JP2003501390A - Pharmaceutical formulations for treating postmenopausal and menopausal women, and uses thereof - Google Patents

Abstract

  (57) [Summary] Including various combinations of estrogens, progestins, androgens, selective estrogen receptor modulators, selective androgen receptor modulators, and / or selective progestin receptor modulators for use in treating postmenopausal or menopausal women Pharmaceutical formulations are disclosed. Also disclosed are methods of treating such women using the pharmaceutical formulations of the present invention.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to pharmaceutical formulations and methods for treating post- and post-menopausal women.

BACKGROUND e.g. surgical procedures, post-menopausal women comprising irradiation or young woman chemotherapy has caused ovarian failure by removing the induction, of the invention, certain physiological symptoms disorder associated normal ovarian function Indicates. For example, such women generally experience loss of calcium from the bone, which results in loss of bone density and mass. In addition, elevated cholesterol levels in such women cause atherosclerosis. Other symptoms include depression, headaches, and nausea. Menopausal women experience changes in the menstrual cycle intervals, with other associated symptoms of estrogen deficiency, such as vasomotor excitement, vaginal dryness, or worsening of premenstrual syndrome.

SUMMARY OF THE INVENTION The present invention is directed to women of all ages with premature ovarian failure (eg, surgical procedures,
Provided are pharmaceutical formulations and methods for treating near or postmenopausal women, including young women whose ovarian function has been severed by irradiation or chemotherapy. Exemplary pharmaceutical formulations of the invention include (i) an androgen or a selective androgen receptor modulator (SARM), (ii) an estrogen or a selective estrogen receptor modulator (SERM) in a pharmaceutically acceptable carrier. And (iii) a progestin or a selective progestin receptor modulator (SPRM). The pharmaceutical formulation can be administered to post-menopausal or post-menopausal women in a treatment regimen.

In a related aspect, the invention provides (i) SERMs and (i) in a pharmaceutically acceptable carrier.
ii) It features a pharmaceutical preparation containing androgen or SARM. Also optionally included in the pharmaceutical formulation is (iii) progestin or SPRM. Therapeutically effective dose of SERM
And pharmaceutical formulations containing androgens or SERMs, and optionally progestins or SPRMs can be used to treat post-menopausal and post-menopausal women.

The present invention also includes pharmaceutical formulations comprising (i) SERMs and (ii) estrogens, and optionally (iii) progestins or SPRMs. Such pharmaceutical formulations can contain therapeutically effective amounts of SERMs and estrogens, and optionally progestins, and can be used in methods for treating post- and post-menopausal women.

In another variation of the pharmaceutical formulation described above, the invention provides (i) SERMs, (ii)
Included are pharmaceutical formulations comprising estrogen, and (iii) androgen or SARM, and optionally (iv) progestin or SPRM. SERMs for such pharmaceutical formulations,
Estrogens, androgens, and optionally progestins are included in therapeutically effective amounts, which can be used in the methods of treating post- and post-menopausal women.

Various estrogen, progestin, androgen, SERM, SEAM, and SP
RM can be used in the present invention. Examples of suitable estrogens include complex estrogens, estrogen esters, estradiol valerate, estradiol benzoate, 17-β estradiol, estradiol cypionate, estrone, piperazine estrone sulfate, estriol, ethyl estradiol, polyestradiol phosphate, estrone. Mention may be made of potassium sulphate, benzestrol, chlorotrianisene, metallenestril, dienestrol, diethylstilbestrol diphosphate, mestranol, diethylstilbestrol (DES), quinestranol and phytoestrogens. Animal-derived estrogens (eg, horse estrogens) and their metabolizable derivatives are also suitable for use in the present invention and are commercially available.

Examples of suitable progestins include progesterone, 17-hydroxyprogesterone derivative, 19-nor-testosterone derivative, norethindrone, norethindrone acetate, norethinodrel, norgestrel, norgestimate, ethinodiol diacetate, allylestrenol, rhinoestreon. Nord, wingestanol acetate, medrogeston, norgestrienone, dimethiderome, etisterone, cyproterone levo-norgestrel, dl-norgestrel,
Examples include cyproterone acetate, gestodene, desogestrol, phytoprogestin, daidrogesterone, ethinodiol diacetate, medroxyprogesterone acetate, phytoprogestin, and megestrol acetate. Animal-derived progestins (eg, equine progestins) and their metabolizable derivatives are also suitable for use in the present invention.

Examples of suitable androgens include testosterone, methyltestosterone, fluoxymesterone, testosterone cypionate, testosterone enanthate,
Testosterone propionate, oxymetholone, ethylestrenol, oxandrolone, nandrolone phenpropionate, nandrolone decanoate, stanozolol, dromostanolone propionate, androstenedione,
Dehydropepiandrosterone, dehydroepiandrosterone sulfate (D
HEAS), dihydrotestosterone, and phytoandrogens. Animal-derived androgens (eg, horse androgens) and their metabolizable derivatives are also suitable for use in the present invention.

Examples of suitable SERMs include tamoxifen, raloxifene, clomiphene, droloxifene, idoxifene, toremifene, tribolone, ICI 182,780, ICI.
164,384, diethylstilbestrol, genistein, nafoxidine, moxestrol, 19-nor-progesterone derivatives, and 19-nor-testosterone derivatives.

Examples of suitable SARMs include cyproterone acetate, hydroxyflutamide, bicalutamide, spironolactone, 4- (trifluoromethyl) -2 (1H) -pyrrolidino [3,2-g].
Included are quinolinone derivatives, 1,2-dihydropyridono [5,6-g] quinoline derivatives, and piperidino [3,2-g] quinolinone derivatives.

Examples of suitable SPRMs include RU486, CDB2914, 19-nor-progesterone derivative, 19-
Nor-testosterone derivative, 6-aryl-1,2-dihydro-2,2,4-trimethylquinoline derivative, 5-aryl-1,2-dihydro-5H-chromeno [3,4-f] quinoline derivative, 5-
Included are alkyl 1,2-dihydrocomeno [3,4-f] quinoline derivatives and 6-thiophene hydroquinoline derivatives.

In various preferred embodiments, the pharmaceutical formulations described herein are included in a transdermal patch or intravaginal ring for delivering the pharmaceutical formulation to a woman. Other transdermal routes (eg, by use of topically applied creams, ointments, etc.) and other vaginal routes (eg, suppositories, creams, etc.) can also be utilized in the present invention. Also, the pharmaceutical preparation may be administered by oral route, intranasal route, oral route, intraocular route, intraocular route, injectable supplemental route, subcutaneous route, intraperitoneal route, intrauterine route, sublingual route, or intramuscular route. Can be prepared for administration via If desired, one or more routes of administration may be estrogen, androgen, progestin, SERM, SARM, and / or SPR.
It is available to deliver M to women (eg, oral and transdermal routes). Multiple estrogens, androgens, progestins, SERMs, SARMs, and / or SPRMs, if desired, to prepare a pharmaceutical formulation, or a single estrogen,
It can be used to treat women in place of androgens, progestins, SERMs, SARMs, and / or SPRMs.

“Post-menopausal” women are women who have been amenorrhea for at least 12 months or who have serum follicle stimulating hormone levels above 30 mIU / ml and have not been given hormone replacement therapy or other medication. is there.

“Menopausal” women have altered intervals during the menstrual cycle with associated symptoms of estrogen deficiency, such as vasomotor excitement, vaginal dryness, and exacerbation of premenstrual syndrome, Women who have not received hormone replacement therapy or other medications. Also, no hormone replacement therapy or other medication, at least 12
It also includes women who have been amenorrhea for less than a month.

An “androgen” is a natural or synthetic agent that stimulates the action of male organs of the accessory gonad and / or muscle enhancement and / or stimulatory growth of male characteristics.
Examples of suitable androgens include, but are not limited to, testosterone, methyltestosterone, fluoxymesterone, testosterone cypionate, testosterone enanthate, testosterone propionate, oxymetholone, ethylestrenol, oxandrolone, nandrolone. Phenpropionate,
Nandrolone Decanoate, Testosterone Basylate, Stanozolol, Dromostanolone Propionate, Androstenedione, Dehydropepiandrosterone, DHEAS, Dihydrotestosterone, Phytoandrogens, Animal-induced Androgens, and Animal-induced Androgen Metabolism And a sex derivative.

“Progestin” is a natural or synthetic agent that affects some or all of the physiological changes produced by the progesterone luteinizing hormone. For example, progestins can induce secretory changes in the endometrium. Examples of progestins include, but are not limited to, progesterone, 17-hydroxyprogesterone derivative, 19-nor-testosterone derivative, 19-nor-progesterone derivative, norethindrone, norethindrone acetate, norethinodrel,
Norgestrel, norgestimate, ethinodiol diacetate, allylestrenol, rhinoestrenol, wingestanol acetate, medrogestone, norgestrienone, dimethiderome, etisterone, cyproterone levo-norgestrel, dl-norgestrel, cyproterone acetate, gestodene, desogest Rolls, daidrogesterone, ethinodiol diacetate, medroxyprogesterone acetate, megestrol acetate, phytoprogestin, animal-derived progestins, and animal-derived metabolic derivatives.

“Estrogen” is a natural or synthetic drug that exerts the characteristic physiological effects of estrogenic hormones such as esteradiol. As used herein, the term "estrogen" refers to an amorphous, natural, water-soluble, complexed form of a mixed estrogen (eg, sodium estrone sulfate) normally obtained from the urine of pregnant mares. It also includes the "complexed estrogen" that is the product.
Also included are "estrogen esters," which are mixtures of sulfate esters of the sulfuric acid complex of estrus or sodium salts of glucanolide. Examples of suitable estrogens include, but are not limited to, estradiol valerate, estradiol benzoate, 17-β estradiol, estradiol cypionate, estrone,
Piperazine estrone sulfate, estriol, ethyl estradiol, polyestradiol phosphate, estrone potassium sulfate, benzestrol, chlorotrianisene, metharenestril, dienestrol,
Diethylstilbestrol diphosphate, mestranol, DES, quinestranol, phytoestrogens, animal-derived estrogens (eg, horse estrogens), and metabolic derivatives of animal-derived estrogens.

“Selective estrogen receptor modulators” (SERMs) are compounds of estrogen analogs that exhibit tissue-selective effects. Such compounds can function as estrogen antagonists, or partial agonists.

“Selective androgen receptor modulators” (SARMs) are compounds of androgen analogs that exhibit tissue-selective effects. Such compounds can function as androgen antagonists, or partial agonists.

“Selective progestin receptor modulators” (SPRMs) are compounds of progesterone analogs that exhibit tissue-selective effects. Such compounds can function as progesterone antagonists, or partial agonists.

The present invention offers several advantages. For example, the hormone replacement methods of the present invention can be used to redeposit all gonadal steroids at normal physiological levels for optimal management of symptoms. Other features and advantages of the invention will be apparent from the following detailed description of the preferred embodiments, and from the claims.

Description of the Preferred Embodiments The pharmaceutical formulations and methods of treatment of the present invention are suitable for substantially all post- and post-menopausal women.

Preparation of Pharmaceutical Formulations The pharmaceutical formulations of the present invention comprise a pharmaceutically acceptable carrier and one of the following combinations of active ingredients: (A) (i) androgen or SARM, (ii) ) Estrogen or SERM, and (iii)
Progestin or SPRM; (B) (i) SERM and (ii) Androgen or SARM, and optionally (iii) Progestin or SPRM; (C) (i) SERM and (ii) Estrogen, and optionally (iii) Progestin or SPR
M; or (D) (i) SERM, (ii) estrogen, and (iii) androgen or SAM, and optionally (iv) progestin or SPRM.

[0025] Such formulations are typically about 0.1% to 90% by weight (1% to 20%, or 1%
From 10% to 10%) in a pharmaceutically acceptable carrier.

In a preferred embodiment, the pharmaceutical formulation is prepared for delivery via the intravaginal ring. Intravaginal rings are well known in the art, and such rings can be readily adapted to contain a combination of the active ingredients described above in a pharmaceutically acceptable carrier. Generally, oils or water are used as carriers when preparing pharmaceutical formulations for administration via intravaginal rings.

Examples of suitable intravaginal rings include US Pat. Nos. 4,762,717, 5,130,137, 4,012,496, 3,854,480, 4,391,79, incorporated herein by reference.
7, No. 4,591,496, and No. 5,330,768. A common intravaginal ring that can be adapted for use in the present invention is made from ethyl vinyl acetate. In general, the vaginal ring contains sufficient levels of estrogen or SERM to recreate estrogenic effects equivalent to those appearing in the early follicular phase of the typical normal menstrual cycle. Androgens or SARMs are usually included in the ring at levels sufficient to recreate an effect equivalent to that of androgens that occurs during the early follicular phase of the typical normal physiological cycle. Generally, progestin or SPRM
It is included at a level sufficient to recreate an effect equivalent to the progestin effect that occurs in the luteal phase of the typical normal menstrual cycle. Examples of preferred dosages are given below.

In another preferred embodiment, the pharmaceutical formulation of the present invention is contained in a transdermal patch. Numerous transdermal patches are known in the art and can be readily adapted to contain and deliver the pharmaceutical formulations of the present invention. Examples of suitable transdermal patches are U.S. Pat.Nos. 5,223,261, 3,598,123, incorporated herein by reference.
Nos. 4,460,372, 3,598,122, 4,573,996, and 4,624,665. A typical transdermal patch comprises a flexible backing, a drug-retaining layer, a semipermeable membrane, and an adhesive layer coated on the outer surface of the semipermeable membrane. For example Theratech
Patch technology can be used in the present invention. If desired, the patch may include a skin permeation enhancer (eg, fatty acid esters of fatty acids such as ethyl oleate, glyceryl monolaurate, and / or isopropyl myristate).

In another patch, the pharmaceutical formulation is contained within an adhesive coating rather than a separate drug-retaining layer. Such patches include, for example, a flexible backing (eg, polyethylene, polypropylene, polyurethane, etc.) and a pressure sensitive adhesive coating that is continuously adhered to one surface of the backing. A mixture of acrylic acid polymers containing hydrophobic, monomeric acrylic or methacrylic acid esters of alcohols (containing 4 to 10 carbons), polyanhydrides, polyvinylacetate, polylactide or polyglycolide, ( ii) the active ingredients, each in an amount of about 0.2% to 12% of the total amount of the adhesive coating, and (iii) in an amount of 1% to 20% of the weight of the adhesive coating, respectively, isopropyl myristate and glyceryl monolaurate. A homogeneous mixture of skin permeation enhancers including. These examples are non-limiting and other transdermal patches can be used in connection with the pharmaceutical formulations of the present invention.

Solid formulations for oral administration include corn starch, gelatin, lactose, liposomes, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol,
Suitable carriers or excipients such as dicalcium phosphate, calcium carbonate, sodium chloride, or alginic acid can be included. Disintegrators that can be used include, but are not limited to, microcrystalline cellulose, corn starch, sodium starch glycolate and arginine acid. Tablet binders that can be used include acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropylmethylcellulose, sucrose, starch, and ethylcellulose. Lubricants that can be used include magnesium stearate, stearic acid, silicone fluid, talc, waxes, oils, and colloidal silica.

Liquid formulations for oral or sublingual administration are usually prepared in water or other aqueous vehicle. Liquid formulations also include solutions, emulsions, syrups, and elixirs, which contain active ingredients as well as wetting agents, sweetening agents, and coloring and flavoring agents. Various liquid and powder formulations can be prepared by any convenient method for inhalation by women.

Injectable formulations include vegetable oil, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polylactide, polyglycolide, polyols (glycerol, propylene glycol, liquid polyethylene glycol). Various carriers) can be included. For intravenous infusion, the compound may be administered by infusion,
Thereby, a pharmaceutical formulation comprising the active ingredient and a pharmaceutically acceptable carrier is infused. Pharmaceutically acceptable carriers can include, for example, 5% dextrose, 0.9% saline, Ringer's solution, or other suitable carrier. For intramuscular preparations, sterilized preparations containing the active ingredient are treated with water-for-inje
ction), 0.9% saline, or 5% glucose solution in a pharmaceutical carrier.

Topical semi-solid ointment formulations usually contain active ingredient in a carrier such as a pharmaceutical cream-based agent at a concentration of about 1% to 20% (eg, 5% to 10%). Various formulations for topical use include drops, tinctures, lotions, creams, solutions and ointments containing the active ingredient and various support materials and vehicles.

The pharmaceutical formulations of the present invention can be administered to a female via various combined routes of administration. For example, androgens, estrogens, and progestins can be combined and delivered transdermally (eg, via a transdermal patch). Alternatively, estrogen may be orally administered, while progestin and androgen may be transdermally administered. In yet another preferred method, androgens, estrogens, and progestins are administered orally. Similarly, androgens, estrogens, and progestins can be administered by intravaginal ring. These examples are non-limiting and various combinations of administration routes can be used in the present invention.

Therapeutic Regimens Virtually all post- and post-menopausal women can be treated with the present invention. If desired, determine whether the woman requires hormone replacement therapy before treating the woman with the methods of the invention (e.g., the American College of Physician Guidelines (the
Can be identified (using standard criteria as described by the American College of Physicians Guidelenes) (incorporated herein by reference). A variety of treatment regimens are suitable for use in the present invention, and practitioners of ordinary skill in the art will monitor women for signs and symptoms of hormone deficiency, increasing or decreasing the dose and / or frequency of treatment as desired. By doing so, a specific management method can be easily optimized for a specific woman.

Regardless of the route of administration, androgens are usually administered at 0.01 μg to 5 mg / kg body weight per day (eg, 1 μg / kg to 5 mg / kg) and estrogens are usually at 0.0
Administered at a dose of 1 μg / kg to 4 mg / kg (eg 0.2 μg / kg to 100 μg / kg),
And progestin is usually 0.02 mg / kg to 200 mg / kg (e.g., 2 μg / kg to 10 mg / k
g) is administered. SARMs are usually 0.01 μg / kg to 100 mg / day of body weight
/ kg (eg, 1 μg / kg to 4 mg / kg), and the SERM is usually 0.01
administered at a dose of from 100 μg / kg to 100 μg / kg (eg 1 μg / kg to 2 mg / kg), and
SPRMs are usually administered at a dose of 0.01 μg / kg to 100 mg / kg (eg, 1 μg / kg to 30 mg / kg). If desired, the pharmaceutical formulation can be administered multiple times per day, with the total amount achieving the desired daily dose. In general, women are considered to be treated for months or years, or for life, alleviating the signs and symptoms that result from natural or induced impairment of ovarian function.

In one example of a suitable treatment method, the treatment management method is at least once a day for 13 to 14 days, respectively (i) androgen or SARM, (ii) estrogen or SERM.
And (iii) administering to the woman a pharmaceutical formulation comprising progestin or SPRM,
Subsequent administration of (i) estrogen or SERM and (ii) androgen or SARM, respectively, at least once a day for 13 to 14 days is required. The dosages listed above are suitable.

In another method, a woman is treated with a pharmaceutical formulation comprising (i) SERM, (ii) androgen or SARM, respectively, and optionally (iii) progestin or SPRM. In a general treatment regimen, this pharmaceutical formulation is given to women at least once daily (eg, delivered orally, or transdermally or by replacement) and for at least 30 days at the doses listed above. Is administered. Usually, the woman will be treated for a period of months or years, or for the rest of her life, alleviating the signs and symptoms that result from a natural or induced impairment of ovarian function.

Alternatively, the woman may be treated with a pharmaceutical formulation comprising (i) SERM and (ii) estrogen, respectively, and optionally (iii) progestin or SPRM. In a typical therapeutic regimen, a pharmaceutical (eg, delivered orally or by transdermal or supplemental) formulation is administered at least once daily for at least 30 days at the doses listed above. . Usually, the woman will be treated for a period of months or years, or for the rest of her life, alleviating the signs and symptoms that result from a natural or induced impairment of ovarian function.

In yet another method, it may be treated with a pharmaceutical formulation comprising (i) SERM, (ii) estrogen, (iii) androgen or SARM, respectively, and optionally (iv) progestin or SPRM. In a typical therapeutic regimen, the pharmaceutical formulation is administered at least once a day for at least 30 days at the dosages listed above. Usually, the woman will be treated for a period of months or years, or for the rest of her life, alleviating the signs and symptoms that result from a natural or induced impairment of ovarian function.

In all of the above methods where progestin is administered, it can be administered continuously or periodically (ie, administered only on the days on which the other drug is administered).

Conventional methods known to those skilled in the medical arts can be used to administer the pharmaceutical formulation to the woman. Generally, a pharmaceutical formulation is applied to the female skin with a transdermal patch containing the pharmaceutical formulation, and the patch is left on the skin (typically 1 to 5 hours per patch). Can be administered. In another common method, an intravaginal ring containing the pharmaceutical formulation is inserted into the woman and left in place for 1 to 90 days (eg, 15 to 30 days) per intravaginal ring. Other transdermal and intravaginal routes for administration (eg, topically applied creams, ointments, suppositories, etc.) can be used by applying simple methods. The pharmaceutical formulations can also be administered by other conventional routes by standard methods (eg, oral, subcutaneous, intraperitoneal, intrauterine, sublingual, or intramuscular routes). In addition, is the pharmaceutical formulation injectable by depot for 1, 3, or 6 months?
Alternatively, it can be administered to a woman by an injectable replacement route of administration, such as by using biodegradable materials or methods.

Other Embodiments Although the present invention has been described in connection with its detailed description, the foregoing description is intended to be exemplary and not limiting of the scope of the invention, which is attached. It is defined only by the claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

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Claims (43)

[Claims] 1. In a pharmaceutically acceptable carrier   (i) estrogen or selective estrogen receptor modulator (SERM),   (ii) androgen or selective androgen receptor modulator (SARM), and   (iii) Progestin or selective progestin receptor modulator (SPRM) A pharmaceutical formulation for treating a post-menopausal or post-menopausal woman comprising. 2. A transdermal patch containing the pharmaceutical formulation of claim 1. 3. An intravaginal ring containing the pharmaceutical formulation of claim 1. 4. A depot inj containing a pharmaceutical formulation according to claim 1.
ectable) Vehicle. 5. The estrogen is a complex estrogen, an estrogen ester, estradiol valerate, estradiol benzoate, 17-β estradiol, estradiol cypionate, estrone, piperazine estrone sulfate, estriol, ethyl estradiol, polyestradiol phosphate, estrone. Estron potassium sulfate, benzestrol, chlorotrianisene, metallenestril, dienestrol, diethylstilbestrol diphosphate, mestranol, diethylstilbestrol, quinestranol, phytoestrogen, animal-induced estrogen And the pharmaceutical derivative according to claim 1, which is selected from the group consisting of: and an animal-derived metabolic derivative of estrogen. 6. The androgen is testosterone, methyltestosterone,
Fluoxymesterone, testosterone cypionate, testosterone enanthate, testosterone propionate, oxymetholone, ethylestrenol,
Oxandrolone, Nandrolone phenpropionate, Nandrolone decanoate, Stanozolol, Dromostanolone propionate, Androstenedione, Dehydropepiandrosterone, DHEAS, Dihydrotestosterone, Testosterone buccilate phytoandrogens
enus), an animal-derived androgen, and a metabolic derivative of an animal-induced androgen, The pharmaceutical preparation according to claim 1. 7. The progestin is a progesterone, a 17-hydroxyprogesterone derivative, a 19-nor-testosterone derivative, a 19-nor-progesterone derivative, a norethindrone, a norethindrone acetate, a norethinodrel, a norgestrel, a norgestimate, an ethinodiol diacetate, an allyl estreol. Knoll, lynoestrenol, fuingestanol acetate, medrogeston, norgestrienone, dimethiderome, ethisterone, cyproterone levonorgestrel, dl-norgestrel, cyproterone acetate, gestodene, desogestrol, phyto Progestin, daidrogesterone, ethinodiol diacetate, medroxyprogesterone acetate, megestrol acetate Animals induced progestin, and is selected from the group consisting of metabolic derivatives of animal-induced progestin formulation of claim 1, wherein. 8. SERM is tamoxifen, raloxifene, clomiphene,
Droloxifene, idoxifene, toremifene, tibolone, IC
The pharmaceutical preparation according to claim 1, which is selected from the group consisting of I 182,780, ICI 164,384, diethylstilbestrol, genistein, nafoxidine, moxestrol, 19-nor-progesterone derivatives, and 19-nor-testosterone derivatives. 9. SARM is cyproterone acetate, hydroxyflutamide,
Bicalutamide, spironolactone, 4- (trifluoromethyl) -2 (1H) -pyrrolidino [
2. The pharmaceutical agent according to claim 1, which is selected from the group consisting of a 3,2-g] quinolinone derivative, a 1,2-dihydropyridono [5,6-g] quinoline derivative, and a piperidino [3,2-g] quinolinone derivative. Formulation. 10. SPRM is RU486, CDB2914, 19-nor-progesterone derivative, 19-nor-testosterone derivative, 6-aryl-1,2-dihydro-2,2,4-trimethylquinoline derivative, 5-aryl- 1,2-dihydro-5H-chromeno [3,4-f] quinoline derivative, 5-alkyl 1,2-dihydrochomeno [3,4-f] quinoline derivative,
The pharmaceutical preparation according to claim 1, which is selected from the group consisting of and a 6-thiophene hydroquinoline derivative. 11. A method of hormone replacement for treating post-menopausal or menopausal women, which comprises the step of administering a therapeutically effective amount of the pharmaceutical preparation of claim 1 to post-menopausal or menopausal women. 12. The method of claim 11, further comprising the step of identifying a woman in need of hormone replacement therapy prior to administering the pharmaceutical formulation to the woman. 13. The method of claim 11, wherein the hormone replacement method comprises administering the pharmaceutical formulation to the woman at least once a day for at least 30 days. 14. A method of hormone replacement comprising administering a pharmaceutical formulation to a woman at least once per day for at least 13 days, followed by at least once per day for at least 14 days, comprising (i) estrogen or SERM, and (ii) Androgen or SARM
12. The method of claim 11, comprising the step of administering each of. 15. The method of claim 11, wherein the pharmaceutical formulation is administered to a woman in a depot injectable vehicle. 16. The pharmaceutical preparation is transdermal route, vaginal route, oral route, subcutaneous route, buccal route, depot injectable route, ear route, intraocular route, intranasal route, intraperitoneal route, intrauterine route. 12. The method of claim 11, wherein the method is administered to the female via at least one route selected from the group consisting of the sublingual route, and the intramuscular route. 17. The method of claim 11, wherein the estrogen in the pharmaceutical formulation is administered at a dose of 0.01 μg / kg to 4 mg / kg per day of the female body weight. 18. The method of claim 11, wherein the androgen in the pharmaceutical formulation is administered at a dose of 0.01 μg / kg to 5 mg / kg per day of female body weight. 19. The method according to claim 11, wherein the progestin in the pharmaceutical preparation is administered at a dose of 0.02 μg / kg to 200 mg / kg per day based on the body weight of a woman. 20. The SERM in the pharmaceutical preparation is 0.
The method according to claim 11, which is administered at a dose of 01 μg / kg to 100 mg / kg. 21. The SARM in the pharmaceutical preparation is 0 per day based on the weight of the woman.
The method according to claim 11, which is administered at a dose of 01 μg / kg to 100 mg / kg. 22. The SPRM in a pharmaceutical preparation is 0 per day based on the weight of a woman.
The method according to claim 11, which is administered at a dose of 01 μg / kg to 100 mg / kg. 23. A pharmaceutical formulation for treating post-menopausal or menopausal women comprising (i) SERM and (ii) androgen or SARM in a pharmaceutically acceptable carrier. 24. A transdermal patch containing the pharmaceutical formulation of claim 23. 25. An intravaginal ring comprising the pharmaceutical formulation of claim 23. 26. A depot injectable vehicle comprising the pharmaceutical formulation of claim 23. 27. The pharmaceutical formulation of claim 23, further comprising progestin or SPRM. 28. A method of hormone replacement for treating a post-menopausal or post-menopausal woman, the method comprising administering a therapeutically effective amount of the pharmaceutical preparation of claim 23 to a post-menopausal or post-menopausal woman. How to include. 29. The method of claim 28, wherein the pharmaceutical formulation further comprises a progestin or SPRM. 30. A pharmaceutical formulation for treating post-menopausal or menopausal women comprising (i) SERM, (ii) estrogen, and (iii) androgen or SARM in a pharmaceutically acceptable carrier. 31. A transdermal patch containing the pharmaceutical formulation of claim 30. 32. An intravaginal ring comprising the pharmaceutical formulation of claim 30. 33. A depot injectable vehicle comprising the pharmaceutical formulation of claim 30. 34. The pharmaceutical formulation of claim 30, further comprising progestin or SPRM. 35. A method of hormone replacement for treating a post-menopausal or post-menopausal woman, the method comprising the step of administering a therapeutically effective amount of the pharmaceutical preparation of claim 30 to a post-menopausal or post-menopausal woman. How to include. 36. The method of claim 35, wherein the pharmaceutical formulation further comprises a therapeutically effective amount of progestin or SPRM. 37. A pharmaceutical formulation for the treatment of post-menopausal or menopausal women comprising SERM and estrogen in a pharmaceutically acceptable carrier. 38. A transdermal patch containing the pharmaceutical formulation of claim 37. 39. An intravaginal ring comprising the pharmaceutical formulation of claim 37. 40. The pharmaceutical formulation of claim 37, further comprising progestin or SPRM. 41. A depot injectable vehicle comprising the pharmaceutical formulation of claim 37. 42. A hormone replacement method for treating a post-menopausal or post-menopausal woman, the method comprising administering a therapeutically effective amount of the pharmaceutical preparation of claim 37 to a post-menopausal or post-menopausal woman. How to include. 43. The method of claim 42, wherein the pharmaceutical formulation further comprises a progestin or SPRM.