WO1998016232A1 - Use of 8,9-dehydroestrone for the manufacture of a medicament for the treatment of vasomotor symptoms - Google Patents

Use of 8,9-dehydroestrone for the manufacture of a medicament for the treatment of vasomotor symptoms

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Publication number
WO1998016232A1
WO1998016232A1 PCT/US1997/018545 US9718545W WO9816232A1 WO 1998016232 A1 WO1998016232 A1 WO 1998016232A1 US 9718545 W US9718545 W US 9718545W WO 9816232 A1 WO9816232 A1 WO 9816232A1
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WO
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Application
Patent type
Prior art keywords
salt
pharmaceutically acceptable
dehydroestrone
carbon atoms
acceptable salt
Prior art date
Application number
PCT/US1997/018545
Other languages
French (fr)
Inventor
Cecil Richard Lyttle
Original Assignee
American Home Products Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone

Abstract

This invention provides a method of treating vasomotor symptoms in a mammal in need thereof which comprises administering 8,9-dehydroesterone or a pharmaceutically acceptable salt of its 3-sulfate ester.

Description

USE OF 8,9-DEHYDROESTRONE FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF VASOMOTOR SYMPTOMS

5 BACKGROUND OF THE INVENTION

The use of naturally occurring estrogenic compositions of substantial purity and low toxicity such as PREMARIN (conjugated equine estrogens) has become a preferred medical treatment for alleviating the symptoms of menopausal syndrome,

10 osteoporosis/osteopenia in estrogen deficient women and in other hormone related disorders. The estrogenic components of the naturally occurring estrogenic compositions have been generally identified as sulfate esters of estrone, equilin, equilenin, 17-β-estradiol, dihydroequilenin and 17-β-dihydroequilenin (U.S. Patent 2,834,712). The estrogenic compositions are usually buffered or stabilized with

15 alkali metal salts of organic or inorganic acids at a substantially neutral pH of about 6.5 to 7.5. Urea has also been used as a stabilizer (U.S. 3,608,077). The incorporation of antioxidants to stabilize synthetic conjugated estrogens and the failure of pH control with tris(hydroxymethyl)aminomethane (TRIS) to prevent hydrolysis is discussed in U.S. 4,154,820.

20 8,9-Dehydroestrone is a known compound useful as an intermediate in the synthetic production of estrone by isomerization to 9,11 unsaturation (U.S. Patent 3,394,153) and as an intermediate in the production of 3-cyclopentyloxy-17-ethynyl derivatives of the hormone (U.S. Patent 3,649,621). In addition, 8,9- dehydroestrone is known to possess estrogenic activity and to lower blood lipid

25 levels (U.S. Patent 3,391,169). The alkali metal salts of 8,9-dehydroestrone, 8,9- dehydroestrone-3- sulfate ester and its alkali metal salts, and their use in estrogen replacement therapy, atherosclerosis, and senile osteoporosis are disclosed in U.S . Patents 5,210,081 and 5,288,717.

30 Menopause is defined as the physiologic cessation of menses as a result of decreasing ovarian function. Natural menopause occurs at an average age of 50-51 yr. As ovaries age, response to pituitary-produced gonadotropins (FSH and LH) decreases, initially with shorter follicular phases, fewer ovulations, decreased progesterone production, and more cyclic irregularity. Eventually, the follicle fails

35 to respond and, without feed back of estrogen, the circulating gonadotropins rise substantially. Circulating levels of estrogens are markedly reduced. Premature menopause refers to ovarian failure of unknown cause that occurs before age 40. Smoking is associated with early menopause. Radiation exposure, chemotherapeutic drugs and surgery that impairs ovarian blood flow can also hasten menopause. Artificial menopause follows ovariectomy or radiation of the pelvis, including the ovaries. Menopausal women may be asymptomatic, or they may have severe symptoms. Hot flushes and sweating secondary to vasomotor instability affect 75% of menopasual women. Psychological and emotional symptoms of fatigue, irritability, insomnia, and nervousness may be related to estrogen deprivation. Intermittent dizziness, parathesias, and cardiac symptoms of palpitations and tachycardia may occur. The incidence of heart disease increases. Dyspareunia, increasing pelvic relaxation, urinary incontinence, cystitis, and vaginitis often occur. Nausea, flatulence, constipation, diarrhea, arthralgia, and myalgia are also reported. Osteoporosis is also a major health hazard related to menopause related estrogen deficiency. [The Merck Manual, 16th ed. 1793 (1992)].

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a method of treating or inhibiting vasomotor symptoms in a mammal in need thereof, which comprises administering a low dose of 8,9-dehydroestrone or a pharmaceutically acceptable salt of its 3-sulfate ester.

Typically, the 8,9-dehydroestrone or a pharmaceutically acceptable salt of its 3- sulfate ester will be administered to a female with an estrogenic deficiency. Such deficiencies are typically caused by the female being either naturally menopausal or artificially menopausal. Natural menopause includes the climacteric stage in which the woman is still pre-menopausal, around 40 years of age, and whose hormone levels are waning. The climacteric woman still ovulates (albeit may have irregular ovulation), but she still experiences many of the symptoms of the hypoestrogenic menopausal woman, such as insomnia, hot flushes, and irritability. Natural menopausal also includes women actively going through menopause, as well as post-menopausal women. Artificial menopause follows ovariectomy or radiation of the pelvis, including the ovaries. In particular, this invention is useful in treating or inhibiting vasomotor symptoms, which include hot flushes, sleep interruptions, and insomnia. In an average female, preferred low doses of 8,9-dehydroestrone are 0.01 mg/day to 0.1 mg/day and more preferred doses are 0.03 mg/day to 0.1 mg/day. As used in accordance with this invention, treating covers treatment of an existing condition, ameliorating the condition, or providing palliation of the condition and inhibiting includes inhibiting or preventing the progress or development of the condition.

Pharmaceutically acceptable salts of 8,9-dehydroestrone 3-sulfate ester include, but are not limited to, the alkali metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group. It is preferred that the sodium is the salt of the 3- sulfate ester.

8,9-Dehydroestrone or a pharmaceutically acceptable salt of its 3-sulfate ester can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. The pharmaceutical carrier may be solid or liquid.

A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. 8,9-Dehydro- estrone or a pharmaceutically acceptable salt of its 3-sulfate ester can also be administered orally either in liquid or solid composition form.

8,9-Dehydroestrone or a pharmaceutically acceptable salt of its 3-sulfate ester may be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the 8,9- dehydroestrone or a pharmaceutically acceptable salt of its 3-sulfate ester may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. 8,9-Dehydroestrone or a pharmaceutically acceptable salt of its 3-sulfate ester may also be administered transdermally 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-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 semipermiable 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. In addition, 8,9-dehydroestrone or a pharmaceutically acceptable salt of its 3- sulfate ester may be employed as a solution, cream, or lotion by formulation with pharmaceutically acceptable vehicles containing 0.1 - 5 percent, preferably 2%, of active compound.

Preferably, the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

Claims

WHAT IS CLAIMED IS:
1. A method of treating or inhibiting vasomotor symptoms in a mammal in need thereof which comprises administering to said nτammal 0.001 - 0.1 mg day of 8,9- dehydroestrone or a pharmaceutically acceptable salt of its 3-sulfate ester.
2. The method according to claim 1, wherein the pharmaceutically acceptable salt of the 3-sulfate ester is an alkali metal salt, alkaline earth metal salt, ammonium salt, alkylammonium salt containing 1-6 carbon atoms, or dialkylammonium salt containing 1-6 carbon atoms in each alkyl group, or trialkylammonium salt containing 1-6 carbon atoms in each alkyl group.
3. The method according to claim 2, wherein the pharmaceutically acceptable salt is sodium.
4. The method according to claim 3, wherein the compound administered is 8,9- dehydroestrone-3-sulfate sodium salt.
5. The method according to claim 1, wherein the vasomotor symptom is hot flushes.
6. The method according to any of claims 1 to 4, wherein the vasomotor symptoms are sleep interruptions or insomnia.
7. Use of 8,9-dehydroestrone or a pharmaceutically acceptable salt of its 3-sulfate ester for the preparation of a medicament for administering 0.001 - 0.1 mg/day to a mammal for the treatment or inhibition of vasomotor symptoms in a mammal in need thereof.
8. Use according to claim 7, wherein the pharmaceutically acceptable salt of the 3- sulfate ester is an alkali metal salt, alkaline earth metal salt, ammonium salt, alkylammonium salt containing 1-6 carbon atoms, or dialkylammonium salt containing 1-6 carbon atoms in each alkyl group, or trialkylammonium salt containing 1-6 carbon atoms in each alkyl group.
9. Use according to claim 8, wherein the pharmaceutically acceptable salt is sodium.
10. Use according to claim 9, wherein the compound administered is 8,9-dehydro- estrone-3-sulfate sodium salt.
11. Use according to any preceding claim wherein the vasomotor symptom is hot flushes.
12. Use according to any of claims 7 to 10, wherein the vasomotor symptoms are sleep interruptions or insomnia.
PCT/US1997/018545 1996-10-16 1997-10-15 Use of 8,9-dehydroestrone for the manufacture of a medicament for the treatment of vasomotor symptoms WO1998016232A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US73305196 true 1996-10-16 1996-10-16
US08/733,051 1996-10-16

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
AU4756697A AU4756697A (en) 1996-10-16 1997-10-15 Use of 8,9-dehydroestrone for the manufacture of a medicament for the treatment of vasomotor symptoms

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WO1998016232A1 true true WO1998016232A1 (en) 1998-04-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1494679A1 (en) * 2002-04-03 2005-01-12 Barr Laboratories, Inc. Step-down estrogen therapy

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5210081A (en) * 1992-02-26 1993-05-11 American Home Products Corporation Alkali metal 8,9-dehydroestrone sulfate esters

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5210081A (en) * 1992-02-26 1993-05-11 American Home Products Corporation Alkali metal 8,9-dehydroestrone sulfate esters
US5288717A (en) * 1992-02-26 1994-02-22 American Home Products Corporation Alkali metal 8,9-dehydroestrone sulfate esters

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BERKOW R. ET AL.: "THE MERCK MANUAL OF DIAGNOSIS AND THERAPY", 1992, MERCK RESEARCH LABORATORIES, USA, XP002051988 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1494679A1 (en) * 2002-04-03 2005-01-12 Barr Laboratories, Inc. Step-down estrogen therapy
EP1494679A4 (en) * 2002-04-03 2009-10-28 Barr Lab Inc Step-down estrogen therapy

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