN is indicated in the treatment of moderate to severe vasomotor symptoms associated with the menopause.

C1 PREMARIN and CENESTIN are available from commercial sources (Wyeth- Ayerst PREMARIN; Duramed CENESTIN).

00 It is preferred that the conjugated estrogen constituent is PREMARIN. It is Spreferred that the dosage of PREMARIN is from about 0.25 mg per day to about 0.1 OO mg per day, and is more preferred that the dosage of PREMARIN is from about 0.2 mg Sper day to about 0.1 mg per day, with a daily dosage of about 0.2 mg being specifically r 10 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.

-6- 00 1) The term "continuous and uninterrupted" means that there is no break in the treatment regimen, during the treatment period. Thus, "continuous, uninterrupted C- 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 O 5 for the ERT regimens of this Invention will be for at least 30 days, preferably 120 days, 00 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 00 postmenopausal disorders. Treatment periods also may vary depending on the 00 Ssymptoms 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, thai: 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 cortinuous, 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 -7- 00 components of the combination are preferably administered at the same time; either T 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.

00 In accordance with this invention, continuously and uninterruptedly providing a Sdaily dosage from about 0.25 mg to about 0.1 mg conjugated estrogens is useful in cN treating or inhibiting menopausal or postmenopausal disorders In perimenopausal, 00 0menopausal, 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, myagia, 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 perirnenopausal, 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.

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, adull 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 Sor 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, 00 non- onic 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 C administration desired. Adjuvants customarily employed in the preparation of 00 O pharmaceutical compositions may be advantageously included, such as flavoring C 10 agerts, 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 hardfilled 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 morr:ooleate, 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 triethyl 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 stearate, 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 multiparticulate forms, and, if necessary, coated to provide adequate stability.

-9- 00 (O This invention also provides a pharmaceutical pack, containing any number of L 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 00 consecutive day.

The ERT regimens described in this invention may also be administered as a 0 tranadermal patch or as a vaginal cream. For example, PREMARIN vaginal cream 00 Scontaining 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 carrier 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-inwater 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.

Claims (29)

1. A method of treating or inhibiting menopausal or postmenopausal disorders in a perimenopausal, menopausal or postmenopausal woman in need thereof, which C 5 comprises orally 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 Sconjugated estrogens. 00 0 S2. A method of treating or inhibiting vasomotor symptoms in a perimenopausal, 00 10 menopausal or postmenopausal woman in need thereof, which comprises orally Sproviding 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.

3. A method of inhibiting or retarding bone demineralization or treating or inhibiting osteoporosis 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 daily dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens.

4. A method of treating or inhibiting vaginal or vulvar atrophy; atrophic vaginitis; vaginal 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 daily dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens. 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 perimenopausal, menopausal or postmenopausal woman in need thereof, which comprises orally 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. W:UW LESV.U Pmsk703275viionaRO3275 4 5 cdaims d I8.208doc 11 00 O 6. A method of treating or inhibiting free radical involvement in the development of NC cancers, central nervous system disorders, Alzheimer's disease, bone disease, aging, Sinflammatory disorders, peripheral vascular disease, rheumatoid arthritis, autoimmune S 5 diseases, respiratory distress, emphysema, prevention of reperfusion injury, viral Shepatitis, chronic active hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, amyotrophic lateral sclerosis, aging effects, adult respiratory distress Ssyndrome, central nervous system trauma and stroke, or injury during reperfusion 00 procedures in a perimenopausal, menopausal or postmenopausal woman in need 0 thereof, which comprises orally providing to said woman continuously and 00 uninterruptedly over the treatment period, a daily dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens. (N

7. 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 daily dosage in an amount from about 0.25 to about 0.1 mg conjugated estrogens.

8. 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 daily dosage in an amount from about 0.25 to about 0.1 mg conjugated estrogens.

9. 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 period, a daily dosage in an amount from about 0.25 mg to about 0.1 mg. 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 daily dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens.

11. The method according to any one of claims 1 to 10 wherein the conjugated estrogens are conjugated equine estrogens, USP. Wl.VamaTFIL:SAU Pos\703275XDivisiona7O3275 p 1 4 5 d saim div 182.O8doc 12 00 0

12. The method according to claim 11 wherein the daily dosage of conjugated .C equine estrogens is from about 0.2 mg to about 0.1 mg.

13. The method according to claim 12 wherein the daily dosage of conjugated equine estrogens, USP is about 0.2 mg. O 14. The method according to claim 1 or 2, wherein the conjugated estrogens are Ssynthetic conjugated estrogens, A. (N 00 A pharmaceutical composition for use in treating menopausal or C N postmenopausal disorders, which comprises dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens, and a pharmaceutical carrier.

16. The composition according to claim 15, wherein the conjugated estrogens is conjugated equine estrogens, USP.

17. The composition according to claim 16, wherein the dosage of conjugated equine estrogens is from about 0.2 mg to about 0.1 mg.

18. The composition according to claim 17, wherein the dosage of conjugated equine estrogens, USP is about 0.2 mg.

19. A pharmaceutical dosage unit which comprises conjugated estrogens, a dosage in an amount from about 0.25 mg to about 0.1 mg conjugated estrogens and a pharmaceutical carrier. The dosage unit according to claim 19, wherein the conjugated estrogens are conjugated equine estrogens, USP.

21. The dosage unit according to claim 20, wherein the dosage of conjugated equine estrogens is from about 0.2 mg to about 0.1 mg.

22. The dosage unit according to claim 21, wherein the dosage of conjugated equine estrogens, USP is about 0.2 mg. W.WantaFILE SAU PmsX7O3275TMsionaR7O3275 0 4 5 c lims di 182.08.Wc 13 00

23. A pharmaceutical pack for use in the treatment of menopausal or Spostmenopausal disorders comprising a plurality of pharmaceutical dosage units as Sdefined in any one of claims 19 to 22 for continuous uninterrupted daily administration of a daily dosage.

24. Use of conjugated estrogens in the manufacture of a pharmaceutical composition as defined in any one of claims 15 to 18 or one or more pharmaceutical N dosage units as defined in any one of claims 19 to 22 for the treatment of menopausal Sor post-menopausal disorders. (N 00 Use of conjugated estrogens in the manufacture of a pharmaceutical pack as CtN defined in claim 23 for the treatment of menopausal or post-menopausal disorders.

26. Use of conjugated estrogens according to claim 24 or 25 for the treatment or inhibition of vasomotor symptoms in a perimenopausal, menopausal or postmenopausal woman in need thereof.

27. Use of conjugated estrogens according to claim 26 wherein the vasometer symptom is hot flushes.

28. Use of conjugated estrogens according to claim 24 or 25 for inhibiting or retarding bone demineralization or treating or inhibiting osteoporosis in a perimenopausal, menopausal, or postmenopausal woman in need thereof.

29. Use of conjugated estrogens according to claim 24 or 25 for treating or inhibiting vaginal or vulvar atrophy; atrophic vaginitis; vaginal dryness; pruritus; dyspareunia; dysuria; frequent urination; urinary incontinence; urinary tract infections in a perimenopausal, menopausal or postmenopausal woman in need thereof.

30. Use of conjugated estrogens according to claim 24 or 25 for lowering cholesterol, Lp(a), or LDL levels; inhibiting or treating hypercholesteremia; hyperlidemia; 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. W:MamaFILISSAU PmsI7O3275,isson37O3275 pi 4 5 dMMS dri 1820 doc 14

31. Use of conjugated estrogens according to claim 24 or 25 for treating or Sinhibiting free radical involvement in the development of cancers, central nervous Ssystem disorders, Alzheimer's disease, bone disease, aging, inflammatory disorders, T 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 Ssclerosis, aging effects, adult respiratory distress syndrome, central nervous system trauma and stroke, or injury during reperfusion procedures in a perimenopausal, Smenopausal or postmenopausal woman in need thereof. (N 00 S32. Use of conjugated estrogens according to claim 24 or 25 for treating or C inhibiting dementias, neurodegenerative disorders, and Alzheimer's disease; providing neuroprotection or cognition enhancement in a perimenopausal, menopausal, or postmenopausal woman in need thereof.

33. Use of conjugated estrogens according to claim 24 or 25 for minimizing or reducing levels of breast pain in a woman receiving hormone replacement therapy.

34. Use of conjugated estrogens according to claim 24 or 25 for minimizing spotting or breakthrough bleeding; or achieving amenorrhea in a woman receiving hormone replacement therapy. Use of conjugated estrogens according to claim 24 or 25 for increasing bone mineral density in a perimenopausal, menopausal or postmenopausal woman in need thereof.

36. A method according to any one of claims 1 to 10 substantially as hereinbefore described.

37. A composition according to claim 15 substantially as hereinbefore described.

38. A dosage unit according to claim 19 substantially as hereinbefore described.

39. A pharmaceutical pack according to claim 23 substantially as hereinbefore described. W:4amaFILESIAL Pmsl7O32?50MsionaR703275 pI 45 daims dw 182 08c 0 describEd. 00 00 W:\A.MaV ILE SVWU PrS737\1V~oa73 p 1 4 5 &claims di, 18 2.08 doc 1 6