CN1739527A - The use of non-oral androgenic steroids in the manufacture of medicine for improving elevated sex hormone binding globulin levels - Google Patents

Abstract

The present invention provides compositions, methods, and kits for improving health in a woman having elevated sex hormone binding globulin (SHBG) levels, or who is receiving oral estrogen supplementation, by non-orally administering an effective amount of an androgenic steroid. Further, the present invention provides compositions, methods and kits for coadministering an effective amount of an orally administered estrogen and an effective amount of a non-orally administered androgenic steroid for women in need of estrogen supplementation.

Description

Non-oral androgenic steroids is used to prepare the medicine that improves the sex hormone binding globulin levels rising

The application is to be on June 9th, 2000 applying date, and application number is 00811164.2, and the invention exercise question is divided an application for " non-oral androgenic steroids is used to prepare the medicine that improves the sex hormone binding globulin levels rising ".

Related application

The application requires the priority of following U.S. Provisional Patent Application: 60/138,851; 60/138,854 and 60/139,323, they are all submitted on June 11st, 1999.Each application is hereby incorporated by.

Invention field

The present invention relates generally to the administration of androgen to the women.Therefore, the present invention covers pharmacy science and medical domain.

Background of invention

The sensation of promotion Sexual health of the androgen of functional level and sexual life, health, maximization muscle quality and function and the loss of inhibition bone in known women's body.In addition, the androgen of functional level can promote cardiovascular and coronary artery health, reduces breast tenderness, reduces vasomotor instability, regulates immunologic function, strengthens some cognitive competence, improves apparatus urogenitalis health, reduce estrogen and replenish relevant side effect and direct neuroprotective effect is provided.

Functional level androgen in the human female can be subjected to the serum-concentration influence of sex hormone binding globulin (SHBG) as reaching of testosterone.SHBG is the protein that is produced by liver, and its associativity hormone is as testosterone in the blood and estradiol.The bonded gonadal hormone of SHBG-generally is " not function ", promptly can not the sex hormone receptor in target tissue on performance biological agent and/or from blood, remove away.

The use of oral estrogen improves the serum levels of SHBG.The SHBG level also raises under various conditions, as hyperthyroidism and gestation with because some other medicines, as anticonvulsant.The SHBG level that raises has changed the level of androgen and need reach the dosage of functional level.

The invention provides method, compositions and test kit so that the women that the SHBG level raises reach the functional level of androgenic steroids and therefore improve their health.

Summary of the invention

Therefore, the invention provides and be used to improve sex hormone binding globulin (SHBG) level and raise, or the method and the test kit of the women's that significantly raises health.In addition, the invention provides and be used to improve method and the test kit of accepting the WomanHealth that oral estrogen replenishes.In addition, the invention provides and be used to improve method and the test kit that needs the WomanHealth that oral estrogen replenishes.

In one aspect, such method is included under the situation of the SHBG level that raises or significantly raise, with the non-orally give androgenic steroids of q.s so that therapeutic effect to be provided.On the other hand, such method is included under the situation of oral estrogen administration, with the non-orally give androgenic steroids of q.s so that therapeutic effect to be provided.On the other hand, such method comprises the androgenic steroids that gives effective dose oral estrogen and the non-orally give of effective dose altogether, and it is enough to provide therapeutic effect under the situation of oral estrogen administration.

The example of the concrete androgenic steroids that can adopt comprises, but be not limited to: testosterone, methyltestosterone, ANDROSTENEDIONE, Adrenalone, dehydroepiandrosterone, oxymetholone, Fluoxymesterone, metandienone, testolactone, pregnenolone, 17 α-methylestrenolone, second promise ketone, dihydrotestosterone, danazol, oxymetholone, androsterone, nandrolone, stanozolol, ethylestrenol, oxandrolone, 7 α, 17-clausterone and mesterolone, Testosterone Propionate, depo-testosterone, testosteroni phenylacetas, testosterone enanthatas, aceto-sterandryl, testosterone 4-n-butyl cyclohexane carboxylic acid, testosterone enanthatas, testosterone decanoate (testosteronedecanoate), testosterone decanoate (testeosterone caprate), isodecyl acid testosterone, its isomer and derivant, and compositions.

The androgenic steroids amount that can will give according to several different parameter measurements.In one aspect, the androgenic steroids amount that gives can be the amount that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the total testosterone levels of serum of the about 1000ng/dl of about 15-.In another aspect of the present invention, the androgenic steroids amount that gives can be the amount that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the free serum testosterone levels of the about 30pg/ml of about 0.5-.In another aspect of the present invention, the androgenic steroids amount that gives can be the amount that enough reaches therapeutic effect, and the biology that this therapeutic effect is equivalent to the about 70ng/dl of about 1-can utilize level of serum testosterone.In another aspect of the present invention, the androgenic steroids amount that gives can be the amount that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the testosterone dosage at least about 50mcg/ days.

The concrete estrogen example that can use in the methods of the invention includes, but are not limited to: 17 beta estradiols, 17 alpha-estradiols, PREMAIN, esterified estriol, micronize estradiol, estrogen sodium sulfate, ethinyl estradiol, estrone, 7-tibolone, selective estrogen receptor modulators (SERM ' s), phytoestrogen, its isomer and derivant and compositions thereof.In one aspect of the invention, the amount of estrogen that gives can be the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the about 3.0mg/ of about 0.2-days PREMAIN dosage.

The various forms of the non-orally give of androgen that can adopt according to the inventive method includes, but are not limited to: topical or parenteral or its combination.In one aspect, the form of topical include, but not limited to percutaneous, through mucous membrane or Sublingual or its combination.On the other hand, the form of parenteral includes, but not limited to intramuscular injection or subcutaneous implantation or its combination.

When needing, progestogen can give together with androgenic steroids and estrogen.In one aspect, during the oral estrogen administration, the progestogen administration can be the amount that endometrium safety enough is provided.On the other hand, the progestogen administration can be the amount that effective contraception enough is provided.

The effect that method of the present invention produces has many indications that improve about health.Particularly, but be not limited to the recovery of following feature, strengthen, improve and prevent: libido, the sexual life frequency, stimulation to the sexual organ, reach orgastic ability, the pleasant sensation of sexual life, vitality, healthy sensation, the emotion of Mental Health and sensation, shy, cognitive competence, muscle quality and function, health constitutes, bone mineral density, skin and hair situation, pubes, urogenital atrophy, vagina drying, sears optical, the health that autoimmune is regulated, vasomotor instability, breast tenderness, syndromic symptom before the menopause, with its combination.

The accompanying drawing summary

During Fig. 1 was illustrated in and gives percutaneous testosterone patch (300mcg/ days specified conveyings) to the patient who accepts percutaneous estradiol or oral conjugated premarin simultaneously, total testosterone levels was to the variation of baseline SHBG level.

During Fig. 2 was illustrated in and gives percutaneous testosterone patch (300mcg/ days specified conveyings) to the patient who accepts percutaneous estradiol or oral conjugated premarin simultaneously, free testosterone level was to the variation of baseline SHBG level.

Describe in detail

A. definition

Describing and requiring to use following term in the process of the present invention.

This paper unless otherwise indicated, singulative (English " a " " an " " the ", Chinese does not translate) comprises the indicant of plural number. Therefore, for example, " through the skin patch " comprises one or more such through the skin patch, and " estrogen " comprises the estrogen that one or more are such.

" sex hormone " expression can affect growth or the function of reproductive organs, or any hormone of the growth of secondary sex characters. In one aspect, sex hormone includes, but not limited to androgen, estrogen, progestational hormone and other hormone known in the art.

Natural or the anabolic steroids of " androgenic steroids " or " androgen " expression, they are mainly by bringing into play their biology or drug effect in conjunction with androgen receptor. Example comprises, but be not limited to: testosterone, methyltestosterone, androstenedione, adrenalone, dehydrobenzene, Oxymetholone, methyl fluoride cortisol, Dianabol, Testolactone, pregnenolone, 17 α-Methylestrenolone*, second promise ketone, dihydrotestosterone, DANAZOL, androsterone, nandrolone, Stanozolol, Ethylestrenol, oxandrolone, 7 α, 17-clausterone, mesterolone, testosterone propionate, depo-testosterone, testosterone phenylacetate, testosterone enanthatas, aceto-sterandryl, testosterone 4-n-butyl cyclohexane carboxylic acid, testosterone enanthatas, testosterone decanoate, testosterone decanoate, isodecyl acid testosterone and ester, derivative, prodrug and isomers.

(17 β)-17-hydroxyl androstane-4-alkene-3-ketone that " testosterone " expression has the IUPAC title, and Δ⁴The compound of-androstene-17 β-alcohol-3-ketone, and their isomers. Testosterone is included in the Merck index, enter to hide numbers 9322, the 12nd edition 1569 pages (1996).

Natural or the synthetic any material of " estrogen " and " female hormone " expression, they mainly bring into play their biology or drug effect by the CE acceptor. Example includes, but are not limited to: 17 beta estradiols, 17 alpha-estradiols, estriol, oestrone and phytoestrogen. These estrogen can derive or modification to form, for example, PREMAIN, esterified estriol, ethinyl estradiol etc. The example of esterified estriol includes, but are not limited to: estradiol-3,17-diacetate esters, estradiol-3-acetic acid esters, estradiol-17-acetic acid esters, estradiol-3,17-two valerates, estradiol-3-valerate, estradiol l7-valerate. Also comprise SERM (SERMS), for example, Raloxifene can be from Eli Lilly with trade name Evista^Buy, etc. Estrogen also can exist with the form of salt, (such as estrogen sodium sulphate), isomers or prodrug.

Also comprise phytoestrogen, they are the estrogen of plant derivation. Isoflavones is a kind of main plant estrogen form and has common diphenol structure that it is similar to potential synthetic estrogen, such as the structure of diethylstilbestrol and hexestrol. The main isoflavones of finding in the human body includes, but not limited to genistein, dyad zeatin (diadzein) and equol.

" oral estrogen " expression is suitable for any estrogen of oral administered dosage form.PREMAIN, esterified estriol and micronize estradiol are the examples of oral estrogen.Commercially available oral estrogen product comprises from the Wyeth-Ayerst laboratory with trade name Premarin ^The PREMAIN of buying, from the Solvay pharmacy with trade name Estratab ^The esterified estriol of buying and from BristolMeyers Squibb with trade name Estrace ^The micronize 17-β estradiol of buying.

Any natural or synthetic of " progesterone " or " progestogen " expression, they mainly bring into play their biology or drug effect by the progestagen receptor.Example includes, but are not limited to: progesterone, medroxyprogesterone acetas, norethindrone and norethisterone acetate and ester, derivant, prodrug and isomer.Give progestogen to reach various effects to the women.Non-limitative example is included in and gives simultaneously during the estrogen, endometrium safety is provided and effective contraception is provided.Although for each women, the progestogen amount that requires to reach such effect can change, be used for determining to reach the progestogen appropriate amount of required purpose or effect or the method for effective dose, and be known to those skilled in the art.

" sex hormone binding globulin " or " SHBG ', be also referred to as sex hormone binding protein matter (SHBP) and testosterone EBG (TeBG), the expression with various gonadal hormone have the serum albumin of high-affinity (to see Table 1; From Dunn etc., the conveying of steroid hormone: 21 kinds of endogenous steroid are to the combination of testosterone-haptoglobin and corticosteroid-haptoglobin, clinical endocrine and metabolism magazine, 53 volumes: 58-67 (1981)) in the human plasma.The representative binding affinity constant (K value) of concrete hormone and SHBG sees the following form 1.(selecting from Dunn etc., 1981).

Table 1

Gonadal hormone K (10 ⁶ Liter/mole)

Androstanediol 1300

Androstenediol 1500

ANDROSTENEDIONE 29

Androsterone 14

Dehydroepiandrosterone 66

Dihydrotestosterone 5500

Estradiol 680

Estriol 4.3

Estrone 150

Progesterone 8.8

17-OH progesterone 9.9

Testosterone 1600

In order to reach the object of the invention, surpass about 1 * 10 ⁶The SHBG binding affinity constant of liter/mole is represented the high affinity combination.

The structure of SHBG and possible function have been described and had characterized.Referring to, for example, Rosner etc., the steroid hormone signal conduction at sex hormone binding globulin mediation plasma membrane place, J.SteroidBiochem.Mol.Biol.69 volume: 481-5 (1999); Petra, P.H. blood plasma sex steroid conjugated protein (SBP or SHBG).Key to the latest developments of structure, molecular biology and function is looked back, J.Steroid Biochem.Mol.Biol.40 volume: 735-53 (1991).Having made ins all sorts of ways measures the concentration of serum SHBG, comprises the charcoal and the radioimmunoassay of ammonium sulfate precipitation, gel filtration, equilibrium dialysis, glucosan bag quilt.Referring to, for example, Khan etc.; The radioimmunoassay that is used for human body testosterone-estradiol-haptoglobin, " clinical endocrine and metabolism magazine ", 54 volumes: 705-710 (1982)).Use effective monoclonal immunity-radiometric determination " endocrine science ", Calabassas Hills, CA), in the human female, average serum SHBG level is the 84nmole/ liter before the menopause of health in discovery, be the 36-185nmole/ liter normal range.Known in following human female level of SHBG raise: with oral estrogen, the women who contains estrogenic oral contraceptive, clomifene, tamoxifen, raloxifene, phenytoin and sodium valproate in treating and gestation, hyperthyroid, as the to suffer from chronic hepatopathy women who infects with HIV.Referring to, for example, Bond etc., the sex hormone binding globulin in the clinical observation, " Scandinavia department of obstetrics and gynecology journal " (Acta.Obstet.Gynecol.Scand.), 66 the volume: 255-262 (1987); Miller etc., acquired immune deficiency syndrome (AIDS) consumes women's percutaneous providing testosterone: exploratory development, " clinical endocrine and metabolism magazine ", 83 volume: 2717-2725 (1998).

The mode of main body is given medicine in " administration " and " giving " expression.Can finish administration by various paths well known in the art, as oral and non-oral methods.

" oral administration " can reach by swallowing, chew or suck the peroral dosage form that comprises medicine." non-oral administration " represents any medication, and wherein pharmaceutical composition is not to provide with solid or liquid oral dosage form, and wherein such solid or liquid oral dosage form are generally used for basic gastrointestinal tract release and/or conveying medicine after mouth and/or oral cavity.Such solid dosage forms comprises conventional tablet, capsule, Caplet (caplet) etc., and they do not discharge medicine substantially in mouth or in the oral cavity.

Think that during swallowing these preparations, many peroral dosage forms such as solution, suspension, emulsion etc. and some oral dosage forms can discharge some medicines in mouth or in the oral cavity.Yet because they are very short by the time in mouth or oral cavity, in mouth or in the oral cavity, medicine can be thought minimum or inadequate from the release of these preparations.Therefore, buccal bioadhesive tablet, binder film, sublingual lozenge and the lozenge that is designed in mouth discharging medicine is to be used for non-oral composition of the present invention.

Therefore, term " non-oral " comprises parenteral, partial, suction, implantation, occular, nasal cavity and vagina or rectal formulation and administration.In addition, no matter the physical location of implanting, implantation preparation is included in the term " non-oral ".

" parenteral " administration can by with in intravenous, intra-arterial, intramuscular, the sheath or mode injectable pharmaceutical compositions such as subcutaneous reach.

The such compositions of " topical formulations " expression, its Chinese medicine can directly be coated onto on the skin surface and therefrom discharge the medicine of effective dose.The example of topical formulations includes, but not limited to ointment, emulsifiable paste, gel, percutaneous patch, spray, pessary and paste.The approach of " percutaneous " expression administration, it transmits medicine by skin surface, wherein transdermal composition is given on the skin surface.

Percutaneous dosing can by be coated with, smear, roll extrusion, paste, pour into, extrude, mode such as friction, percutaneous preparation be given on the skin surface and realize.These and other medication is being known in the art.

The conveying device of " transdermal delivery system ", " percutaneous patch " or simple " patch " expression substrate or liquid container type, it was used in the concrete application time, and percutaneous is carried the material of determining dosage.

An example that is used to give the percutaneous patch of androgenic steroids according to the present invention is a matrix type patch preparations, it comprises closed backing, it is impermeable and the face of definite patch or end face for androgenic steroids, with solid or semisolid matrix layer, it is by hormone, and the homogeneous mixture of polymer pressure-sensitive adhesion agent carrier and non-essential one or more skin penetration enhancers is formed.Matrix patch is known in the impart transdermal drug delivery field.The non-limitative example of adhesive stroma percutaneous patch is at United States Patent (USP) 5,122, describes in 383 and 5,460,820 or those of reference, and these two pieces of patents are incorporated herein by reference in full at this.

Another example that is used to give the percutaneous patch of androgenic steroids according to the present invention is liquid storehouse system (LRS) type patch, and it comprises other the non-essential component in androgen and the vehicle excipients, as penetration enhancers.Vehicle excipients comprises the fluid with required viscosity, as gel or ointment, preparing them makes and is confined to following storehouse: contain the storehouse of impermeable backing and the permeable membrane that contacts skin, or the film adhesive laminated material of disperse contact is provided between storehouse content and skin.During application, remove release liner and patch is attached on the skin surface.The LRS patch is known in the impart transdermal drug delivery field.The non-limitative example of LRS percutaneous patch is at United States Patent (USP) 4,849, describes in 224 and 4,983,395 or those of reference, and these two pieces of patents are incorporated herein by reference in full at this.

" skin ", " skin surface ", " corium ", " epidermis " is used interchangeably at this with similar term, not merely represents patient's the body surface that comprises the epidermis part, and also expression can give the mucomembranous surface of pharmaceutical composition.The example of mucomembranous surface comprises the mucosa and the rectum surface of respiratory system (comprising nasal cavity and lung), oral cavity (mouth and buccal), vagina, inlet, lip.Also comprise " through mucous membrane " at this term " percutaneous ".

" administration altogether " represented to give the administration of body one by one with a plurality of materials with similar term, administration simultaneously or sequential administration.Therefore, for estrogen and androgen, this term comprises that the women accepts any situation of oral estrogen and non-oral androgenic.This term does not represent that estrogen and androgen must give simultaneously.But as long as the women accepts oral estrogen, the administration of non-oral androgenic is just in the range of definition of the present invention for " administration altogether ".Being to be understood that does not need estrogen to be provided with single product with androgen or carry out " administration altogether " by identical approach.

Terms " formulation " and " compositions " are used interchangeably at this.Term " pharmacy " and " medicine " also exchange and use with expression pharmaceutically active substance or compositions.These technical terms are known in pharmacy and medical domain.

" total serum level ", " total blood level " and " endogenous serum levels " expression androgen or estrogenic total serum level comprise all protein bound and free androgen or estrogen.Some protein such as albumin make that in conjunction with androgen or estrogen these gonadal hormone are functional (biological available) (promptly producing their biological agents known or that wish) with low-affinity.In contrast, some protein make them become non-functional with high affinity in conjunction with androgen or estrogen as SHBG.Those skilled in the art will know that how to measure and characterize these bond types.Referring to, Dunn etc. for example.

Therefore, term " total testosterone serum levels " is expressed as follows: (1) free testosterone; (2) be attached to the testosterone on the serum albumin a little less than, as the testosterone of albumin bound; (3) strong bonded to high affinity in conjunction with the testosterone on the serum albumin, as the bonded testosterone of SHBG.

Term " protein bound " comprises all types of protein conjugates.

The total serum testosterone can be by known determination techniques, and (RIA) measures as radioimmunoassay.Referring to, for example by endocrine science and technology company (Calabassas Hills, CA) the RIA method of Shi Yonging.The method is used for the radioimmunoassay of plasma testosterone, steroid 1970 based on the RIA of publication such as Furuyama; 16:415-428.Adopt this assay method, be reported as 14-54.3ng/dL (Miller etc., 1998) normal range of the total serum testosterone levels of before the menopause of health, measuring among the women by endocrine science and technology company.

" endogenous free testosterone level " or " physiological free testosterone level " should represent free testosterone (FT) serum levels, it is normally found in such adult women: they do not have testosterone to lack and/or the excessive symptom of testosterone, and/or the unbalanced symptom of estrogen/androgen.

" biological available ", " the serum biology is available ' represent not to be attached to androgen or estrogen on the SHBG with similar term.Therefore, it is biological available " dissociating " that androgen on (unconjugated) androgen or " a little less than be attached to " (division easily) serum albumin is considered to tissue.Owing to the high binding ability (degree of unsaturation) of albumin for testosterone, the serum-concentration of the testosterone of albumin bound, general, proportional with the concentration of free testosterone.Scale factor is corresponding to albumin-testosterone binding constant (3.6 * 10 ⁴L/mole) and the product of seralbumin concentration (rising expression) with mole/.Referring to, Vermeulen etc., to the key evaluation of the simple forecast method of free testosterone in the serum, clinical endocrine and metabolism magazine, 84 volume: 3666-3672 (1999).Because seralbumin concentration remains in the narrow relatively scope (as 4-5g/dL; 5.8 * 10 ^-4-7.6 * 10 ^-4The mole/ liter), this scale factor is about 22.Because this relation, biology can utilize the concentration of testosterone can be approximately 23 times of free testosterone concentration and the concentration of total testosterone and SHBG has nothing to do.

Usually adopt the ammonium sulfate precipitation method to measure the biological concentration that can utilize testosterone.Referring to, for example, Nankin etc., testosterone, LH, estrone, the tiring in the daytime of estradiol and testosterone-binding protein matter: LH and discharge the acute effect of LH hormone, clinical endocrine and metabolism magazine, 41 volume: 271-81 (1975) in the males.Use the method, the biology of being measured among the women before the menopause of health by endocrine science and technology company can utilize be reported as 1.6-12.7ng/dL the normal range of testosterone levels, or about 2-13ng/dL.

" free ", any protein represented not to be connected in " unconjugated " or similar term, as androgen on SHBG or the albumin or estrogen.Therefore, think to be not " free " by the androgen of protein bound or estrogen.

By non-limitative example, term is as " free testosterone ", " not in conjunction with testosterone ", in " free serum testosterone " expression serum not by the testosterone of protein bound.Can comprise equilibrium dialysis, ultrafiltration, similar RIA method measurement free serum testosterone levels by various laboratory methods, and from total testosterone, SHBG and albuminous level calculation free serum testosterone levels.Referring to, for example, Winters etc., similar free testosterone is measured: whether be clinically to male's useful results, clinical chemistry, 44 volume: 2178-2182 (1998); Also referring to, Vermeulen etc., (1999).Think that at present the equilibrium dialysis method provides result the most accurately.Referring to, Mathor etc., the free plasma testosterone level in normal menstrual cycle, " endocrine research magazine " (J.Endocrinol Invest), 8 volume: 437-41 (1985).Use the method, be reported as 1.3-6.8pg/mL the normal range of the total serum testosterone levels of being measured among the women before the menopause of health by endocrine science and technology company, or about 2-7pg/mL.

The such women of " women " expression, androgen or estrogen that they benefit from by any way replenish.In one aspect, the women may the menopause owing to age, ovariectomy or ovarian failure.On the other hand, the women may accept oral estrogen reaching beneficial effect, as prevents or suppress the bone loss, and preventing or to suppress the variation of blood lipid, otherwise this variation easily makes the women suffer from cardiovascular disease.On the other hand, the women can manifest the shortage of androgen and estrogen, or uneven.On the other hand, the women may accept oral estrogen with contraception.

" improve healthy " and represent to reduce, improve or prevent to lack the appearance and/or the intensity of relevant symptom with androgenic steroids.The example of symptom comprises like this, but be not limited to, sexual dysfunction, it can show as hyposexuality, to sexual stimulus sensitivity reduce, arouse and reach the going down of orgasm ability, vitality goes down, emotion is constrained, healthy sensation reduces, shy, muscle quality and the loss of function easily, disadvantageous health formation, be lean meat to the mass ratio of fat, pubes are rare and come off, urogenital atrophy, hair is dry and become fragile, xerosis cutis, cognitive competence go down, sears optical, autoimmune phenomena, and combination.

Can determine that these symptoms occur and the increase and the minimizing of seriousness by various device known in the art, to estimate each concrete symptom.For example, women's sexual function can use the evaluation of self-evaluating application form, as the Brief index (Taylor etc., 1994) of women's sexual function; The Derogatis of sexual function makes a house call, Derogatis, and L., the Derogatis of sexual function make a house call (DISF/DISF-SR): introductory report, J.Sex.MaritalTher.Winter23 (4): 291-304 (1997); With other application form, as Derogatis etc., the psychological assessment of the sexual function of human body in clinical trial is measured, Int.J.Impot.Res., supplementary issue 2:S13-20 on May 10 (1998); And carry out (Laan, 1998) by the genital blood flow method.Usually use dual intensity X-radiation absorption surveying (DEXA) to measure muscle quality, health formation and bone mineral density.Can be by the depressed catalogue (Beck etc., 1961) of Beck, general mental health index (Dupuy, 1984) and many neuro-cognitive function tests are determined emotion, health and neuro-cognitive function.The sears optical syndrome can be assessed in the following way: the tear function test, as osmotic pressure, volume, flow, the Shirmer test is by the use artificial tear formulations with by the subjective survey table.Referring to, for example, Mathers etc., menopause and tear function: the influence that prolactin antagonist and gonadal hormone produce human tears, " cornea " volume 17:353-8 (1998).Immunologic function can be assessed in the following way: by the tiring of circulation autoantibody, by CD4+ and the lymphocytic counting of CD8+ and the symptomatology by specific autoimmune disorder, as systemic lupus erythematosus (sle), rheumatoid arthritis etc.

When " rising " and SHBG level are used together, be illustrated in and specify the SHBG serum-concentration of measuring among the women, this concentration value has wherein been measured the SHBG level greater than the meansigma methods by women before the healthy menopause of clinical laboratory's report.For example, by the numerical value that the immunoradiometric assay method of using " endocrine science " obtains, wherein use their immunoradiometric this numerical value can think to raise greater than the 84nmole/ liter.The SHBG serum-concentration that the SHBG water-glass first finger of " significantly raising " decide the women is much higher than the higher limit of the normal range of the SHBG level of measuring among the women before the healthy menopause of being reported by clinical laboratory.For example, by using " endocrine science " if the numerical value that obtains of immunoradiometric assay method rise greater than 185nmole/ and can think remarkable rising.Consider the distinct methods that in the clinical reference experiment of difference, is used to measure SHBG, with meansigma methods of being reported by them and the respective change of normal range, above-mentioned definition for rising and remarkable rising SHBG value is applicable to any effective ways with suitably definite normal range.

" effective dose " expression enough reaches its required purpose or the amount of effect.The material that various biological factors can influence conveying carries out the ability of its required task.Therefore, " effective dose " can be dependent on such biological factor.By non-limiting example, be that the women of 100nmole/L compares with the SHBG serum levels, the SHBG serum levels is 225nmole/L or may needs bigger testosterone dosage to reach required effect greater than the women of 300nmole/L.Therefore, although testosterone dosage may change in these women, as long as it has reached its required effect, each dosage all can be thought " effective dose ".The definite of " effective dose " is known to those skilled in the art.

Under the situation of androgen and estrogen administration, can adopt many evaluation methodologys to be used for determining the realization of required effect, these methods are being known in the art.Such evaluation methodology can be by the doctor, or other qualified medical worker carries out and can comprise health check-up, and blood count waits to be carried out.

The desired effects that " therapeutic effect " expression acquires a certain degree.Under the situation that the androgen that provides as the present patent application and estrogen replenish, many desired effects are called " improving healthy ".In one aspect, can make therapeutic effect reach the degree of selection by the material of carrying " effective dose " that can reach desired effects.Although can use evaluation methodology known in the art to determine the realization situation of therapeutic effect, think individual variation and can make the subjective decision of therapeutic effect influence to the reaction of treatment by doctor or other qualified medical worker.

At this, concentration, the form that quantity, dissolubility and other numerical data can certain limits occurs.Should be appreciated that such range format only be for convenience with succinct needs, it should be construed to neatly and not only comprise the numerical value that is clearly provided by the scope bound, be also included within all the single numerical value in this scope or be included in wherein more among a small circle, as each numerical value with clearly provide more among a small circle the same.

For example, the concentration range of 0.5-15pg/ml should be construed to and not only comprise concentration limit value 0.5pg/ml and the 15pg/ml that clearly provides, be also included within the single concentration in this scope, as 0.5pg/ml, 0.7pg/ml, 1.0pg/ml, 5.2pg/ml, 11.6pg/ml, 14.2pg/ml with more among a small circle as 0.5-2.5pg/ml, 4.8-7.2pg/ml, 6-14.9pg/ml etc.No matter the scope of describing or the width of feature, this explanation all should be suitable for.

B. the present invention

The recent androgen, particularly testosterone of studies show that is of value to the healthy and happy of women in fact.Ebert etc., United States Patent (USP) 5,460,820 in one aspect, has been instructed compositions and method by patch induction system transdermal administration testosterone.By from testosterone substrate, the about 50-500mcg/ of transdermal administration days testosterone, these compositionss and method keep " physiological range " of total testosterone serum blood level at about 15-80ng/dL.Because the first pass metabolism effect is bypass (bypass), compare with oral route, think androgenic non-oral delivery to liver than safety and more persistent conveying is provided.On the other hand, estrogenic oral delivery can be improved the situation of serum lipids.Yet, have been found that the women who raises or significantly raise for the SHBG level, as above-mentioned total testosterone serum levels of accepting oral estrogenic those women may not be the accurate indication of treatment effectiveness testosterone levels.

Known testosterone has reduced testosterone to androgen sensitivity tissue to the combination of SHBG, as the supply of the tissue of expressing androgen receptor.Also known such metabolite clearance speed that has all reduced testosterone in the masculinity and femininity body that is combined in.Referring to, for example, Vermeulen etc., the influence of androgenic metabolite clearance speed and exchange and free androgen composition, clinical endocrine and metabolism magazine, 48 volume: 320-326 (1979); Longcope etc., women's free estradiol before the menopause, free testosterone, and sex hormone binding globulin, clinical endocrine and metabolism magazine, 64 volume: 513-518 (1987).Because the SHBG level is to the influence of testosterone combination and removing, total by what androgen is given specified individual reaches, freely and biological can utilize androgenic serum levels will depend on this individual SHBG level.Yet the SHBG level can not calculate to a nicety from present knowledge to the influence of the androgen serum levels that reaches and need experimental data.

For such data are provided, the women of three groups of operation menopause is carried out pharmacokinetic study, give these women with the testosterone intradermic matrix patch with 300mcg/ days dosage, weekly twice, totally 7 days.Accepted no estrogen replacement therapy (ERT) at least one month for first group, it is 0.1mg/ days percutaneous estradiol (E2) that second winding is subjected to dosage, and it is 1.25mg/ days oral conjugated premarin (CEE) that the 3rd winding is subjected to dosage.The measurement of using the SHBG level that obtains before the patch and before second 3.5 days patch application cycle and during total and measurement free testosterone level that obtains, undertaken by " endocrine science ".Participate in the gained hormonal data (meansigma methods ± SEM) see the following form 2 of three groups of operation menopausal womens of clinical research.

Should be noted that use " endocrine science " assay method, be 36-185nmol/L the normal range of SHBG level.In addition, the variable quantity of total testosterone and free testosterone level is represented the time equal variable quantity that changes from baseline values during 3.5 days patches are used.

Table 2

Hormone (unit)	No ERT n=19	Percutaneous E2 (0.1mg/ days) n=12	Oral CEE (1.25mg/ days) n=13
				SHBG(nmol/L)	85.6±9.6	90.8±12.9	226.3±13.5
Total T variable quantity (ng/dl)	57.2±4.4	53.6±7.2	70.8±9.6
				Free T variable quantity (pg/mL)	4.60±0.40	4.20±0.70	2.56±0.30

In the last table:

E2 is an estradiol

T is a testosterone

CEE is a PREMAIN

As shown in table 2, the average SHBG level of oral estrogen group approximately is 2.5 times of other group numerical value, and the paranormal upper limit.The SHBG level of percutaneous estrogen group and the situation of not accepting estrogen replacement therapy (ERT) women have comparability.Compare with other two groups, the average recruitment of oral estrogen group total serum testosterone levels during patch is used, promptly from baseline the time all change approximately big by 30%.

In contrast, the average recruitment of the free level of serum testosterone of oral estrogen group is approximately than other two groups low 40%.These find expression by reducing the removing of testosterone, and the SHBG level of rising causes the increase of the testosterone total serum level that obtains during the percutaneous providing testosterone.Yet, although the total serum level raises, free level of serum testosterone and by reasoning, biology can utilize the upborne SHBG level of level of serum testosterone to reduce, may be since SHBG to testosterone in conjunction with increase.These discoveries are new and unexpectedly can not predict out from research early.

As SHBG further specifying to the influence of the novelty of testosterone levels, in Fig. 1 and 2 the single increment of total serum testosterone and free serum testosterone is mapped to single SHBG level respectively, these increments are to obtain during the percutaneous testosterone that the operation menopausal women of accepting percutaneous or oral estrogen is given 300mcg/ days is treated.As represented on logarithmic scale, total serum testosterone increment increases with the SHBG level and becomes big, and free serum testosterone increment diminishes with the increase of SHBG level.

Be novelty and the unpredictable influence of the SHBG level that further specifies rising to the non-oral administration of testosterone, following table 3 provides the predictive value that need reach the testosterone transfer rate of specifying free testosterone (FT) recruitment, this predictive value is to use the power law regression equation that provides among Fig. 2, provides as the function of SHBG level.As shown in table 3, when the SHBG level increases, reach FT and specify the necessary transfer rate of recruitment (variable quantity) significantly to increase.For example, be the patient that 700nmol/ rises for the SHBG level, reach the required transfer rate of 15pg/mL recruitment and be predicted as 2484mcg/ days, this value enlarges markedly than the value of prior art instruction.

Table 3

SHBG(nmol/L)	50	84	100	200	400	600	700
								FT changes (pg/mL)	The transfer rate (mcg/ days) of prediction
1 2.5 5 10 15	55 139 277 554 831	69 172 344 687 1031	74 185 369 739 1108	98 246 492 985 1477	131 328 656 1313 1969	155 388 777 1553 2330	166 414 828 1656 2484

For the above transfer rate that provides, the variable quantity (ng/dL) corresponding to total testosterone levels of the required variable quantity of free testosterone level and given SHBG level can use the power law regression equation prediction that provides among Fig. 1.Following table 4 provides the explanation of such predictive value.As shown in table 4 below, when the SHBG level increases, corresponding to the increase that is changed significantly of total testosterone levels of the given variation of free testosterone level.For example, be the patient that 700nmol/ rises for the SHBG level, be the situation (being 2484mcg/ days transfer rate) of 15pg/mL corresponding to the free testosterone variable quantity, the increase predictive value of total testosterone is 820ng/dL.

Table 4

SHBG(nmol/L)	50	84	100	200	400	600	700
								FT changes (pg/mL)	Total testosterone of prediction changes (ng/dL)
1 2.5 5 10 15	9 21 43 85 128	12 31 61 123 184	14 35 69 139 208	23 57 113 226 339	37 92 184 368 553	49 123 245 490 736	55 137 273 547 820

Will be understood that with table 2 when 3 and 4 discovery and prediction were extrapolated to actual patient, people must be added to patient's baseline testosterone levels (i.e. total or free testosterone level before the treatment) from treating on the desirable testosterone levels variable quantity.For the unusual individuality of baseline values, can be by the final hormonal readiness that treatment reaches near variable quantity self.

Above-mentioned discovery and prediction expression boil on the nape opposite the mouth clothes estrogen women, or SHBG level rising women's androgen administration generally can produce free and/or biological available testosterone levels significantly is lower than some women's level like this: and they accept non-oral estrogen treatment or have lower or normal SHBG level.In addition, accept the women of oral estrin treatment, or the women that the SHBG level raises generally can require such dosage, this dosage surpasses before had considered it is the dosage of the best for the horizontal normal women of SHBG.And the administration meeting of dosage produces total serum testosterone levels that it is generally acknowledged that normal range is above like this.It should be noted that for some therapeutic use as androgenic short application use, required free and/or biology can utilize the testosterone treatment level also may be greater than corresponding normal physiological scope.Therefore, under the situation that women SHBG level raises, the invention provides and be used to give androgenic steroids to improve the method for WomanHealth, compositions and test kit.

C. various aspects

In one aspect, the invention provides and be used for, give women's method and test kit as androgen and estrogen gonadal hormone.In yet another aspect, the invention provides the method and the test kit that are used for the non-orally give SHBG of androgenic steroids level rising women, to alleviate the symptom that lacks owing to androgen.On the other hand, the invention provides method and the test kit that is used for the non-orally give of androgenic steroids is accepted the additional women of oral estrogen.On the other hand, the invention provides the method and the test kit of the androgenic steroids of the estrogen that is used for giving altogether orally give and non-orally give.Have been found that these methods that are used to give estrogen and/or androgenic steroids and test kit can be used for improving healthy, sexual function and happiness.

In one aspect of the invention, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the free testosterone serum levels of the about 30pg/ml of about 0.5-.In another aspect of the present invention, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the free testosterone serum levels of the about 15pg/ml of about 1-.In another aspect of the present invention, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the about 6.8pg/ml of about 1.3-, or the free testosterone serum levels of the about 7pg/ml of about 2-.In another aspect of the present invention, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the free testosterone serum levels of the about 10pg/ml of about 3-.

In one aspect of the invention, androgen can give with the dosage that enough reaches therapeutic effect, and the biology that this therapeutic effect is equivalent to the about 70ng/dl of about 1-can utilize the testosterone serum levels.In another aspect of the present invention, androgen can give with the dosage that enough reaches therapeutic effect, and the biology that this therapeutic effect is equivalent to the about 35ng/dl of about 2-can utilize the testosterone serum levels.In one aspect of the invention, androgen can give with the dosage that enough reaches therapeutic effect, and the biology that this therapeutic effect is equivalent to the about 13ng/dl of about 2-can utilize the testosterone serum levels.

In one aspect of the invention, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to total testosterone serum levels of the about 1000ng/dl of about 15-.In another aspect of the present invention, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to total testosterone serum levels of the about 1000ng/dl of about 85-.In another aspect of the present invention, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to total testosterone serum levels of the about 1000ng/dl of about 100-.

In one aspect of the invention, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the testosterone dosage at least about 50mcg/ days.On the other hand, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the about 3000mcg/ of about 75-days testosterone dosage.On the other hand, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the about 3000mcg/ of about 600-days testosterone dosage.On the other hand, androgen can give with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the about 3000mcg/ of about 700-days testosterone dosage.

One of non-oral route of carrying androgen preparation is a topical.Topical formulations can comprise that skin penetration enhancer is to strengthen androgenic skin flux level.The non-limitative example of operable skin penetration enhancer is described and with reference at United States Patent (USP) 5,122, and in 383 and 5,153,997, the disclosure that they is related to skin penetration enhancer is incorporated herein by reference.In addition, the index of penetration enhancers is disclosed in the Internet publication of the skin penetration enhancer that adopts in their technical literature by name by David W.Osborne and Jill J.Henke, this publication can find in following global network address: pharmtech.com/technical/osborne/osborne.htm is introduced into as a reference at this.The reinforcing agent of effective dose can be incorporated in pharmaceutically suitable carrier.Various carriers based on the type of required conveying preparation are suitable.By non-limitative example, when needs adhesive stroma percutaneous patch, carrier can be a binding agent.On the other hand, when needs liquid storehouse system (LRS) patch, carrier can be gel, emulsifiable paste, ointment, washing liquid or other appropriate formulation known in the art.

The percutaneous patch that is used for the conveying of androgenic steroids percutaneous can be by the routine techniques manufacturing of impart transdermal drug delivery devices field use.For example, can be with androgen, carrier and reinforcing agent with required mixed to form homogeneous mixture and to be introduced in the percutaneous device.Being used to prepare all kinds percutaneous device, is known as the various technology of adhesive stroma patch and liquid storehouse system (LRS) patch in this area.

Except that percutaneous testosterone patch, be used to carry androgenic other non-oral delivery system to include, but are not limited to: the subcutaneous implantation of the intramuscular injection of testosterone ester, fusion testosterone and testosterone, methyltestosterone and other androgenic topical formulations.The Apparatus and method for that is used for those non-oral application is being known in the art.

The complementarity hormone should be by doctor or other health care professional signal and the symptom according to the monitoring sex hormone deficiency as estrogen and androgenic demand, or determines according to the needs in response to the pharmacologic intervention condition of hormone therapy.Not that each women can present identical symptom and sex hormone level even may be within the acceptable scope of physiology, but according to other factors, for example, the SHBG of increase, it still may be suitable that gonadal hormone replenishes.

Androgen, the symptom that comprises the inferior functional level of testosterone can comprise, but be not limited to: sexual dysfunction, it can show as hyposexuality, to sexual stimulus sensitivity reduce, arouse and reach the going down of orgasm ability, vitality goes down, emotion is constrained, healthy sensation reduces, shy, muscle quality and the loss of function easily, disadvantageous health formation, be lean meat to the mass ratio of fat, pubes are rare and come off, urogenital atrophy, hair is dry and become fragile, xerosis cutis, cognitive competence go down, sears optical, autoimmune phenomena, and combination.

Because it can reduce the breast tenderness that takes place when estrogen uses, accept oral estrogenic women and also can have benefited from the androgen treatment.Because known anti-mammoplasia effect, androgen also can reduce the excessive danger of using relevant breast carcinoma with estrogen.Therefore in demandly be that if not what force, replenishing for the testosterone of female patient should be based on doctor's diagnosis, the mode of this doctor's given application, dosage and treatment cycle.

When being total to administration with androgenic steroids, estrogen can be by about 0.2-3.0mg/ days dosage range orally give as PREMAIN.Can regulate dosage according to women's human needs and the estrogenic potential that gives.The dosage of oral estrogen can be dosage or give with twice or repeatedly less dosage once a day.Ideally, for the women that vasomotor symptoms is arranged, use minimum effective dose with the control vasomotor instability.Can use littler dosage to the women who does not have vasomotor symptoms, but can make other healthy being benefited, be benefited as cardiovascular and bone.Under the situation of using oral contraceptive, ethinyl estradiol is typically taked administration in 21 days clinically, the periodicity therapy of 7 days placebo.

In one aspect, the invention provides method and the test kit that is used to give with the progestogen of androgen and estrogen.The known women's of giving progestogen are in order to prevent endometrial hyperplasia.Progestogen also are the essential active of many oral contraceptive preparations.According to an aspect of the present invention, can pass through any method afford known in the art according to the individual need progestogen.For each women, the progestogen amount that reaches required purpose may change.Being used for determining the progestogen effective dose, promptly enough reaching the method for the amount of required therapeutic effect, is known for those skilled in the art.

According to above-mentioned dosage and laboratory test, those skilled in the art can easily determine to give many a spot of specific androgenic steroids or testosterone derivative, to reach required androgenic steroids serum levels, this level can be used more than a kind of androgenic steroids, or testosterone form and reaching.Importantly the dosage of androgenic steroids or testosterone derivative enough makes the women receiver be benefited, and does not give too big dosage.Giving the proper dosage level is known to obtain best danger/benefit comparison those skilled in the art.

In the embodiment in being contained in following experimental example, with estrogen replacement therapy (ERT) or as the androgenic steroids of the about 50-3000mcg/ of the women days dosage of oral contraceptive.Dosage in this scope enough obtains the treatment effect usually.Yet, can determine (as by changing delivered dose and assessment effect) by experience to libido, sexual function, emotion, healthy general sensory etc. for concrete women's optimum dosage.Therefore, because the normal variation of hormone-sensitive, true dosage comes importantly not as obtaining required physiological effect for concrete patient, and this effect can be corresponding to total testosterone serum levels of the about 400ng/dl of about 15-, or the free testosterone serum levels of the about 15pg/mL of about 0.5-.

Following examples only are used to illustrate various aspects of the present invention disclosed herein, and do not limit the present invention in any way the scope of requirement.Thought equivalent others of the present invention also within the scope of the invention by those skilled in the art.

Embodiment 1

To the age at the operation menopausal women of 20-55 between year, give oral estrogen and percutaneous testosterone as follows.By PREMAIN (Premarin ^Tablet) estrogen dosage every day of Zu Chenging is 0.625-2.5mg.Give the percutaneous testosterone by matrix type percutaneous patch, it is applied to abdominal part twice weekly, transfer rate is 300mcg/ days.The persistent period of administration was 12 weeks altogether.After 12 weeks, the person compares with only giving the PREMAIN, and this therapy has been improved sexual function, emotion and health.

By " endocrine science " (Calabassas Hills, CA) hormone serum level of this therapy of Ce Lianging is in following scope: total testosterone (15.5-254.3ng/dl), free testosterone (1.7-33.7pg/mL), biology can utilize testosterone (2.3-71ng/dl), estradiol (5-280pg/mL), and estrone (8-410pg/mL).The level of sex hormone binding globulin is 62.7-563nmol/L, wherein 92% raises about " rising " and " significantly raising " definition according to above, and the 48%th, significantly raise.It should be noted that 73% women who accepts oral estrogen and percutaneous testosterone therapy has reached the total testosterone levels that surpasses 80ng/dL, 80ng/dL is generally considered to be the upper limit of normal range in this area.In contrast, 78% women's free testosterone level is lower than 6.8pg/mL (upper limit of the normal range of " endocrine science ") and 97% women's free testosterone level is lower than 15pg/mL, and this is within the acceptable scope of the treatment of this hope.Similarly, 68% women's biology can utilize testosterone levels to be lower than 12.7ng/dL (upper limit of the normal range of " endocrine science "), and 97% women's biology can utilize testosterone levels to be lower than 35ng/dL, and this is within the acceptable scope of the treatment of this hope.

Embodiment 2

According to following therapy, the conjugate of male hormone compound and estrogen compound is given the women of natural menopause:

Androgen: at the suitable carrier excipient, as the topical of testosterone in emulsifiable paste or the ointment, it can optionally comprise penetration enhancers to reach required testosterone serum levels as needs.The androgen emulsifiable paste can comprise cetyl ester, cetyl alcohol, white beeswax, glyceryl monostearate, propylene glycolmonostearate, methyl stearate, benzylalcohol, sodium lauryl sulphate, glycerol and mineral oil.Every gram emulsifiable paste comprises the testosterone of about 400mcg.In the bedtime, about 1 gram emulsifiable paste is coated onto on skin or the abdominal part.The free testosterone serum-concentration that reaches can be in the 0.5-15pg/ml scope and the total testosterone that reaches can be in the 30-250ng/dL scope.

Be the testosterone amount that control gives, can adopt metering dosing device.Can be according to remission, as the libido that recovers, or reach required free testosterone serum-concentration and carry out dosage and regulate.The scope of remission can change within the free serum testosterone of 1-20pg/mL.

Estrogen compound: oral conjugated premarin tablet can give by 0.625mg/ days starting dose.In case of necessity, dosage can be increased to 1.25mg/ days, or when vasomotor symptoms is calmed down, dosage be reduced to 0.3mg/ days to keep bone and serum lipids benefit with controlling symptoms better.

For the women with complete uterus, the progesterone that importantly has q.s in serum is to avoid endometrial hyperplasia, and this hypertrophy can derive from the controversies in hormone replacement in the elderly that does not have antagonism.

The patient can be in the benefit of feeling in 6 weeks at first of administration in conjunction with hormonotherapy, but different effects can take place.Typically, on chronic basis, give hormone to reach health-care effect.

Embodiment 3

Male hormone compound and estrogen compound can be given postmenopausal women to alleviate and fragile relevant sign and symptom, as the loss of bone and muscle quality and function, cognitive competence reduces and energy reduces.

Androgen: intramuscular injection 150mg testosterone enanthatas on every month basis.Can in Oleum sesami, testosterone enanthatas be mixed with every mL comprise 200mg.For 150mg is provided testosterone enanthatas, injected dose is 0.75mL.

Estrogen: the scope with 0.3-3.0mg/ days gives oral estrogen.

As long as the attending doctor think the treatment benefit be need with suitable just can administration.

Embodiment 4

The women that male hormone compound and estrogen compound can be had premature ovarian failure is as the women of the forfeiture of ovarian function before 40 years old.

Androgen: can give methyltestosterone to reach the improvement of sexual function with 1mg/ days dosage by the buccal approach, it is equivalent to by serum levels is the improvement that testosterone produced of about 50-300ng/dL.The bilayer tablet that the buccal tablet can be made up of medicine layer and biological adhesive layer (every layer all is 50mg).The composition of medicine layer (by weight percentage) can be: 2% methyltestosterone, 0.75% magnesium stearate, 0.1%FD﹠amp; C yellow #6,24%Klucel HXF and 73.15% mannitol.The composition of biological adhesive layer (by weight percentage) can be: 69.25% poly(ethylene oxide), 30% carbomer 934 P and 0.75% magnesium stearate.The binding agent face of tablet is attached on the upper jaw gingiva and with the medicine of the tablet buccal mucosa on it.When tablet dissolved in time, the medicine through mucous membrane was absorbed.Tablet can early be used after the meal in every day.

Estrogen: Estrace ^, Bristol Meyers Squibb Co. with the oral microparticles estradiol product of tablet pattern, can give by 2mg/ days dosage to be alleviated symptoms of menopause and prevent the bone loss.

In addition, progestogen as medroxyprogesterone acetate, can give at least ten days every month by 5mg/ days oral dose to induce endometrium to peel off.

Carry androgenic steroids so that required replenishing to be provided although embodiment relates generally to based on the needs of this type of material, administration also can be carried out simultaneously with the oral administration of estrogen preparation.

Claims (12)

1. one kind is used for improving and suffers from sex hormone binding globulin levels and raise, or the test kit of the disease women's that significantly raises health, the non-peroral dosage form that comprises androgenic steroids, adopt enough amounts with under the situation of the sex hormone binding globulin levels that raises or significantly raise, therapeutic effect is provided.

2. the test kit of claim 1, wherein this androgenic steroids is selected from: testosterone, methyltestosterone, ANDROSTENEDIONE, Adrenalone, dehydroepiandrosterone, oxymetholone, Fluoxymesterone, metandienone, testolactone, pregnenolone, 17 α-methylestrenolone, second promise ketone, dihydrotestosterone, danazol, oxymetholone, androsterone, nandrolone, stanozolol, ethylestrenol, oxandrolone, 7 α, 17-clausterone and mesterolone, Testosterone Propionate, depo-testosterone, testosteroni phenylacetas, testosterone enanthatas, aceto-sterandryl, testosterone buciclate, testosterone enanthatas, testosterone decanoate, testosterone decanoate, isodecyl acid testosterone, its isomer and derivant, with its conjugate.

3. the test kit of claim 1, wherein this androgenic steroids exists with the non-peroral dosage form that enough reaches therapeutic effect, and this therapeutic effect is equivalent to total testosterone serum levels of the about 1000ng/dl of about 15-.

4. the test kit of claim 1, wherein this androgenic steroids exists with the non-peroral dosage form that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the free testosterone serum levels of the about 30pg/ml of about 0.5-.

5. the test kit of claim 1, wherein this androgenic steroids exists with the non-peroral dosage form that enough reaches therapeutic effect, and the biology that this therapeutic effect is equivalent to the about 70ng/dl of about 1-can utilize the testosterone serum levels.

6. the test kit of claim 1, wherein this androgenic steroids exists with the non-peroral dosage form that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the testosterone dosage at least about 50mcg/ days.

7. the test kit of claim 1, wherein this non-peroral dosage form is part or parenteral dosage form, or its combination.

8. the test kit of claim 1 further comprises the estrogen of the peroral dosage form of effective dose.

9. the test kit of claim 8, wherein this estrogen exists with the dosage that enough reaches therapeutic effect, and this therapeutic effect is equivalent to the about 3.0mg/ of about 0.2-days PREMAIN dosage.

10. the test kit of claim 8, wherein this estrogen is selected from: 17 alpha-estradiols, 17 beta estradiols, PREMAIN, esterified estriol, micronize estradiol, estrogen sodium sulfate, ethinyl estradiol, estrone, selective estrogen receptor modulators, phytoestrogen, its isomer and derivant and its conjugate.

11. the test kit of claim 8 further comprises the progestogen that endometrium safety enough is provided of effective dose.

12. the test kit of claim 8 further comprises the progestogen that effective contraception enough is provided of effective dose.

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