Interrupted hormone-substitution therapy with low estrogen dosages

FIELD: medicine, gynecology.

SUBSTANCE: the present innovation deals with carrying out hormone-substitution therapy in women during menopause period or in sterilized women. For this purpose the above-mentioned therapy consists of the phase of relative dominant estrogen activity including three daytime dosages of a substance inducing estrogen activity being equivalent to approximately to 1 mg 17beta-estradiol daily, and the phase of relative dominant progestogen activity including combination of a substance inducing estrogen activity being equivalent to approximately 1 mg 17beta-estradiol daily and a substance that demonstrates progestogen activity being equivalent to approximately 90 mcg norgestimate daily. To fulfill such a therapy a pharmaceutical preparation is, also, suggested and a set of mentioned preparations. The innovation provides maximal weakening the symptoms of the disease, in particular, congestions along the safety of application due to decreased risk of known complications of estrogen therapy.

EFFECT: higher efficiency of therapy.

31 cl, 1 dwg, 1 ex, 2 tbl

 

The scope of the invention

The present invention relates to hormone replacement therapy (HRT) for women in menopause or sterilized women. More specifically, the present invention relates to the regimen of hormone replacement therapy comprising a combination of specific dosages, which includes a reduced amount of estrogen that provides a reduced risk of cancer, this scheme provides relief of vasomotor symptom that is usually possible at higher levels of estrogen.

Background of the invention

Prior art

There are a number of patents related to hormone replacement therapy, and many different commercially available preparations. Many drugs involve long-term administration of estrogen and progestogen, while other schemes can be characterized as intermittent or cyclophane. Examples of patents related to intermittent regimens include Robert F. Casper's U.S. patent No. 5108995 dated August 28, 1992 for HRT-way; 5256421 from October 26, 1993 for HRT-way; 5422119 on June 6, 1995 for transdermal HRT-way preparation and packaging; and 5382573 dated January 17, 1995, which refers to the drug HRT and packaging. Casper is also the patentee of U.S. patent No. 5276022 from January 4, 1994 and 5585370 of 17 December 1996, both of which relate to contraceptive therapy. Description sun the x data of the patents included in this application as references.

Casper hormone replacement therapy (HRT) and, therefore, cyclophane scheme disclosed Casper, designed to induce increased levels of receptors gestagen and estrogen through estrogen-induced increase in the production of receptors. A large concentration of steroid receptors increases the sensitivity of target organs to the gestagen and estrogen and allows the use of smaller doses of exogenous steroids. Cyclophane or intermittent Casper positively regulate the receptors of estrogen and progestogen to estrogen-dominant phase and then negatively regulate the same receptors in the progestogen-dominant phase. In both phases of the scheme Casper dose of estrogen constant, whereas the dose of progestogen vary, receiving, respectively, a progestogen-dominant or estrogen-dominant effects. These alternating phases in the HRT scheme Casper continue without interruption.

Hot flashes or hot flashes occur in 75 percent of women in menopause. Tides can begin in perimenopausal period, when the relative estrogen deficiency occurs with irregular cycle after anovulation, but they usually begin during or after menopause. Hot flashes typically begin as a sudden sensation of heat on the face and upper chest, which is spreading rapidly. Feeling the heat lasts from two to four minutes, often is connected with profuse sweating and occasionally palpitations and often accompanied by fever and chills [Casper, RF, Yen, SSC. Neuroendocrinology of menopausal flushes: An hypothesis of the flush mechanism. Clin. Endocrinol. 1985; 22: 293].

Hot flashes usually occur several times a day, though the number can vary from one to two times per day to once per hour, day and night. Tides are caused by the Wake from sleep, leading to sleep disorders. In addition, many women have excessive sweating, which can cause embarrassment in social situations.

The cause of the tides is unknown. Believe that they are caused by dysfunction of thermoregulation caused by removal of estrogen at the level of the hypothalamus [ibid]. Confirmation of the Central mediation of temperature changes obtained in studies demonstrating that tides occur simultaneously with the pulses of luteinizing hormone [Casper RF, Yen, SSC, Wilkes, MM. Menopausal flushes: A neuroendocrine link with pulsatile luteinizing hormone secretion. Science 1979; 205: 823 and Tataryn IV, Meldrum, DR, Lu KH, et al. LH, FSH and skin temperature during the menopausal hot flash. J. Clin. Endocrinol. Metab. 1979; 49: 152].

theoretical mechanism of initiation of tides is the removal of endogenous opioid peptides. Estrogen increases the Central opioide-peptide activity, while menopause, apparently, associated with a reduction or absence of Central endogenous opioid activity [Reid, RL, Quigley ME, Yen SS. The disappearance of opiodidergic regulation of gonadotropin secretion in postmenopausal women. J. Clin. Endocrinol. Metab. 1983; 57: 1107].

Whatever may be the cause of the tides, the most effective method known for their prevention or treatment in women with estrogen-deficiency, is the introduction of estrogen.

Women who were not exposed to hysterotomy, estrogen should always be given in combination with a progestogen to prevent the development of endometrial hyperplasia and associated malignant diseases of the endometrium. Estrogen-gestagenna therapy is also more effective than applying for ease of tides one estrogen, perhaps because gestagen increases Central opioide-peptide activity [Casper, RF, Alapin-Rubillowicz, SJ. Progestogen increases endogenous opioid peptide activity in postmenopausal women. J. Clin. Endocrinol. Metab. 1985; 60: 34].

Introduction one gestagen can inhibit the secretion of gonadotropin, to increase the activity of endogenous opioid peptides in the hypothalamus [Casper, RF, Alapin-Rubillowicz, SJ. Progestogen increases endogenous opioid peptide activity in postmenopausal women. J. Clin. Endocrinol. Metab. 1985; 60: 34] and to facilitate the tides [Schiff, I. The effects of progestogens on vasomotor flushes. J. Reprod. Med. 1982; 27 (Suppi): 498]. As an example, magistralata (at a dose of from 20 to 80 mg/day) reduces the frequency of tides 85 percent (as opposed to 21 percent with placebo) [Loprimi, CL, Michalak, JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N. Engl. J. Med. 1994; 331:347]. Efficient and also other gestagens such as norethindrone (10 mg/day).

Debilitating symptoms tides are the most frequent is th reason women turn to hormone replacement therapy. Relief tides requires long-term use of hormone replacement therapy with many additional benefits such use, including a 50% reduction in heart disease, prevention of osteoporosis and possibly, as new studies show that prevention of Alzheimer's disease. Currently, the main discussion area associated with the risk of use of hormone replacement therapy that includes breast cancer. Believed, but not proven, that the risk of breast cancer in women taking hormone replacement therapy, is associated with dose and duration of exposure to estrogen.

Despite the considerable efforts undertaken to date, there is still a need to improve HRT-treatments to reduce the effects of estrogen in the effective relief of symptoms such as hot flashes.

Summary of invention

Currently detected that the selected dosage schedule for a broad class of compounds proposed in the aforementioned U.S. patents, provides an unexpectedly beneficial effect that is essential for the patient.

A remarkable finding of this regimen is that get maximum relief of symptoms, particularly hot flushes, and it is a relief equivalent result is for schemes of a similar type, where the level of estrogen on 100 percent higher. It was unexpected that the relief of symptoms is the same for both levels of estrogen in the scheme of this type.

The advantage of this scheme over schemes of the same class with higher levels of estrogen is that it offers increased safety margin due to lower levels of estrogen while providing similar relief of symptoms.

Regimen of the present invention is also compared with known HRT scheme sold under the names KLIOGEST® and KLIOSEM® and is known for the effective relief of symptoms. This well-known product contains 100 percent more estrogen than the real drug. Relief of symptoms is the same for both schemes.

In one aspect the present invention provides a pharmaceutical preparation for the reception of a woman needing hormone replacement therapy, consisting of multiple doses for serial reception in alternating phases, and these phases consist of phase relative dominant estrogenic activity, comprising three daily doses or an equivalent substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol, and phase relative dominant progestogenic activity, comprising three daily doses or an equivalent combination of prophetic is TBA, exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 μg per day of norgestimate.

In a more preferred embodiment of the present invention is provided a pharmaceutical preparation for the reception of a woman needing hormone replacement therapy containing multiple daily doses for serial reception, with a dose take successively in alternating phases, and these phases include phase relative dominant estrogenic activity, comprising three daily doses for serial reception of a substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol, and the relative phase of the dominant progestogenic activity, comprising three daily doses for serial reception combination of a substance exhibiting estrogenic activity equivalent to about 1 mg / day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 μg per day of norgestimate.

In another embodiment of the present invention provided with a package containing a pharmaceutical preparation for the reception of a woman needing hormone replacement therapy containing multiple doses for serial reception in alternating phases, p is ICEM these phases consist of phase relative dominant estrogenic activity containing three daily doses or an equivalent substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol, and phase relative dominant progestogenic activity, comprising three daily doses or an equivalent combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 μg per day of norgestimate.

In a more preferred embodiment of the present invention is provided a pharmaceutical package containing a pharmaceutical preparation for admission under the scheme the woman needing hormone replacement therapy, and dose prepared for serial reception in alternating phases, and these phases consist of phase relative dominant estrogenic activity, comprising three daily doses for serial reception of a substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol, and phase relative dominant progestogenic activity, comprising three daily doses for serial reception combination of a substance exhibiting estrogenic activity equivalent to about 1 mg / day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to the example is about 90 μg per day of norgestimate.

In another aspect, the invention provides a method of treatment of women needing hormone replacement therapy, including the appointment of a specified woman regimens pharmaceutical products containing multiple doses prepared to accept in alternating phases, and these phases include phase relative dominant estrogenic activity, comprising three daily doses or an equivalent substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol, and the relative phase of the dominant progestogenic activity, comprising three daily doses or an equivalent combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 μg per day of norgestimate.

In another aspect, the invention provides the use of substances with estrogenic activity and substances with progestogenic activity upon receipt of a drug, wherein the drug for hormone replacement therapy is designed to receive the woman seeking such treatment, this this medicine includes many doses for serial reception in alternating phases, and the data is the basics consist of phase relative dominant estrogenic activity containing three daily doses or an equivalent substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol, and phase relative dominant progestogenic activity, comprising three daily doses or an equivalent combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 μg per day of norgestimate.

In a more preferred embodiment of the present invention is provided the use of substances with estrogenic activity and substances with progestogenic activity to obtain the drug, wherein the drug for hormone replacement therapy is designed to receive the woman seeking such treatment, this drug contains multiple daily doses for serial reception in alternating phases, and these phases consist of phase relative dominant estrogenic activity, comprising three daily doses for serial reception of a substance exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol, and phase relative dominant progestogenic activity, comprising three daily doses for consecutive welcome to the munali substances, exhibiting estrogenic activity equivalent to about 1 mg per day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 μg per day of norgestimate.

Detailed description of the invention

In preferred embodiments of all aspects of the present invention, a substance exhibiting progestogenic activity, selected on the basis that it binds progestin receptors, shows a low affinity relative to the androgen receptor and has no affinity relative binding hormone globulin (SHBG).

In the most preferred embodiment, this invention provides for treatment or medical scheme, in which three daily doses in phase relative dominant estrogenic activity include about 1 mg / day 17β-estradiol, and in phase relative dominant progestogenic activity include about 1 mg / day 17β-estradiol and about 90 μg per day of norgestimate.

Usually the drug of the present invention consists of separate tablets for oral administration once a day. In the days of treatment from the first to the third tablet contains 17β-estradiol. In the days of treatment from the fourth to the sixth tablet contains as 1.0 mg 17β-estradiol, and 90 μg or 0.09 mg norgestimate. This unique scheme, which includes admission for three days only the 17β seconds and then within three days 17β-estradiol and norgestimate, repeat continuously during treatment.

Definition

The woman needing hormone replacement therapy

Usually this term includes a woman of childbearing age or older, which terminated the ovarian production of estrogen and progesterone due to natural menopause, surgery, irradiation, chemical decomposition or removal of the ovaries or premature fading of ovarian function.

The relative phase of the dominant estrogenic activity

The relative phase of the dominant progestogenic activity

You can start treatment with any phase, although the preferred initial phase is the phase relative dominant estrogenic activity.

The word “relative” determines the activity of phase relative to the preceding phase or directly next phase.

The only activity phase is estrogenic activity, and, therefore, it is dominant in this phase, and this activity is relative to other estrogenic activity phase, where there is also a substance with progestogenic activity. In phase relative dominant progestogenic activity is the dominant hormone actively the TEW is a progestogenic activity, and also this activity in this phase is dominant relative to the activity in the other phase.

In phase relative dominant estrogenic activity estrogen stimulates endometrial growth and gestagenna receptors. Therefore, the endometrium is more sensitive to subsequent progestogenic action that limits growth by reducing estrogen receptors and increase 17β-hydroxysteroiddehydrogenase. The interaction of progestogen in the second phase relative dominant estrogenic activity with progestogen receptors induces endometrial secretory changes, resulting in more dense stroma and endometrial stability. Return to the relative dominant estrogenic activity again stimulates the receptors of estrogen and progestogen and resumes the sensitivity of the endometrium to the gestagen. This “push/pull” effect keeps endometrial activity at the level of the weak dependence on the number of days estrogenic and progestogenic activity [see: Cameron, Sharon T., et al. Continuous transdermal oestrogen and interrupted progestogen as a novel bleedfree regimen of hormone replacement therapy for postmenopausal women, British Journal of Obstetrics and Gynaecology, October 1997, Vol.104, pp.1184-1190]. In this case, the duration of phases relative dominant estrogenic activity is three days for each phase relative domin nteu estrogenic activity that, as it was discovered that maximizes the “push/pull” effect.

A substance exhibiting estrogenic activity, and substance exhibiting progestagen activity

In the present invention it is possible to use any substance that manifests appropriate estrogenic activity. As shown, the preferred estrogen is 17β-estradiol. Other suitable estrogens include 17α-ethinylestradiol, simple and complex esters 17α-ethinyl estradiol, such as, for example, 17α-ethinylestradiol 3-dimethylaminopropionic, 17α-ethinylestradiol 3-cyclopentyloxy ether (quinestrol) and 17α-ethinylestradiol 3-methyl ether (mestranol). You can also apply natural estrogens such as estrone, astrosolar, pieperazinove salt etranslate, estradiol and estriol, and their esters, and synthetic estrogens. The choice of estrogen doses are usually made on the basis of the literature, which is well known to specialists in this field. The dose depends on cyclophanes regimens. Following further discussion on the choice of progestogen or doses can be used as a guide in the choice of estrogen.

The preferred gestagen is norgestimate. Norgestimate also known under the chemical name D-17β-acetoxy-β-ethyl-17α-ethinyl-gon-4-EN-3-one the oxime. If h is about instead of norgestimate you can use other gestagens, selection criteria for a suitable progestogen and, in particular, norgestimate include the degree of affinity relative to the gestagen receptor, the lack of affinity for androgen receptors and the fact that substitution or nezlesine the gestagen of androgen binding hormone globulin (SHBG) [see: Phillips, Audrey et al., Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity. Am. J. Obstet. Gynecology, October 1992, Vol.167, N 4, Part 2, pp.1191-1196]. If norgestimate it connects progestin receptors, shows a very weak affinity for androgen receptors and has no affinity relative to SHBG. All of these effects make it similar to natural progesterone.

In this treatment scheme, you can use other gestagens as long as they meet the established above set of criteria for selection norgestimate. Essentially gestagen must have a profile similar to norgestimato. There are a number of progestogen, which satisfy these requirements include desogestrel, dydrogesterone, medroxyprogesterone, norethynodrel, cyproterone, chlormadinone, magistralata, 17D-acetyl norgestimate, dienoguest, trimegestone, drosperinone and nomegestrol. Examples of gestagens with the wrong profile include norethindrone and norgestrel. In the literature there are descriptions of many of gestagens and rationale for above criter the pits, the person skilled in the art can make the right choice.

As installed, the preferred dose of norgestimate is about 90 μg. Equivalent doses of other progestogen can be determined by a specialist when referring to published sources, for example to model the work of the Treatment of the Menopausal Woman, Basic and Clinical Aspects, Ed. Lobo, H. E. Rogerio A., Raven Press, New York, pp.73-80. The choice of dosage do with the efficiency and nature of the medical scheme, which is cyclophanes and allows low levels of hormones. Examples of suitable doses equivalents include approximately 54 mg/day of desogestrel, about 180 mg/day of 3-keto-desogestrel, about 90 μg/day 17D-acetyl norgestimate, about 180 mg/day of cyproterone, about 720 mg/day dienoguesta, approximately 1080 µg/day drospirenone and about 27 μg/day gestogen. When selecting a dose of the subject routine experiment for professionals in this field should be the selection of the equivalent dose level selected hormone and further study of multiple doses of about this value for its refinement.

Three daily doses or an equivalent

Daily dose of the present invention can be introduced in any convenient form. As established earlier, the preferred tablet for a single daily administration, but you can use any other suitable shape. Single pill prefer the d, because it reduces the likelihood of confusion for the patient. Assume that the expression “cash equivalents” includes forms, which do not include daily doses, for example transdermal form.

Generally speaking, these preparations are prepared according to conventional known methods in accordance with the desired method of administration. For drugs of different types may require different amounts of active ingredients, but it is essential that the number of substances with estrogenic activity and substances with progestogenic activity is chosen in such a way as to ensure the equivalence of doses for the above treatment regimen. The percentage of active ingredients can be varied in accordance with the effectiveness of hormone delivery system or method of administration, and it is chosen in accordance with the usual known in the practice of the methods.

Compositions of estrogen and progestogen, you can enter any recognised in the practice of the method, which is used in the pharmaceutical industry. For example, estrogen and gestagen, by itself or in combination, can be prepared, therefore, to be taken orally, through the skin patch for transdermal absorption, in the form of intramuscular injections, as the content of the inert matrix that is implanted in the body, and in the vault view, or nutritional what about in the matrix, which slowly releases the active composition (such implants are described, for example, in U.S. patent No. 4957119 and 5088505).

Pharmaceutical compositions containing the compounds of this invention may optionally contain pharmaceutically acceptable carriers and can be in solid form or in liquid form. Solid preparations include powders, tablets, dispersible granules, capsules and other Media can be one or more substances which act as diluents, flavoring agents, solubilization, sizing, suspendresume agents, binding or leavening agents for tablets as well as capsules. Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, Patin, dextrin, starch, methylcellulose, sodium carboxymethylcellulose and the like. Liquid preparations include solutions, which are suitable for oral or parenteral administration, or suspensions and emulsions suitable for oral administration.

Examples of liquid preparations suitable for parenteral administration are sterile aqueous solutions of the active component or sterile solutions of the active components in solvents including water, ethanol or propylene glycol. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding the EU is required, suitable flavoring agents, dyes, stabilizers and thickeners. Aqueous suspensions for oral use can be prepared, dispersive active component in water together with a viscous substance, such as natural or synthetic resins, methylcellulose, sodium carboxymethylcellulose, and other suspendium agent known in the pharmaceutical preparation. Other solid dosage forms include dosage forms for local use, which include solutions, powders, fluid emulsions, fluid suspensions, semi-solid substances, ointments, pastes, creams, gels or jellies, and foams; and dosage forms for parenteral use, which include solutions, suspensions, emulsions, or dry powders containing an effective amount of estrogen and progestogen, as disclosed in this invention.

For the preparation of pharmaceutical compositions, including solutions, suspensions, tablets or capsules, you can apply various well-known techniques known to experts in this field and disclosed, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Part 8, Chapters 76-93, Pharmaceutical Preparations and Their Manufacture, pp.1409-1677 (1985).

The pharmaceutical preparations can be obtained in the form of a set, preferably containing compositions of the three standard dosages, and each includes a phase relative dominant ect is agenoy activity and is in a suitable form, for example in the form of drops or tablets. The kit can contain a package with a scale or a strip of foil, as is well known in practice. Typically, the kit includes an even number of doses for each phase, presents an even number of phases relative dominant estrogenic activity. Thus, the standard dosage will be collected in each pack of six, so that each package was attended by an even number of phases.

Used herein, the term “standard dosage form” refers to physically discrete units suitable as standard doses, each unit contains a predetermined quantity of active ingredient calculated to provide the desired therapeutic effect, in combination with the required pharmaceutical carrier. Used herein, the term “dose” in a broad sense includes the term “standard dosage form” or “dosage unit”, and prolonged dosage of the compositions of the store or in other ways.

Mixed drug

This expression is used to specify that the treatment or the drug includes both substances, the substance with estrogenic activity and substance with progestogenic activity. Only the relative phase of the dominant progestogenic activity includes both substances, taking aemia in combination.

Consistently

Usually hormone replacement therapy is used daily, the patient is given the drug every day. It is an object of the present invention, but there may be instances when it is advisable to refrain from the introduction of the hormone in some days. In this case, can be incorporated into the scheme-dose, placebo or some other not containing hormones agent. Examples of suitable alternative agents that do not contain hormones, include vitamins and/or iron supplements. It should be noted that phase is administered to the patient sequentially.

Active ingredients usually are combined with the selected carrier and, for example, in the case of tablets placed in the device forming tablets, getting pills, which are then Packed in accordance with the selected remedial scheme.

Packaging in the form of a preparation for oral administration should contain a daily dose, cooked to the proper consistency in application. Packing can be provided with information on the use of the drug. Packing can be a tube or a box or plate. The box can be round, square or other form of tablets that are separate for ease of use. Next to each tablet may be represented by the date corresponding to the day that you should take each pill. It is preferable to present the UPA is information, regardless of its form, indicating the sequence in which these tablets should be taken.

Hereinafter the invention will be illustrated by examples of research including the method of the present invention. These examples are not intended to limit the scope of the present invention. They should be read in conjunction with the above detailed and General description for a deeper understanding of this invention and to outline the conditions for the exercise of ways HRT of the present invention to women in menopause, menopause and post menopause.

EXAMPLES

In a multicenter study of blind selection parallel groups conducted by the research center in R.W.Johnson Pharmaceutical Research Institute, compared the three different hormone replacement scheme in relation to effects on symptoms during menopause, the nature of bleeding and lipid and carbohydrate metabolism. The primary end point in terms of menopausal symptoms and the subsequent approval of the treatment by the patient, was the effectiveness of each scheme in the relief of the tides.

In a multicenter study scheme of the present invention (containing 1 mg of estradiol and 90 mcg of norgestimate) compared with other intermittent progestogenic scheme, which is taken from the previously cited Casper U.S. patents (and contains 2 mg of estradiol and 180 µg n is gestimate), and with the reference preparation containing 2 mg estradiol and 1 mg of norethindrone, which is currently sold in Europe under the brand name KLIOGEST® and KLIOSEM®. Patients in this study were recorded in a laboratory diary the number of tides per day (24 hour period). During the period prior to the treatment phase relative dominant estrogenic activity diary was filled for at least 5 days in order to obtain the reference number of the tides. Then the patient took various hormone replacement therapy for 12 months and during treatment every day, celebrated their tides in the diary. For evaluation of this study, information on tides observed during the 30 days preceding the end of the study, compared with a reference point to determine improvements in the treatment of the tides. The percentage change from the reference point to the last 30 days was calculated for 182 patients receiving circuit of the present invention, compared with 186 patients receiving circuit with 2 mg estradiol with breaks for gestagen, and 188 patients receiving comparator drug containing 2 mg of estradiol.

For the 12 months all 3 schemes showed a reduction of more than 90% frequency of tides per day. Table 1 shows the number of tides in the 12 months sravnitelnoj the research.

Table 1

Vasomotor symptoms of a 12-month comparative study
 Scheme of the present invention with a low dose (CP-L) estrogen 1 mg E2/90 µg NGMScheme with a high dose (CF-N) estrogen 2 mg E2/180 µg NGMScheme HRT KLIOGEST® 2 mg E2/1 mg NETA
Average (SD)% reduction in quantity. P/day from the starting point to the last. visit-94,9(16,2)-92,5 (22,8)-92,8 (30,0)
% Of patients without P 12-th month73,682,772,4
The average quantity. days before without P (Kaplan-Meier Estimates)141311

Table 1: P denotes the hot flashes or hot flashes; CP-L denotes a low dose of estrogen present invention; WED-N denotes the scheme with a dose of 2 mg estrogen, which compares the present invention. This scheme is identical to the scheme of the present invention except for the levels of estrogen and progestogen. E2means 17β-estradiol, NGM denotes norgestimate, and NETA means norethindrone.

The present study, a low dose of estrogen, resulting in an average reduction in the number of tides per day 94,9% compared with it is what counts. Comparative diagram KLIOGEST®, containing 2 mg of estradiol reduces the number of tides in an average of 92.8%, and the drug with 2 mg of estradiol, interrupted progestogen reduces the number of tides 92.5%.

These results show that the symptoms of relief for all schemes more or less clinically equivalent in reasonable statistical limits. However, it should be noted that at low levels of estrogen in the scheme of the present invention margin of safety of this drug is considered to have significantly increased due to the reduction of breast cancer risk.

Brief description of drawing

The drawing is a graphical representation according to % of patients without tides of the month.

Detailed description drawing

In the drawing symbols and the corresponding symbols have the following meanings:

CP-L: scheme with a low dose of the present invention;

CF-H: scheme with a high dose of the present invention.

Comparison: the drug is sold under the registered trademark Kliogest.

The original data (BL), celebrated during the 30 days preceding the survey according to the method of blind selection.

In the following Table 2 presents the number of patients per month recorded during the last thirty days preceding the survey according to the method of blind selection. These results represent the lower value is for the graphical results of the drawing.



Table 2
Month12345678910111213
Ven-youNumber of patients
CP-L207220217205199194193192182181178177178
CF-H203218209190169147135133123118117114110
Against.202216209206200194193192187189188187185

The drawing shows the proportions of the number of patients without tides per month. You can see that the reduction in seizures during the 12 month same scheme of the present invention, which includes 1 mg of estradiol, and the comparison drug, containing the 2 mg estradiol. The present invention requires on average 3 days longer to achieve day without tides compared with the reference preparation containing 2 mg estradiol, and 1 day compared with the scheme, including 2 mg estradiol with breaks for gestagen.

These results are unexpected, since, as described above, it is known that the tides are the result of a lack of estrogen, and estrogen replacement is the most effective treatment for the prevention or relief of tides. In addition, it is known that the introduction of one gestagen can also relieve hot flashes [Schiff, I. The effects of progestogens on vasomotor flushes. J. Reprod. Med. 1982; 27 (Suppl.): 498 and Loprinzi CL, Michalak, JC, Quella SK, et al. Megestrol acetate for the prevention of hot flushes. N. Engl. J. Med. 1994; 331: 347].

It is expected that the combination of estrogen and progestogen should have a synergistic effect in reducing the number of flushes, more than one estrogen. The present invention contains half the dose of estrogen, compared with the other two investigated schemes and at least half of the progestogen. Therefore, the fact that the circuit of the present invention facilitates the tides in the same degree as the other two drugs, containing at least twice as much estrogen, is unexpected and surprising.

Apparently, the scheme of the present invention effectively enhances the estrogenic activity of the specific estrogen-sensitive tissues, such as the brain, in the case of the tides. Such additional estrogenic effects of the present invention confirmed by the observation that the level of two estrogen-induced lipoprotein HDL and HDL-2, which are deemed to be the main protective lipoproteins against diseases of the coronary vessels of the heart, increases to the same extent in the scheme of the present invention containing 1 mg of estradiol, and in the schema containing 2 mg estradiol with breaks for gestagen. Both schemes outperform the drug comparison KLIOGEST®, containing 2 mg estradiol and 1 mg of norethindrone. As increasing HDL-2 is considered an estrogen-dependent effect, the fact that achieve the same level of improvement with 1 mg of estradiol in the present invention and 2 mg estradiol in a similar drug with breaks for gestagen, consistent with the unexpected estrogenic response.

The clinical relevance of the basic observations related to vasomotor symptoms, is important because the majority of women experience hot flashes during menopause, and debilitating symptoms tides are the most frequent reason for women to turn to hormone replacement therapy. Relief tides leads to long-term use of hormone replacement therapy with many additional benefits such use, including a 50% reduction in the number of the tion of heart disease, prevention of osteoporosis and possibly, as new studies show that prevention of Alzheimer's disease. Currently, the main discussion area about the risk of use of hormone replacement therapy that includes breast cancer. Believed, but not proven, that the risk of breast cancer in women taking hormone replacement therapy, is associated with dose and duration of exposure to estrogen. The currently used scheme breaks gestagen probably not increased estrogenic effects in the breast, as the gestagen not negatively regulates estrogen and progestogen receptors in breast tissue (see Clarke, Christine L. and Sutherland, Robert L., Progestin Regulation of Cellular Proliferation, Endocrine Reviews, Vol.11, 1990, N2, pp.266-300).

Thus, in the breast does not occur fluctuations receptors, which are involved in the mechanism of action of the present invention, and direct linear estrogenic effect should prevail. In the present invention, including a half-dose of estrogen, compared with the other two preparations containing 2 mg of estrogen, should give increased margin of safety against breast cancer, while providing the same relief of hot flashes, as in schemes with a higher dose of estrogen.

Despite the fact that this invention is described with reference to the con is its specific embodiments of, it should be clear that the person skilled in the art may make changes and modifications not departing from the scope and spirit of the following claims.

In the claims the word “including” means “including the following elements (in the body), but not to the exclusion of others”; the expression “consisting of” means “excluding more than trace ingredients other than those listed”; and the expression “mainly comprising” means “excluding unspecified ingredients which materially affect the basic characteristics of this composition.

1. Pharmaceutical preparation for the introduction of a woman needing hormone replacement therapy containing multiple daily doses for sequential introduction in alternating phases, with phases include phase relative dominant estrogenic activity, comprising three consecutive daily doses or an equivalent substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol, and the relative phase of the dominant progestogenic activity, comprising three consecutive daily doses or an equivalent combination of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol and a substance exhibiting progestogenic activity, equivalent to 90 mg per day norgestimate.

p> 2. The pharmaceutical preparation according to claim 1 for the introduction of a woman needing hormone replacement therapy containing multiple daily doses for serial reception, while doses are to receive in alternating phases, and these phases include phase relative dominant estrogenic activity, comprising three consecutive daily doses of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol, and the relative phase of the dominant progestogenic activity, comprising three consecutive daily doses of a combination of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol, and substances exhibiting progestogenic activity equivalent to 90 mg per day norgestimate.

3. The pharmaceutical preparation according to claim 2, where the substance exhibiting progestogenic activity, selected on the basis that it binds progestin receptors, shows a low affinity relative to the androgen receptor and has no affinity relative binding hormone globulin.

4. The pharmaceutical preparation according to claim 3, where the substance exhibiting estrogenic activity, selected from 17α-ethinyl estradiol, simple and complex esters 17α-ethinylestradiol, 17α-ethinylestradiol 3-dimethylaminopropionic, 17α-ethinylestradiol 3-cyclopent the gross ether (quinestrol) and 17α -ethinylestradiol 3-methyl ether (mestranol); natural estrogens, estrone, etranslate, piperazino salt etranslate, estradiol and estriol, and their esters, and synthetic estrogens, and a substance exhibiting progestogenic activity, selected from desogestrel, dydrogesterone, medroxyprogesterone, norethynodrel, cyproterone, chlormadinone, magistralata, 17D-acetyl norgestimate, dienoguesta, trimegestone, drosperinone and nomegestrol.

5. The pharmaceutical preparation according to claim 1, where doses represent a form for oral administration.

6. The pharmaceutical preparation according to claim 5, where the form for oral administration is a tablet.

7. The pharmaceutical preparation according to claim 1, in which the daily dose in phase relative dominant estrogenic activity contain 1 mg / day 17β-estradiol, and in phase relative dominant progestogenic activity contain 1 mg / day 17β-estradiol and 90 mg per day norgestimate.

8. The pharmaceutical preparation according to claim 7, where doses represent a form for oral administration.

9. The pharmaceutical preparation of claim 8, where doses are tablets.

10. Set containing pharmaceutical preparation for the introduction of a woman needing hormone replacement therapy, including multiple doses, prepared for the mA in alternating phases, moreover, these phases consist of phase relative dominant estrogenic activity, comprising three consecutive daily doses or an equivalent substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol, and phase relative dominant progestogenic activity, comprising three consecutive daily doses or an equivalent combination of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to 90 mg per day norgestimate.

11. The set of claim 10, containing a pharmaceutical preparation for injection according to the scheme a woman needing hormone replacement therapy, and the dose is prepared to accept in alternating phases, and these phases consist of phase relative dominant estrogenic activity, comprising three consecutive daily doses of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol, and phase relative dominant progestogenic activity, comprising three consecutive daily doses of a combination of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to 90 mg per day norgestimate.

12. Set according to claim 11, where the prophetic is STV, exhibiting progestogenic activity, selected on the basis that it binds progestin receptors, shows a low affinity relative to the androgen receptor and has no affinity relative binding hormone globulin.

13. Set according to claim 11, where the substance exhibiting estrogenic activity, selected from 17α-ethinyl estradiol, simple and complex esters 17α-ethinylestradiol, 17α-ethinylestradiol 3-dimethylaminopropionic, 17α-ethinylestradiol 3-cyclopentenone ether (quinestrol) and 17α-ethinylestradiol 3-methyl ether (mestranol); natural estrogens, estrone, etranslate, piperazino salt etranslate, estradiol and estriol, and their esters, and synthetic estrogens, and substance exhibiting progestogenic activity, selected from desogestrel, dydrogesterone, medroxyprogesterone, norethynodrel, cyproterone, chlormadinone, magistralata, 17D-acetyl norgestimate, dienoguesta, trimegestone, drosperinone and nomegestrol.

14. The set of claim 10, where doses represent a form for oral administration.

15. Set in 14, where the form for oral administration is a tablet.

16. The set of claim 10, in which the daily dose in phase relative dominant estrogenic activity contain 1 mg / day 17β-estradiol, and in the phase Rel is a relatively dominant progestogenic activity contain 1 mg / day 17β estradiol and 90 mg per day norgestimate.

17. Set in clause 16, where doses represent a form for oral administration.

18. Set on 17, where doses are tablets.

19. A method for the treatment of women needing hormone replacement therapy, including the introduction of specified women under the scheme pharmaceutical drug containing multiple doses, prepared for use in alternating phases, and these phases include phase relative dominant estrogenic activity, comprising three consecutive daily doses or an equivalent substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol, and the relative phase of the dominant progestogenic activity, comprising three consecutive daily doses or an equivalent combination of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to 90 mg per day norgestimate.

20. A method for the treatment of women needing hormone replacement therapy, according to claim 19, including the introduction of specified women under the scheme pharmaceutical drug containing multiple doses, prepared for use in alternating phases, with phases include phase relative dominant estrogenic activity containing t and daily doses of a substance, exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol, and the relative phase of the dominant progestogenic activity, comprising three daily doses of a combination of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to 90 mg per day norgestimate.

21. The method according to claim 20, where the substance exhibiting progestogenic activity, selected on the basis that it binds progestin receptors, shows a low affinity relative to the androgen receptor and has no affinity relative binding hormone globulin.

22. The method according to claim 20, where the substance exhibiting estrogenic activity, selected from 17α-ethinyl estradiol, simple and complex esters 17α-ethinylestradiol, 17α-ethinylestradiol 3-dimethylaminopropionic, 17α-ethinylestradiol 3-cyclopentenone ether (quinestrol) and 17α-ethinylestradiol 3-methyl ether (mestranol); natural estrogens, estrone, etranslate, piperazino salt etranslate, estradiol and estriol, and their esters, and synthetic estrogens, and substance exhibiting progestogenic activity, selected from desogestrel, dydrogesterone, medroxyprogesterone, norethynodrel, cyproterone, chlormadinone is the magistralata, 17D-acetyl norgestimate, dienoguesta, trimegestone, drosperinone and nomegestrol.

23. The method according to claim 19, where doses represent a form for oral administration.

24. The method according to item 23, where the form for oral administration is a tablet.

25. Application estrogen-active substances and progestagen-active substances as active ingredients in obtaining medicines, characterized in that this drug is intended for hormone replacement therapy for introduction in need of such treatment a woman, and this medicine includes many doses for serial reception in alternating phases, and these phases consist of phase relative dominant estrogenic activity, comprising three consecutive daily doses or an equivalent substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol, and phase relative dominant progestogenic activity, containing three consecutive daily doses or an equivalent combination of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to 90 mg per day norgestimate.

26. Use A.25, where the specified drug vkluchennosti doses for serial reception in alternating phases, and these phases consist of phase relative dominant estrogenic activity, comprising three consecutive daily doses of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol, and phase relative dominant progestogenic activity, comprising three consecutive daily doses of a combination of a substance exhibiting estrogenic activity equivalent to 1 mg / day 17β-estradiol and a substance exhibiting progestogenic activity equivalent to 90 mg per day norgestimate.

27. Use p where a substance exhibiting progestogenic activity, selected on the basis that it binds progestin receptors, shows a low affinity relative to the androgen receptor and has no affinity relative binding hormone globulin.

28. Use p where a substance exhibiting estrogenic activity, selected from 17α-ethinyl estradiol, simple and complex esters 17α-ethinylestradiol, 17α-ethinylestradiol 3-dimethylaminopropionic, 17α-ethinylestradiol 3-cyclopentenone ether (quinestrol) and 17α-ethinylestradiol 3-methyl ether (mestranol); natural estrogens, estrone, etranslate, piperazino salt etranslate, estradiol and estriol, and their esters; and synthetic estrogens, and substance exhibiting progestogenic activity, selected from desogestrel, dydrogesterone, medroxyprogesterone, norethynodrel, cyproterone, chlormadinone, magistralata, 17D-acetyl norgestimate, dienoguesta, trimegestone, drosperinone and nomegestrol.

29. Use p, in which the daily dose in phase relative dominant estrogenic activity contain 1 mg / day 17β-estradiol, and in phase relative dominant progestogenic activity contain 1 mg / day 17β-estradiol and 90 mg per day norgestimate.

30. The application of clause 29, where doses represent a form for oral administration.

31. The application of article 30, where doses are tablets.



 

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1 ex, 1 tbl

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1 ex, 5 tbl

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1 ex, 1 tbl

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1 ex

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1 ex

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11 cl, 1 tbl, 9 ex

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