UA77934C2 - Estrogen (progestin) - antiprogestin method and pharmaceutical composition for oral contraception - Google Patents

Abstract

The invention relates to the medicine, in particular to estrogen (progestin) -antiprogestin set, the pharmaceutical composition and the method for the oral contraception.

Description

Description of the invention

The present invention relates to a method and a set of drugs for achieving oral 2 contraception in gonadal female mammals and regulating menstruation and/or reducing sudden bleeding in pre-, para- and post-menopausal females using strogen, or strogen-progestin, in combination with antiprogestin.

Although inhibition of ovulation in the form of oral contraceptives based on estrogen/progestin combination is the most effective strategy for achieving reversible 10. pharmacological regulation of fertility in women, however, due to known adverse side effects associated with long-term contraception with this method, especially in smoking women in the age group from 40 to 44 years of age, for a number of years there has been an interest in achieving contraception with smaller doses of strogen.

Thus, during the more than 30-year history of combined oral contraception with the help of a 72 estrogen/progestin combination, a steady decrease in the daily dose of estrogen has been observed, both for the purposes of oral contraception in premenopausal females and for estrogen replacement therapy in postmenopausal females. See, for example, IR-A-0253607, which discloses, as a preferred option, administration to premenopausal females of a tablet containing 1 mg of 17-stradisol and 0.075 mg of levonorgestrel daily for 23 or 24 (23-26) days followed by 5 or 4 (2-5) "pill-free" or empty-pill days, totaling 28 days per cycle, and indicating literary sources, the content of which is included in this application as a link to them.

At the same time, although the progestin component is somewhat reduced, reduced androgenicity remains an unchanging priority. Together, there are adaptations of the composition of representations in various modes, both single-phase and multiphase. As a result, today's oral contraceptives with 22 are much safer from the point of view of the prevalence and severity of estrogen-induced blood coagulation disorders, as well as the cumulative effect of more "lipid-friendly" progestins, which support circulating levels of high-density lipoprotein cholesterol. |See, ZreiYIaeu, MUM ei a).; "At U ObBvivi Supeso!" 1980; 137; 109; dream, 997 ei ai., "Repiiviegis" 1978; 30:141; Mivpei, OM g. ei ai., "U Kergod May." 1990; 35 (Zirri. 4): 477-481; Zregoii |., "Sopietr ObBzgiei Supeso!" 1991; 36:65; Meiyiv OV ei Z 30 aI., "Sopigaseriop" 1991; 43; 23; apa 5iatrigeg MU, UUShen US eiai., "At U). OBvivi Supeso!" 1990; 163:2851I. co

This evolution of oral contraceptives occurred most rapidly in Europe and is steadily occurring in America as well. And indeed, the accumulation of data based on oral contraceptive pills containing only 20-35 mcg of strogen per day prompted the Advisory Committee on Protective Drugs! Maternal Health Department of Food and Drug Administration

Zo Uukazat low-dose oral contraceptive! for healthy non-smoking women during perimenopause - (women, for example, from 35 to 50 years old), see Mizpei! (1990) apa Zregoii (1991), see above; Sh.5. Rosod apa Ogyd

Aatipivigayop, Aidmisogu Sottiye op Maiegpai apa Kergodisiime Neayyy, 1989, KosKmyShe, Maguiapa; apa

Kozepbego, I. ei aiI., "AMA 1985; 253:2965). "

In Japan, oral contraceptives are currently being evaluated for the first time according to 0 safety and effectiveness criteria, and they are expected to be fully available! for doctors and patients) after approximately one hour.

And" When considering the further reduction of the daily dose! strogen-progestin drugs in oral contraceptives need to study two main points, namely: (1) preservation of contraceptive effectiveness and (2) prevention of further erosion in the regulation of zondometrial bleeding. While the contraceptives available today, intended for 7 oral administration even in the smallest doses, demonstrate stable contraceptive effectiveness, the overall spread of bleeding regulation problems, manifested as sudden bleeding (untimely bleeding or bleeding) or due to withdrawal drugs for amenorrhea during the "pill-free" week (expected menstruation) increased with a decrease in doses of 20 estrogens/progestins. | See OSgau, KN. in "Epdoteiiigia! Vieedipd apa iegoiidai Sopigaseriop"; Oislarvu E,

Egaseg KB, MUerr ETE (Eva). Waiye, Epaiiapa: Riytap Rgevzv; 1990: 14-19, apa SoiIreu 0. ei ai., "Sopigaseriop"

T" 1982; 26:229).

The purpose of the present invention is to solve problems! regulation of bleeding associated with a decrease in the daily dose of strogen and/or progestin, when both are taken simultaneously, in oral contraceptives, in hormone replacement therapy.

GF) The second goal is to propose a method of achieving contraception in a gonadal female mammal with ultralow oral doses of strogen and/or progestin. o Another goal is to offer such a method that ensures normal menstruation and regulates its onset. 60 Another goal is to offer a method in which the drug is administered without the supervision of a physician.

The further goal is to offer a method that does not have side effects associated with regular or low-dose oral estrogen/progestin contraception or hormone replacement therapy.

Another goal is to offer (a set of drugs for the implementation of method 62 according to the present invention.

Another goal is to provide a pharmaceutical composition effective to induce menstruation and/or reduce untimely bleeding (sudden bleeding, spotting) in females on estrogen/progestin oral contraception or estrogen and/or progestin replacement therapy.

Other purposes will be obvious to a person skilled in the art to which the present invention relates.

This invention relates to a way to avoid problems! bleeding, associated with administration to a female mammal of dosage amounts of strogen, alone or in combination with progestin, low enough to cause sudden bleeding or amenorrhea due to withdrawal of the drug, 70 which consists in periodically giving the female an amount of antiprogestin selective for that , in order to reduce or eliminate sudden bleeding and, if desired, also cause the rejection of the accumulated zondometrial tissue, thanks to which menstruation is induced.

The present invention also relates to a pharmaceutical composition suitable for oral administration and for inducing menstruation in a female on oral estrogen-progestin 7/5 Contraception or estrogen- or estrogen-progestin hormone replacement therapy, containing a menstruation-inducing amount of antiprogestin, in a mixture with the amounts of strogen and progestin, which are taken to achieve oral contraception, when such amounts are to be taken! inside the gonad female daily without a break for at least 20 consecutive days.

The present invention relates to a set of medicinal products containing, in a conventional manner, such as "Levien 21" Laboratories Berlex, at least 20 oral dosage units, each containing an estrogen and a progestin in amounts in which they are collectively effective when one dosage unit of the set is taken orally daily for 20 or more days to achieve oral contraception in women, but which contribute to cases of sudden bleeding and/or amenorrhea caused by withdrawal of the drug. with

In the first variant of the kit according to the present invention, an additional unit of oral doses is provided, containing only the menstrual-inducing amount of antiprogestin, arranged in such a way that it is taken orally after 20 or more strogen/progestin oral units of doses.

In one variant of this variant of the implementation of a set of medicinal products, the number of oral dosage units based on the estrogen/progestin combination, which precedes the antiprogestin-containing "E" oral dosage units, is increased, for example, to 21 or more, making, for example, 20 to 180 units. In the second variety, intended for use in estrogen replacement therapy by females in pregnancy and postmenopause, progestin is absent in some or all tablets, and antiprogestin is present in an amount that significantly reduces or eliminates unexpected bleeding and/or causes rejection of the accumulated endometrial tissue. These varieties are intended for people who wish to increase the duration of their menstrual cycles, regulated by drugs, beyond the usual 4-week period.

In the second version of the set according to the present invention, the provisions! arrangement for reception after 20 or more oral units of doses of the first option described above, for example, like "Levien 28" Laboratory; Berlex, 6 or more units of oral doses of "placebo" to maintain the regimen "one pill in "

ONE day" and reminding the person when to start a new cycle of taking. In a third and preferred version of the kit, instead of one or more units of oral doses of the "placebo" described above, the kit contains 28 or 29 or 30 units of oral doses, each of which contains )" low-dose amounts of strogen and progestin corresponding to the first 21 dosage units of the first variant. In this variant, the dosage unit arranged for reception on the 22nd day also contains visible menstruation

Amount of antiprogestin. - And the present invention is based on the discovery that the case of unexpected bleeding and amenorrhea caused by drug withdrawal, the frequency of which increases when oral contraception is achieved with lower than usual doses of strogen and progestin, can be reduced to a minimum or completely eliminated by the way of menstruation with an antiprogestin, or during the "medication-free" period, i.e. free from strogen and progestin, weeks of the monthly cycle of daily oral administration of strogen and progestin for approximately 21 days, or preferably at any time when menstruation is desired, during continuous daily administration of strogen and/or progestin.

Normal menstruation is also achieved by antiprogestin without interruption of the simultaneously ongoing continuous contraceptive regimen with the help of small oral doses of estrogen/progestin. 5B Continuous regimen of oral contraception with the help of ultrasmall estrogen/progestin doses in combination with periodic administration, for example after an interval of 30, 60 or 90 days, antiprogestin, IF, for example Ki 486, provides predictable menstrual regulation. The physiological motive for such an approach is to maintain a lower degree of pharmacological inhibition of the pituitary-ovarian-uterine axis, but with the help of an uninterrupted regimen 60 to avoid "follicular leakage". With today's low-dose oral contraceptives, the growth of the ovarian follicle can resume faster during the "pill-free" interval than when high-dose pills were used! in the past decade.

In turn, the enhanced endogenous secretion of estradiol with rapid endometrial proliferation, which is known to accelerate during the "pill-free" 7-day period, has as its result 65 Less unexpected intermenstrual bleeding and even less amenorrhea caused by the withdrawal of the drug. Prershvistaya dacha of a progesterone antagonist is scheduled in such a way as to ensure the rejection of the accumulated zondometrial tissue every four weeks or more, for example, after 60, 90, 120, 150, 180 or more days, without a pill-free break in the oral contraceptive regimen.

Prairie, i.e. monthly or with a long interval, for example two- or three-monthly quarterly or half-yearly introduction of an antiprogestin to stimulate menstruation in accordance with the present invention, allows to avoid the problems of abnormal bleeding, for example, sudden bleeding and amenorrhea caused by the withdrawal of the drug, by maintaining the follicular-phase level of nodogenic serum of estradiol at a higher value than that associated with conventional 7/0 preoral contraception with low doses of estrogen/progestin.

In a normal menstrual cycle, progesterone is produced from the corpus luteum, which occurs after ovulation. In the method of contraception according to the present invention, progestin is administered together with estrogen at least towards the end of each regulated cycle, for example during approximately the last two weeks of each cycle, in order to convert the enlarged endometrium into the secretory phase, thereby reducing the risk of 7/5 endometrial carcinomas associated with with unimpeded action strstrogena. However, menstruation is achieved with one antiprogestin, regardless of whether or not the administration of strogen and/or progestin is interrupted during the menstrual week of the menstrual cycle when the antiprogestin is administered.

Daily oral dose! strogen and progestin, which are introduced, are generally considered to be low enough to provide reliable contraception or hormone replacement therapy for women, namely 2 doses, contraceptively equivalent to approximately 5-35 μg of stynyla estradiol and approx. 0.5-1.5 mg of norstindrone acetate. Daily doses can be the same throughout the month, or they can change from week to week, as in the case of "Tri-Levien" of the Berlex Laboratory, for example, when menstruation is desired once a month, in which case the doses of both or one of them can beat reductions or exclusions! during the menstrual week of the cycle. However, if their introduction is excluded or reduced during the menstrual week, their dose! during the second week of the cycle, they preferably increase accordingly, for example, during the second and especially during the third week in order to ensure the absence of i) sudden bleeding before menstruation.

Similarly, when menstruation once a month is undesirable, for example, in the case of post-menopause, the dosage is adjusted and/or the progestin can be periodically increased for a short time, for example, in advance "E from a certain period after the last menstruation, more than the initial long-term dose for suppression isolated cases of sudden bleeding as a result of low levels of strogen and/or progestin in the course of a long period of time. b

Examples of progestins that can be used in the present invention include progesterone (15-5 ug/day), norsthindrone and its complex derivatives, for example acetate (0.1-0.75 mg/day), norsthinodrel (0.3-0 , bmg/dec); ztynodioldiapetate (0.3-0.75mg/day), norgestrel (0.05-0.2mg) and levo-norgestrel (0.03-0.15mg/day), chlormacinone acetate, cyproterone, cyproterone acetate, norstindrone, desogestrel , norgestimate, dihydro-spirenone, spirrenone, levo-norgestrel and gestodene |Schering AG, Berlin; stalemate. USA 4081537) (equivalent to 0.03-0.15 mg levonorgestril).

For a list of compounds, see | articles from the book by V. Kipperbats, "Reta|e Sopigaseriiop: Oraaye apa Tgepav", «

Zrhipdegmegpiad, Vepip, 1988, pp. 64-90, 109-121, 122-128, apa 129-140), describing active compounds that contribute to the onset and maintenance of pregnancy. See, for example, p. b65 and p. 68-70, which list various progestins!; p. 110 and 11 (figure 1 and table 1), which list synthetic )" protestogens; p.122, figure 1, which lists progestogens, and p.129-133 (figures 1-10) and p.137, table 2, which lists progestogens! or long-lasting complex zfir! zstriola, description in pat. US 4,681,875 and 4,738,957. -I Examples of estrogens that can be used in the present invention include: estradiol and estradiol and their ester complexes, such as acetate, valerate, benzoate and undecylate

Sh- (5-15mcg/day), mestranol (20-25mcg/day) and the combination of estrogens (5-15mcg/day). Progestin and estrogen can be introduced into the body by any method in which the combined progestin and estrogen are active, for example, orally, by intraarm injection, or transdermally, or through a vaginal ring. Most estrogens and synthetic progestins are orally active and are therefore introduced into the body in this way, for example in the form of tablets, dragees, capsules! or dusted. If progestin and/or estrogen are administered in the form of a tablet or dragee, the latter may optionally contain a pharmaceutically acceptable carrier, for example, a binder such as tragacanth, cornstarch, or gelatin; a disintegrating agent such as alginic acid and a lubricant such as magnesium stearate. Estrogen and/or progestin can also be injected! transdermally or with

F; vaginal ring. Estrogen and/or progestin are preferably administered without interruption, since aptiprogestin alone effectively induces menstruation, or their administration can be interrupted during or before menstruation, for example, starting from day 1 of administration of aptiprogestin and during approx. b days after that. Thus, estrogen and progestin can be administered without interruption in smaller doses than usual for up to 6 months or longer, during which time menstruation can occur with a desired and preselected frequency, for example, every 20, 30, 60, 90, 120 , 150 or 180 days, by introducing a period-inducing quantity of aptiprogestin for 1, 2 and/or From the day to the desired day of menstruation. 65 Examples of aptiprogestins that can be used in the present invention include: KO 486 ("Mifepristone", Russel Uclaf, Paris); and "Onapristone" (Schering AG, Berlin; US Pat. 4780461) and steroid,

description in the following patents and patent applications: pat. USA 4609651, especially the compound lilopristone (118-(4-dimethylamino-phenyl-17 p-hydroxy-17 p-(3-hydroxy-prop-1-(2)-enzyl-4,9(10)zstradien-3-one ); US patent application see mme06/827050, especially compounds (118-4-acetylphenyl)-17p-hydroxy-17y-(1-propenyl)-4,9-zstradien-3-one and, 11p- (4-acetylphenyl)-17p-hydroxy-17y-(3-hydroxy-1(2)-propenyl)-4,9-zstradien-3-one; US patent application cf.

Meo07/283632; application for patent USA cf. Mo07/541606, corresponding to the published application for European patent EP-A 04042831; and other antigestational substances, for example pat. USA 4891368. The amount of aptiprogestin administered, in the form of a single dose or in the form of a divided total dose during a 10. 24-12-hour period, is usually equal to 50 to 500 mg. The minimum amount required for the predicted appearance of menstruation can be easily determined by routine clinical experiments.

After the antiprogestin is introduced into the body, for example, in the form of a single dose or a divided total dose on the same day or in the following days, menstruation usually occurs within 3-4 days after that.

If desired, the antiprogestin should be administered in admixture with the daily dose of strogen and progestin on the appropriate day or days of the cycle, for example on day 20 or on any day thereafter, i.e. on day 30, 60, 90, 120, 150 and/or 180.

The present invention relates to materials, reagents and sets of medicines for the implementation of the method.

As part of a set of medicinal products, the present invention is directed to, in all other respects, an ordinary product of multiple doses, containing 20 or 28 units of doses, calculated for oral administration into the body. Bee varieties of the set contain in their first 20 or more units a total of such amount of strogen and progestin, which is effective when one unit of the dose from the set is administered independently without supervision by a doctor, for 21 consecutive days, to block folliculogenesis for one cycle, but which less than the amount of them that effectively eliminates probleate bleeding. with

The last unit of the variety, consisting of 21 units, doses, and the 22nd unit of the varieties, consisting of 22 and 28 units of doses, contain the amount of antiprogestin, which is effective in preventing bleeding problems and in stopping menstruation. Units! doses from the 22nd to the 28th of the variety of the product, containing 28 units of doses, each contain, like the first 21 units of doses, low-dose amounts of strogen and progestin. "

Preferably, single doses containing estrogen and progestin and/or antiprogestin should be prescribed! for oral use, but alternatively, you can beat the device! for sublingual, rectal, vaginal or local (through the skin) application. It is also preferable that a single 9-dose calculation for oral use be given in the form of tablets, capsules or dragees. Further, it is preferable that the antiprogestin is contained in the same unit dose, or doses that contain

With strogen and progestin. in.

Pharmacological compositions used in the method of the present invention will generally contain aptiprogestin together with a generally pharmaceutically acceptable carrier. In general, the effective dose of aptiprogestin is approx. 1.0 to approx. 10 milligrams per kilogram of the host's body weight when administered orally. Selective doses will vary with the chosen mode of administration and depending on the type of mammal to which they are administered. but c As part of the pharmaceutical composition, the present invention is directed to the oral dosage form, for example, a pill, tablet, cap or capsule or liquid containing a menstruation-inducing amount of an antiprogestin, mixed with an amount that is orally contraceptive, when corresponding amounts of it are taken inside the gonad by a female mammal for 21 consecutive days, oral estrogen or orally active progestin and, if desired, a general pharmaceutically acceptable carrier, for example, a binder, filler or diluent in the case of solid forms! dose, or aqueous - or alcoholic liquid, for example, as described above.

The composition is intended for ingestion by a person who is in a continuous or continuous mode of contraception with the help of strogen and progestin, for example, a daily combined 50 swallow of strogen and progestin when menstruation is desired.

The pharmacological composition according to the present invention allows to release oral estrogen/progestin, for example, in bottles of 30, 60 or 100 tablets or capsules or in liquid bottles, since the daily dose of them should remain unchanged during the entire period of taking the drug.

Without further clarification, it is believed that a specialist in the field of coins, using the preceding description, will apply the present invention to its fullest extent. The following is preferable to a specific variant of the embodiment of the invention, therefore, you must! is intended solely as an illustrative, non-limiting invention. o In the previous and subsequent examples, all temperatures! bring it! corrections in degrees

Celsius and, unless otherwise specified, all parts and percentages are by weight. 60 Example

Example I:

Intermittent administration of antiprogestin during continuous ultralow-dose contraception

Receive

Beat the vibes! thirty-four adult macaques (Masasa thyatsa) having regular, presumably 65 ovulatory menstrual cycles (28.7-3.4 days per month preceding the beginning of the study).

The duration of their spontaneous menstruation was 3.7--1.6 days. You are a primate! are recognized as valid laboratory surrogates for studies related to the use of human oral contraceptives due to extensive similarities with the functions of the hypothalamic-pituitary-ovarian-uterine axis in women. | See Noddep, 50., "Regions of Ziegye 1982; 38-281; OYUOapiopy OK. ei ai., "Sopigaseriop" 1989; 39-321; apa map Oet

UENM, ei ai., "Sopigaseriiop" 1989; 40-171.

The average body weight of monkeys is 5.8--1.6 kg. (HAEM). They were housed individually in a controlled environment (12 hours of daylight and 232C). Their diet consisted of commercially available primate chow (Purina, St. Louis,

MO), and water without limitation.

The Medical School of Eastern Virginia has registered equipment for animal research, which, thanks to its Animal Care and Use Committee, meets the examination standards established in the "Manual for the Care and Use of Laboratory Animals"

of the National Institute of Health, in "Principles of care and use of laboratory animals",

Public Health Service and Rules of the Department of Agriculture of the USA on the Application of Amendments No. 75 of 1985 to the Animal Protection Act.

The research was conducted in two parts: Part | was an adaptation interval of three cycles of oral contraceptive treatment, each of which consisted of oral drug therapy with the introduction of the drug for 21 days followed by 7 days without the introduction of the drug, thus imitating the traditional regimen of using commercially available packs of oral contraceptive pills. This plan provided that all (32 monkeys completed the course) individuals were exposed during the initial adjustment interval to the regimen of drug therapy, for which previous data obtained with humans showed a short-term higher prevalence of bleeding than is the case among long-term users of contraceptives. (See Sgau (1990); Siireu ei ai., (1982), zirga). Vaginal smears (applicators with a cotton tip soaked in 0.990 saline solution) and other C manual procedures were performed daily between 7 and 9 am to detect bleeding (recorded subjectively as spotting, moderate flow, or clear menstruation). Only in treatment cycle 2, but including the preceding week, daily blood samples were collected from the femoral vein under light ketamine anesthesia (30-5Omg, at Vetalar, Park Dzwys, Maurice Plains, New Jersey). The serum was collected and frozen (-152C) for radioimmunonological analysis of estradiol and progesterone (Oapiogii eiai., (1989); uap Mepiei eiai., (1989) zirga)|, which ended before the beginning of part II of the study, providing such an image that inhibition of ovulation was achieved by regimens of ultra low doses.

In Part II, 30 of these primates were randomly assigned to five treatment groups, six in each of these groups: (I) oral contraceptive therapy used in Part I was continued (214-7-day regimen) during b months, (2) continuous (no "pill-free" interval) 32 daily estrogen-progestin drug therapy, with a combined one-day oral dose - actiprogestin (KO 486) on the 30th, 60th, 90th, 120- th, 150th and 180th day of the study; (3) the same as in group 2, except that the progesterone antagonist was given only on the 60th, 120th, and 180th day; (4) the same as in group 2, except that KO 486 was given only on the 90th and 180th day; and (5) 180 days of continuous daily estrogen-progestin therapy, but without any antiprogestin treatment.

Daily observation for the purpose of detecting vaginal blood, as in Part I above, was stopped on the 187th day. Femoral blood was collected once a week during the entire period for identification

And" possible sudden ovulation due to an increase in progesterone; the values of oxyserum more than 1.Ong/ml were considered indicative of the luteal function of the ovary and possible ovulation. Similarly, the same samples were analyzed for levels of estradiol to observe the incipient estrogen biosynthesis. Two monkeys, in a group | and in group 3, there were exclusions from the current protocol, one due to skin rashes, and the other due to inspection of the thumb cyst, which required local treatment. One of these cases was not believed to be related to hormonal treatment.

To achieve oral contraception with ultra-low doses and to adapt the purchased drugs used in research to the smaller (than in humans) body weight of these laboratory primates 2) 20, an oral dose of 1.2 μg/day of ztinyl estradiol and 0.0 bmg/day was used norstindrone acetate. This was achieved by grinding into powder a commercially available pill ("Loestrin 1/20" in an overnight 21-day pack, Park

T» Davis, Maurice Plains, New Jersey), containing 1 mg of norsthindrone acetate and 2 µg of ztinyl estradiol per tablet.

In the Part I cycle, KO 486 ("Mipepristone", Russel Uclaf, Paris) was given intermittently as the only 5X0-milligram tablets in combination with a continuous regimen of oral contraception

F! strogen-progestin, with the exception of animal groups 1 and 5. Previous studies have shown that this dose of KI 486 will be sufficient to displace natural progesterone from endometrial, myometrial, and cervical receptors, thus it is rapidly (generally within 48 hours) and complete rejection of both uterine fundus and isthmus, comparable to spontaneous menstruation. 60 ISm. Neaiu ОЙ, ей ай., "Repiy Ziegiz" 1983; 40:253; Baptopii OK ei a)!., Sopigaseriiop 1989; 40:199).

Because the estrogen and progestin components! combinations were already performed, progestin was included even during the intervals of giving KI 486.

If compared with the equivalents of the human dose, then the daily dose received by monkeys, taking into account the body weight of monkeys), is equal to approx. bkg, and the body weight of women with bOkg was approx. 12 micrograms of ethynyl estradiol and 0.0 mg northindrone acetate. Thus, this ultra-low-dose oral contraceptive formulation represents a 60-96-fold reduction in the amount of estrogen-progestin that the body is exposed to, compared to one of the lowest-dose combined oral contraceptives currently commercially available in America or Europe. Further, taking in

Please note that with a continuous regime of treatment with ultra-low doses, in which there will be 92 treatment days per hour more than with the traditional 214-7-day protocol, such treatment still reduces the dietary norm of xogenic estrogen-progestin effects by more than 2095.

Statistical evaluation of results

Differences between the group results of the study in Part I, calculated as mean values and 7/0 standard errors, were compared using the P statistical test at the confidence level of P«0.05.

Although two of the observed menstrual factors (power of sudden bleeding and duration of menstruation due to the withdrawal of medication ("pill-free" menstruation)) did not show any significant differences (P»20.05), certain trends were observed, namely (1) power sudden bleeding was noticeably lower in cycles 2 and 3; and (2) the duration of menstruation, 7/5 due to withdrawal of medication during the "needle-free" interval, was slightly less in each month. In turn, the frequency of amenorrhea caused by the withdrawal of medication (the third observed menstrual factor) actually increased significantly (P<0.05) in the treatment cycle C versus the 1st.

The circulating levels of estradiol and progesterone indirectly reflected the inhibitory effect of estrogen-progestin therapy on gonadotropin secretion by the pituitary gland. Although serum estradiol increased markedly by 2% during the "pill-free" intervals adjacent to drug-taking days in cycle 2, follicle maturation was inhibited by the resumption of drug therapy, as indicated by the highest levels of approx. bOpg/ml without therapy and suppression to approx. 25 pg/ml on the 21st day. Since serum progesterone levels remained at or near the lower limit of detection throughout the study, these data strongly indicate that ovulation was probably permanently blocked in all 32 monkeys. with

Now, what you got in Part II of the research, bring it! according to the treatment group with the profiles of zondometrial bleeding After six cycles of treatment up to 180 days. Average (ZEM) number of days of sudden o); bleeding or menstruation was calculated by dividing the total number of registered cases (per treatment cycle in the case of group 1 or a 30-day interval for groups 2-5) by the number of observed individuals in the group. In the table presented by the given menstruation (bleeding as a result of the withdrawal of "E zo lekretsv or izzvannym in the expected interval") was considered vaginal blood, detected during the "no discharge" interval for the groups! 1 or within seven days after intermittent administration of KI 486 during continuous oral contraception with ultralow doses (groups 2-4). Similarly, the absence of vaginal bleeding during those periods of expected menstruation, either as a result of withdrawal of oral contraceptive therapy or shortly after giving a progesterone antagonist, was considered - with 5 amenorrhea due to withdrawal! taking medication Cha

For group 1, the frequency of sudden bleeding changed little from the 1st to the 2nd treatment cycle. However, the data obtained as a whole in Part II, in comparison with the data of Part I, showed a 2.4-fold decrease (Р«0.05), progressively, in the capacity of sudden bleeding. Statistical significance (E «0.05) was also achieved in treatment cycles 3 and 6 of Part II in comparison with treatment cycle 1 of Part I.

For groups 2-4, in connection with the pre-existing single doses of Ki 486, administered at intervals of 30, 60 or 90 h with days, the total frequency of sudden bleeding was reduced by 5095 (P «0.05) when a statistical comparison was made for all combined data from groups 2-4 against group 1. However, group 5 reacted uniquely to oral contraception with ultralow doses. The frequency of sudden bleeding increased moderately in the 5th and markedly in the 6th 30-day interval in comparison with all other studied

In groups (Р«0.05). -i In relation to menstruation caused by the withdrawal of pills or caused by the introduction of KI 486, an ultra-low-dose oral contraceptive administered according to the traditional 214-7-day regimen had as a result fewer (P«e0.05) days of menstrual flow than in the previous treatment (Te) with a spontaneous menstrual cycle (1.7-0.5 days in total versus 3.7-1.6 days, respectively); menstruation from 50 days after the administration of KI 486 was longer (3.1-0.8 days; P.0.05) than in the prairie cycle with the introduction of only pills. There were no noticeable differences in the bleeding profiles among the groups in which Ki 486 was given (P 20.05). Finally, those primates that underwent a continuous course of oral contraceptive therapy with ultra-small doses of the drug for 180 days (group 5) demonstrated a longer duration of menstruation due to the withdrawal of the drug than other treatment groups! (4.9--3.5 days, P«0.05). However, the observed individual differences did not allow us to derive a statistical regularity (Р»0.05) from the data obtained in the previous treatment cycle.

The frequency of amenorrhea in Part I was markedly reduced when KO 486 was added intermittently to a continuous regimen of oral contraception. In fact, none of the monkeys observed the absence of bleeding after the administration of KI 486, although in some the presence of vaginal blood was short-lived, 60 one or two days. In contrast to that, when one common 21-7-day regimen or continuous administration of one ultra-low-dose contraceptive was used, the prevalence of amenorrhoea was 20 to 3095 (Р«0.05).

Throughout Part I, weekly serum progesterone levels remained below 1.0 ng/ml, with the exception of one case when the level was 1.4 ng/ml. Re-analysis of that sample revealed a concentration of 0.2 bng/ml, which allowed us to assume that the initial value could be the result of an incorrect analysis, and did not indicate a possible increased follicular or luteal activity of the ovary. At the same time, total concentrations of serum estradiol during the 180-day study were 37--19, 23-77, 27--7, 22-55, 25--3 and 26-4-6 pg/ml for groups 1-5, respectively, illustrating overall significantly (P<0.05) lower levels of osstrogen during regimens of oral contraceptives with the help of an ultra-low-dose contraceptive, regardless of KO 486.

These data are consistent with the use of an ultra-low-dose oral contraceptive, sufficient to block ovulation, when using either the usual regimen of drug therapy for 21 days plus 7 "pill-free" days, or treatment without a break for 180 days. However, the frequency of occurrence of bleeding problems, both instantaneous bleeding and amenorrhea, caused by the withdrawal of 70 medications, during the "pill-free" interval, increased, regardless of whether the treatment regimen was a traditional 214-7-day scheme or extended continuous therapy, relatively since KI 486 was given in combination with estrogen/progestin therapy.

Addition of antiprogestin KI 486 intermittently at 30-, 60-, or 90-day intervals! was accompanied by two improvements in bleeding profiles. Decreased sudden bleeding in the 75 intermenstrual interval and reliable menstruation at the expected time were observed, thus eliminating amenorrhea caused by drug withdrawal. Also, in general, the duration of induced menstruation was somewhat longer after KI 486. When continuous oral contraceptive treatment was used without KI 486, the frequency of sudden bleeding increased markedly in the 5th and, especially in the 6th 30-day interval. In similarly treated females, which were given a single progesterone antagonist with intervals of 30, 60 or

From 0 days, the power of sudden bleeding was always the lowest (by 5795 lower) in comparison with the data when using the traditional scheme of treatment 21-47 days or continuous dosage, but without anti-progestin.

The frequency of sudden bleeding among women who start using oral contraceptives is known to be higher in the initial cycle! reception of pills than in the following.

It is believed that this observation, which is often reported, probably reflects both the biological effect of hormonal adjustment on drug therapy, and unreliable adherence to the treatment regimen by women who have insufficient oral contraceptive use. The results of the experiments described above and9) in this model with primates partly agree with these opinions, namely, a progressive decrease in the frequency of sudden bleeding was observed during the first 3-4 months of treatment with ultra-low-dose oral contraceptives taken according to the usual 2147-day "f zo" scheme.

Although the observed absolute frequency of sudden bleeding was lower than the often reported frequency in women, this may be due to the forced compliance of the monkeys during the experiment (F and/or other differences related to dose, regimen, or species. Moreover, stabilization of these primates on the same cycle regimen for three cycles in Part I before dividing them into five groups in Part II may have improved our understanding of the effects of KO 486 on the problem of bleeding control associated with oral contraceptive use Not only was KO 486 always associated with significantly less breakthrough bleeding, but aptiprogestin reliably prevented some bleeding in all cases within 72 hours, whether given at 30-, 60-, or 90-day intervals.

Without intermittent treatment of KI 486, the frequency of amenorrhoea during the expected bleeding time increased both with one routine regimen 2147 and with one 180-day continuous treatment (group 5). The last date is 223

The Ghanaians make it clear that the regime is uninterrupted! oral contraceptives require time-to-time removal of the zondometrial tissue to prevent cumulative abnormalities in bleeding. and" Based on the previous data, it is possible to give several possible explanations for the improved regulation of bleeding during a continuous regimen of oral contraception with ultralow doses plus intermittent administration of KI 486. For example, the levels of serum estradiol almost did not change, remaining about 25 pg/ml, and in the absence of secretory vibrations of estradiol, which characterize the "pill-free" interval during the transitional "follicular" leakage, when the traditional regimen is used! 2147 days, 7 treatment with KI 486 can act in three ways: (1) due to its antimutagenic (Ce) properties, it imposes restrictions on zndometrium, on modulation of rapid zndometrial proliferation; (2) elimination of an excessive degree of predominance of progestin over estrogen (and the ratio of norstindrone acetate: ztinyl estradiol is 50:1); and (3) extension of continuous regime! oral

HT" contraceptives, which contain the accumulation of zndopetrial tissue, and extremely high power of sudden bleeding can lead to compensation! by rejection, from time to time, fabrics.

In general, the data obtained in this study of primates are consistent with the feasibility of (1) a further reduced daily dose! estrogen-progestin oral contraceptives; (2) continuous regimens of oral contraception with ultralow doses of contraceptives, in which iF) the interval of daily pill intake is extended to 30, 60, and 90 days without a break; and (3) intermittent administration of a single dose of an antiprogestin in combination with continuous regimens of oral contraception to reduce the intensity of intermenstrual bleeding and to achieve elimination of amenorrhea due to withdrawal of medication, both of which are known to be associated with current regimens of oral contraception lower doses.

Thus, the present invention provides increased reliability of oral contraception, satisfaction of the user and compliance with the regime and schemes! treatment without jeopardizing the effectiveness of contraception. Moreover, since the effectiveness of preventing pregnancy in women is not sacrificed and, in fact, can be increased with a continuous estrogen/progestin regimen that does not require the user to remember the end and start days, as is the case with 21-day pill packs cycle, and the patient's main complaint of menstrual pain is significantly reduced due to the shifting inclusion of an antiprogestin, then ultra-low-dose oral estrogen/progestin contraceptives! thus become highly desirable! for sexually active women from adolescence to menopause! inclusive

In addition, although some women want regular periods every four weeks (13 times a year) from their cyclic oral contraceptive therapy due to withdrawal of the drug, others prefer less frequent periods, assuming that there is a reliable and effective product designed to to ensure menstruation less often, for example, only four times an hour. 7/0 The present invention, which uses a combination of a low-dose estrogen-progestin pill in a continuous mode with aptiprogestin, prescribed only after stretching the interval when menstruation is desired or medically indicated, offers exactly such a product.

Also, menstruation caused by discontinuation of medication in some post-menopausal women, regardless of whether they use sequential or simultaneous estrogen/progestin therapy, /5 is the main reason for non-compliance with regimens and regimens! treatment The therapeutic regimen in accordance with the present invention can overcome the patient's aversion to frequency-dcyclical vaginal bleeding, without sacrificing reliability and efficiency, by using continuous estrogen replacement therapy, combined with progestin with intermittent use of antiprogestin in order to reset the accumulated zondometrial tissue only a few times in year, encourages post-menopausal patients, due to less frequent menstruation, to remain on hormone replacement therapy with its obvious long-term benefits for the cardiovascular system and bone preservation.

In the case of hormone replacement therapy, the patient's main complaint of sudden bleeding is significantly reduced due to the intermittent inclusion of an antiprogestin due to its antimyotic activity, which can serve as an addition to the inhibitory effect of the progestin itself on the growth of the zondometrium, and its beneficial effect on the vascular bed of the zondometrium. Bleeding caused by the withdrawal of the drug, following the administration of an antiprogestin, should not necessarily occur - due to the absence of io) zondometrial transformation of the progestin.

An example of HER

Intermittent inclusion of antiprogestin during estrogen replacement and estrogen plus "Eso progestin therapy"

Receive Fr

Twenty cynomolgus monkeys (Masasa Gazsisciagiz) with pre-cut ovaries were inoculated with Ge! on day 281, one subcutaneous capsule containing estradiol. Excretion of estradiol from the capsule! resulted in a serum estradiol concentration of approximately 75 pg/ml. On the 191st day, a subcutaneous progesterone capsule was implanted, which remained in place until the 281st day. Excretion of progesterone from the capsules resulted in a serum progesterone concentration of approximately 4 ng/ml.

The research was conducted on the equipment intended for the study of animals at the Medical School

Eastern Virginia, described in example I.

Research plan «

The purpose of this study was to assess sudden bleeding before and after treatment with onapristone in ovariectomized monkeys on estrogen replacement and estrogen plus progesterone therapy. Twenty monkeys beat distributions! according to the following four groups: group 1 receives the carrier (saline solution) of onapristone for 30, 60, 90, 120, 150, 180, 210, 240 and 270. day. Group 2 receives Zmg/kg of onapristone intramuscularly on the 30th, 60th, 120th, 150th, 180th, 210th, 240th and 270th day. Group C is given

Omg/kgonapristone intraarm on the same day. Group 4 receives ZOmg/kg of onapristone intramuscularly on the same day. Vaginal swabs were taken daily from the first to the 281st day. The primary parameter for assessment in this study is the occurrence of vaginal bleeding. ш- Preliminary results of ongoing studies with As a result of progressively continuing treatment with estradiol, there is an increase in the power of sudden bleeding in the group that was given the vehicle (group 1). Treatment with onaprion in groups 2-4 does not cause bleeding, but reduces the frequency of sudden bleeding. It is worth starting a combined treatment with estradiol and progestin, as onapristone causes vaginal bleeding.

An example of a set of medicines

A set of medicinal products is offered, containing 28 common single-dose tablets intended for oral use, each containing 12 μg of estrogen-xtinyl-estradiol and 0.bmg of progestin-norsteindrocacetate. iF, (a) In one version, mood pills! in an ordinary round or elongated oval ("hippodrome") configuration, with pointers corresponding to the days of the week, so that the patient could easily confirm compliance with the daily intake regimen. For an example of such products, see "Levien-28" Laboratory Berlex. The tablet, intended for reception on the 21st day or later, contains, in addition to ztinilostradiol and norstindrone acetate, 500 mg of antiprogestin KI 486 ("Mifepristone", Russel Uklaf). (c) In another embodiment, 20 or more, e.g., 20, 23, 24, 30, 60, 90 or 120, estrogen-only and progestin-only or estrogen-only tablets are individually packaged in containers, e.g., 65 flat face bottles or in a flat metal box with a snap-open top, such as is commonly used to store aspirin tablets, or a similar container. Separately packed,

for example, a tablet containing aptiprogestin alone or in a mixture with estrogen and progestin is placed in an available cavity in a bottle cap or in a blister pack glued to one side of a bottle or a metal box. On the package for this pill, there is a place where the doctor (or the patient) must write the day and month when this pill should be taken instead of other pills (when this pill contains both aptiprogestin, estrogen and progestin) or in addition to the second pill (when this pill contains only aptiprogestin). The set contains the amount of tablets required to provide continuous estrogen/progestin therapy during one menstrual cycle of 28, 30, 60, 90 or 120 days. 70 (c) In the second variety, all the descriptions of their sets, which in all other respects correspond to the first version, the amounts of strogen and progestin are changed, i.e. in the first 7 tablets, their amount is 35 μg and 1.5 mg per tablet, respectively; in the next 7 tablets - respectively ZOomkg and 0.8mg per tablet; in the next 7 tablets - respectively 20mg and 0.bmg per tablet and in the last 7 tablets - respectively 5mcg and 0.4mMg per tablet. (4) In the variants of each of the sets described above, norstindrone acetate in tablets is replaced by 25 μg of gestodene. (e) In the second varieties of each of the sets described above, estrogen is replaced by 20 μg of mestranol. () In the second varieties of each of the sets described above, aptiprogestin is replaced by 500 mg 2o onapristone.

Previous examples! can be repeated with similar success by replacing the reagents and/or working conditions used in them to describe the reagents and/or working conditions according to the present invention by generic and species characteristics.

From the above description, a specialist in this field can easily establish the essential c 2g5 characteristics of the present invention, and without going beyond the limit! and without deviating from the essence of the present invention, makes various changes and modifications to it in order to adapt it to various purposes and conditions of use.

Claims (14)

The formula of the invention in 30 so 1. The method of contraception, which involves the introduction of dosed amounts of estrogen and progestin, which are effective in blocking folliculogenesis and thereby create a contraceptive effect, but small enough to prevent the occurrence of cases of sudden bleeding and amenorrhea due to drug withdrawal, which differs in 35 WHEREAS, estrogen is administered continuously daily and at intervals of approximately one month or more to stimulate menstruation by administering to the male mammal an amount of an antiprogestin effective to cause rejection of accumulated endometrial tissue. 2. The method according to claim 1, which differs in that the antiprogestin is administered approximately once a month. C. The method according to claim 1, which differs in that the antiprogestin is administered at intervals longer than a month. sv 4. The method according to claim 1, which is characterized by the fact that the progestin is administered without interruption during the entire cycle, including the time of menstruation. 1" 5. The method according to claim 1, which differs in that the progestin administration is interrupted on the day closest to the antiprogestin administration day. 6. The method according to claim 1, which differs in that the antiprogestin is administered orally. -AND 7. The method according to claim 1, which differs in that mifepristone is used as an antiprogestin. 8. The method according to claim 1, which differs in that ethinyl estradiol is used as an estrogen. - 9. The method according to claim 1, which differs in that norethindrone acetate is used as a progestin. co 10. The method according to claim 1, which differs in that the female mammal is a gonadal female and the amount of injected estrogen and progestin is effective to block folliculogenesis and thereby create a contraceptive state, while the antiprogestin is administered orally; and the introduction of progestin continues without a break throughout their entire cycle, including menstruation. 11. The method according to claim 10, which is characterized by the fact that the antiprogestin is administered approximately once a month. 12. The method according to claim 1, which differs in that ethinyl estradiol or estradiol, or its complex ester (5-15 μg/day), mestranol (20-25 μg/day) or conjugated estrogens (5- 15 μg/day). (F) 13. A contraceptive drug kit with the possibility of regulating menstruation, containing at least GI 28 estrogen- and progestin-containing tablets, all of which are effective, if 21 of them are taken daily, to achieve continuous oral contraception in a gonadal woman, but which contain amounts of estrogen and because of Progestin, are too small to prevent cases of sudden bleeding if the pills were interrupted during each monthly cycle to induce menstruation; and comprising a tablet positioned in the kit to be taken after at least 20 estrogen and progestin containing tablets have been taken and containing an amount of antiprogestin effective to induce menstruation. 14. A pharmaceutical composition in the form of a solid oral standard dose for contraception with the possibility of 65 regulation of menstruation, which includes amounts of estrogen and progestin, contraceptively equivalent from 5 μg to 35 μg of ethinyl estradiol and from 0.5 mg to 1.5 mg of norethindrol acetate, respectively, and the amount antiprogestin, effective in inducing menstruation in a woman who has taken adequate amounts of estrogen and progestin alone daily for at least 20 days. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 2, 15.02.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s o " so (22) cha m. Z s i" -I -I se) o 50 s" F) ime) 60 b5