Pharmaceutical combined preparation for hormonal contraception

 

(57) Abstract:

The invention relates to the field of medicine and relates to a pharmaceutical combination preparation of the two, Packed in spatial terms separately in the same packaging unit, intended for oral administration at a time sequentially hormonal components, which consist, depending on the circumstances, placed in spatial terms separately in one packing unit and retrieved separately daily dosing units, and the first hormonal component as hormonal biologically active substance contains a combination of estrogen and at least sufficient to suppress ovulation dosage gestagenna the drug either in-phase or multi-phase execution, and the second hormonal component as hormonal biologically active substance contains only one estrogen drug, and the first hormonal component covers 23 or 25, and the second hormonal component covers 4-10 daily dosing units, daily dosage units of the first hormonal component does not contain a combination of biogenic estrogen and sintetica. This combination drug that is used to control the ability of women to produce offspring, allows for the possibility of low levels of estrogen in each dosage unit and also has a low total hormone levels on cycle with high contraceptive warranty, few cases of follicle development, immaculate control loop with a reliable avoidance of intermediate bleeding, as well as unwanted side effects. 5 C.p. f-crystals, 4 PL.

The invention relates to pharmaceutical combined preparation of the two, Packed in spatial terms separately in the same packaging unit, intended for oral administration at a time sequentially hormonal components, which consist, depending on the circumstances, from a number placed in spatial terms separately in one packing unit and retrieved separately daily dosing units, and the first hormonal component as hormonal biologically active substance contains a combination of estrogen and at least sufficient to suppress ovulation dosage gestagennye drug Lieb the key active substance contains only one estrogen drug, the first hormonal component covers 23 or 24, and the second hormonal component covers 4-8 daily dosing units, and daily dosage units of the first hormonal component does not contain a combination of biogenic estrogen and synthetic estrogen, and the total number of daily datirovochnykh units hormones equal to the total number of days is desirable, however, lasting at least 28 days cycle; and also to the corresponding containing this combined product packaging.

Oral contraceptives in the form of a combination of drugs known since 1960 in the form of a so-called single-phase drugs. These drugs consist of 21 containing a biologically active substance dosing units and 7 do not contain biologically active substances of tablets or pills. Daily dosing unit consists of estrogen and progestogen. In single-phase drugs daily injected dose of the active substances in each dosing unit is equally high. If the daily injected dose of the active components in separate dosage units in separate periods during the cycle of introducing different, then we are talking about the so-called multiphase products. As is thanks to the emergence of new, more effective progestogen as contained in the first oral contraceptives, can be continuously to reduce the daily dosage of progestogen is also possible to reduce the daily dosage of estrogen, although as estrogen in hormonal contraceptives are still often contain levonorgestrel.

In the development of new, improved contraceptives are at the forefront (and in the foreground are the following three points of view - you need to provide:

(1) contraceptive security;

(2) good control cycle, i.e., minor accident intermediate bleeding; and

(3) a minimum of undesirable side effects.

Contraceptive guarantee is invoked primarily gestagenna component. His daily dosing quantity, depending on the circumstances, corresponds to at least limit the dose, which is provided as required for the appropriate progestogen to suppress ovulation. Used in combined preparations as estrogen is most often levonorgestrel should increase suppressing ovulation effect of progestogen and to provide a first loop stability. Daily Afleet 100 mcg.

Combination of drugs with younger generations of gestagens are, for example, single-phase drugs Hemavan (patent Germany 2546062) or Marvelon (with the description of the invention to unaccepted application for patent in Germany 2361120). As a multiphase drug dosing units which contain a progestogen most of the young generation, namely, gestodene, it should be called, for example, Milan(European patent 0148724). In the case of these three drugs in the first phase injected most often 4-6 tablets, each tablet contains in a low dose amount of estrogen and a low dose gestagen. In the second phase of 4-6 drops each dosage unit contains estrogen in the same or slightly increased, the maximum is increased up to twice the dose and progestogen in the same or slightly increased, the maximum is increased to 1.5 times the dose. In the third phase of 9-11 units each tablet contains estrogen in equal or reduced again, the maximum is reduced to the original values of the dose and progestogen in further increased, the maximum increased three-fold from baseline dose. This cycle add 7 days without pills.

Recently were asked which of up to 24 days reception containing biologically active substance dosage units in a 28-day cycle. The daily dosage amount of gestagen from the first through the second until the third phase or increases (European patent A-0491415) or decreases (European patent A-0491438). To complement lasting 28 days cycle add in the first case, 4 days without pills, 4 placebo or, equally, 4 contains only progestogen dosage units, or in the second case, add 4-7 days without pills or 4-7 days of administration of a placebo.

Development of new oral contraceptives with lower daily dose of the hormone is intended to minimize described in epidemiological studies of side effects. More recent epidemiological data suggest this trend for the better acceptability of drugs with a lower dosage in relation to cardiovascular side effects (Thorogood M., Oral Contraceptives and Cardiovascular Disease: An Epidemiologie Overview; Pharmacoepidemiology and drug safety, Vol. 2:3-16 (1993); Gerstman, B. B., J. M. Piper, D. Tomita K., Ferguson, W. J., B. V., Stadel, Lundin E. F., Oral Contraceptive Estrogen Dose and the Risk of Deep Venous Thromboembolie Disease, Am J. E., Vol. 133, No. 1, 32-36 (1991); Lidegaard O., Oral contraception and rist of a cerebral thromboembolic attack; results of a case-control study; BMJ Vol. 306, 956-963 (1993); Vessey M., Mont D., Smith , A., Yeates D. Oral pl. 7-18 (1991)).

It is assumed relationship between the height (level) of the daily dose of estrogen and frequency of cardiovascular complications.

The drug with the lowest currently dosed amount of estrogen available in the form of Mercilonand contains 20 mcg of ethinyl estradiol in combination with 150 micrograms of desogestrel in each daily dosage unit for reception within 21 days from the subsequent seven-day interval without taking pills. The control loop in the case of this drug compared to drugs with a higher dose of estrogen, as expected, some worse. Further clinically significant problem is a matching in many cases, the observation of a smaller ovarian suppression in the application containing 20 mcg ethinyl estradiol drug. At this very low dose of estrogen in the case of many women come clearly to the maturation of the follicle, which can be detected by ultrasound, respectively, hormonal studies (Lunell, N. O., Carlstrom K., Zador G., Ovulation inhibition with a combined oral contraseptive containing 20 g ethinylestradiol and 250 g levonorgestrel; Acta Obstet Gynecol Scand Suppl. 88: 17-21 (1979); Mall-Haefeli, M., Werner-Zodrow I., Huber P. R. Klinische first experiences mit Mercilon and Marvelon unter besonderer Berucksichtigung der ovary - Contraception 45; 519-521 (1992); A. T. Teichmann , K. Brill, Can Dose Reduction of Ethinylestradiol in OCs jeopardize Ovarion suppression and Cycle Control? Abstract Book, VIII-th World Congress on Human Reproduction. Bali, Indonesia (1993)).

Up until now it was necessary to follow a multi-day break in the reception of containing a biologically active substance bean to invoke the cessation of bleeding and to ensure sufficient control cycle.

Describes other drugs that contain estrogen and gestagenna biologically active substance and which currency is administered for 21 days in unchanging quantities in each individual dosage unit, in which case the reception of these containing estrogen and gestagenna biologically active substance dosing units preceded by a reception containing only estrogen dosing units (Ijzerman, U.S. patent A-3502772; Pasquale, U.S. patent A-4921843; Kuhl and others, European patent A-0499348). In the case of these drugs at the beginning of the admission or on the first day of the cycle (Kuhe), or the earliest on the second day of the cycle (Pasquale) beginning with the admission of dosage units that contain only one biologically active estrogenic substance, namely, at a dose that is below suppressing ovulation dose estrogenic component of (Chowdhury and others, "Escape ovulation in women dueto the missing of low dose combination oral contraceptive pills, Contraception, 22:241-247, 1980, Molloy B. G. et al. , "Messed pill" conception: fact or fiction? Brit. Med. J. 290, 1474-1475, 1985).

Contraceptive protection due to this question. The risk of pregnancy so in particular, if the errors in the case of drugs with 20 g of ethinyl estradiol high.

From the Federal Republic of Germany patent 4308406 (not published) you already know the vast ovulation means in the form of a combined preparation for contraception, in the case of which is provided with at least one containing both estrogen and gestagen hormone component, which contains daily doses as biogenic estrogen and synthetic estrogen. The present invention does not apply to such drugs.

The present invention is to obtain a combined preparation with low estrogen in each individual dosage unit, but also with low total content of hormones in the round, with high contraceptive warranty should be achieved if possible slight chance of maturing follicles, impeccable control loop with a reliable avoidance of intermediate cu is to sagati unwanted side effects.

This task is solved through the preparation of the specified first two-phase combination preparation.

According to the present invention we prefer a combination of drugs, the first hormonal component which covers 24 and the second hormonal component which covers 4-8 daily units.

In the first phase, beginning with the first day of the cycle, introducing a dosage unit containing estrogen in combination with gestagenna component, daily for 23 or 24 days. It is followed by the second phase, in which during the remaining period of time before covering 28 days cycle for 5 or 4 days take one estrogen.

In the preferred case, within 24 days to introduce containing estrogen and gestagennye drug dosing unit and within 4 days shall be solely containing estrogen drug dosing units.

The first, containing both estrogen and the progestogen phase also can be made known to the specialist by way of multi-phase, for example phase (see this, for example, European patent A-0148724). This drug then you want to identify as the four drug. is receiving a proposed according to the invention combined drug in the first round effectively suppressed replenishment of the dominant follicle, which occurs in a spontaneous cycle during the first 6 days of the menstrual cycle. Thus, using the combination drug of the present invention in the first round, you can suppress the development of the follicle and thereby avoid ovulation, improving contraceptive warranty. Especially when incorrect reception it is of great importance, namely in particular in the case of hormonal contraceptives with a low daily dose of ethinyl estradiol. As in the case of 25% of women who take the pill, known errors (omissions dosing units or lengthening the interval to more than 24 hours between daily intake of the second dosing units) (Finlay I. G., Scott M. B. G.; Patterns of contraceptive pilltaking in an inner city practice. Br. Med. J. 1986, 293: 601-602), it is proposed according to the invention and the combined drug when it is used as the vast ovulation funds increases contraceptive warranty. This applies in particular to the medication with the lowest dosage. The increase in the number of dosing units higher than usual number with 21 days to 23 or 24 days results in an effective reduction of the interval without taking pills, in which case the usual combination of drugs is the development of follicles and produces additional endogenous estrogen. These follicles, as already indicated above, lead to the upcoming ovulation. These appear ovulation occur especially when the errors in increased measure.

The subsequent phase in which within 4-8 days daily drive dosage units that contain only estrogen component as hormonal biologically active substances, guarantees bleeding associated with a sudden decrease in ovarian hormones, and causes the stimulation of progesterone receptors in the endometrium, so that in the next cycle of administration is the reduced speed of the intermediate bleeding compared with conventional drugs with a low dosage.

According to a preferred form of the invention, the estrogen of the first hormonal component selected from the group of compounds: 17-estradiol, ethinyl estradiol and 17-estradiolvalerate; and gestagen selected from the group of compounds: gestodene, levonorgestrel, desogestrel, 3-keto-desogestrel, drospirenone, tsiproteronatsetat, norgestimate and norethisterone; and estrogen second hormonal component selected from the group of compounds; 17-estradiol, ethinyl estradiol and 17-estradiolvalerate.

According to the other is filling the dosing unit is contained in a dose of:

1.0 to 6.0 mg of 17-estradiol, 0.01 to 0.04 mg ethinyl estradiol, 1,0-6,0 mg 17-estradiolvalerate;

and gestagen in each daily dosage unit contains:

0.04 to 0.075 mg of gestodene; 0.05 to 0.125 mg of levonorgestrel; 0.06 to 0.15 mg of desogestrel; 0.06 to 0.15 mg of 3-keto-desogestrel; 1,0-3,0 mg drospirenone; 1,0-2,0 mg cyproterone; 0,2-0,3 mg norgestimate; 0,35-0,75 mg norethisterone.

As a daily quantity daily doses of the first hormonal component are particularly preferred 0,015-0,025 mg of ethinyl estradiol, 1.0 to 4.0 mg for 17-estradiolvalerate and 0.05-0.75 mg for gestodene.

Second hormonal component in each daily dosage unit preferably contains estrogen in the amount of:

1.0 to 6.0 mg of 17-estradiol; of 0.002-0.04 mg ethinyl estradiol; 1,0-6,0 mg 17-estradiolvalerate.

According to a particularly preferred variant of the second hormonal component in each daily dosage unit contains as estrogen ethinylestradiol in an amount of 0.01-0.025 mg, 17-estradiol in the amount of 1.0-3.0 mg or 17-estradiolvalerate in the amount of 1.0 to 4.0 mg.

The preparation according to the present invention contains preferably 28 of daily hormone units.

Of these gestagen for the second hormonal component, it should be noted gestodene; also preferred levonorgestrel.

17-Estradiolvalerate that can be contained both in the first and in the second hormonal component, referred to only as a possible representative of these 17-estradiolo esters within the scope of the present invention can also be applied to other similar homologous esters as the estrogenic component.

The following example is for a more detailed explanation of the present invention (see tab. 1).

The formulation of dosage units operate normally when applying for auxiliary preparations containing oestrogen with progestogen, and estrogen tablets, pills, pills, etc. auxiliary substances.

The number of daily doses in separate phases in the first hormonal component in the case of performing the proposed according to the invention combined drug in the form of a four-drug indicated below (see tab. 2).

According to the invention the ratio of the dosage of estrogen/gestagen in daily dosage units of the individual phases are below abuelita dosing in the first phase (see table. 3).

The composition proposed in the invention combined drug in the four-run can be seen from the following example (see table. 4).

Proposed according to the invention a combination drug used to prevent pregnancy women by taking daily dosage units of the first hormonal component for 23 or 24 days, beginning with the first day of the menstrual cycle (first day of menstrual bleeding), followed by 4-8 daily dosage units that contain only estrogen (E), for in General, at least 28 days in a cycle of reception. Using this combined drug can be achieved explicit ovarian suppression without frequent maturation of the follicle, as well as excellent control cycle at a low daily dosage of estrogen, low overall amount of estrogen, and low overall number of hormones on the round.

The benefits made generally within 28 days proposed in the invention combined drug (suppressing ovulation funds) compared with the so far described the preparations, particularly those with daily dozois follows:

1. Significantly lower rate of follicle development in applying this drug to women. This means less danger appearing ovulation and thus greater contraceptive reliability especially in the case of a receive error.

2. Replenishment of the dominant follicle is suppressed by lengthening reception, a combination of up to 23 or 24 days in the first cycle.

3. Welcome 4-8 daily dosage units of estrogen following the introduction for 23 or 24 days combined dosage of the drug leads to clearly improved control cycle and to fewer cases of side effects as headaches, in the framework of premenstrual syndrome.

4. Other clinical symptoms that can be reduced to the strongly varying endogenous levels of estrogen, such as the voltage of the chest, also clearly reduced on the basis of much stronger ovarian suppression in the range between 0.015 to 0.025.

The above advantages, in particular the suppression of follicle development and what is happening together with this, the inhibition of endogenous production of estrogen, in the case of proposed according to the invention kombinirovannykh what they preferred, as mentioned at the beginning.

The formulation of estrogen and progestogen for preparation of the proposed invention the combined drug carried out completely analogously to the known formulation for normal oral contraceptives with duration of treatment 21 days of biologically active substances, such as Hemavan(ethinylestradiol/gestodene) or Microgynon(ethinyl estradiol/levonorgestrel). The formulation containing only estrogen dosing units can also be carried out completely analogously to known formulation already received, intended for oral administration containing estrogen means, for example, as Progynon C.

Containing proposed according to the invention combined product packaging is prepared similarly to the packages already known, commercially available oral contraceptives, with the deviation that instead of the usual 21 containing the active constituent parts dosing units now have 23 or 24 dosage units and other 4-8, containing only estrogen dosing unit. As a packaging form for proposed according to the invention coastie for this purpose packaging forms.

In addition, the invention relates also to method of contraception women, in which the above-described combination drug is administered in this way.

To determine the equivalent effective amounts of ethinyl estradiol and 17-estradiol, on the one hand, and various gestagens, as gestodene, levonorgestrel, desogestrel and 3-ketodesogestrel, on the other hand, reference is given in European patent A-0253607 data. Other details to determine dosing equivalents of various gestagenna biologically active substances are, for example, in "Probleme der Dosisfindung; Sexualhormone"; F. Neumann et al. in Arzneimittelforsehung "(Drug Research) 27, 2a, 296-318 (1977); and in "Aktuelle Entwicklungen in der hormonalen Kontrazeption"; H. Kuhl in Gynakologe" 25: 231-240 (1992).

1. Pharmaceutical contraceptive combined product of the two, Packed in spatial terms separately in the same packaging unit, intended for oral administration at a time sequentially hormonal components, which consist, depending on the circumstances, from a certain number placed in a spatial relationship separately in one packing unit and retrieved separately daily dosing units, and Pervii estrogenic and at least sufficient to suppress ovulation dosage gestagennye drug or single-phase, or in multi-phase execution, and the second hormonal component as hormonal biologically active substance contains only one estrogen drug, and the first hormonal component covers 23 or 24, and the second hormonal component covers 4 - 10 daily dosing units, daily dosage units of the first hormonal component does not contain a combination of biogenic estrogen and synthetic estrogen, and the total number of daily dosage units of hormones is equal to the total number of days desired cycle.

2. Combination drug under item 1, characterized in that the estrogen of the first hormonal component selected from the group of compounds: 17-estradiol, ethinyl estradiol and 17-estradiolvalerate, and gestagen selected from the group of compounds: gestodene, levonorgestrel, desogestrel, 3-keto-desogestrel, drospirenone, tsiproteronatsetat, norgestimate and norethisterone and estrogen second hormonal component selected from the group of compounds: 17-estradiol, ethinyl estradiol and 17-estradiolvalerate.

3. Combination drug under item 2, characterized in that the estrogen of the first hormonal component in each dosage unit contains a dose of the full-time unit contained in the dose: 0,05 - 0.075 mg of gestodene, 0.05 to 0.125 mg of levonorgestrel, 0.06 to 0.15 mg of desogestrel, 0.06 to 0.15 mg of 3-keto-desogestrel, 1.0 to 3.0 mg drospirenone, 1,0 - 2,0 mg cyproterone, 0,2 - 0,3 mg norgestimate, 0,35 - 0,75 mg norethisterone.

4. Combined preparation according to one of p. 2 or 3, characterized in that the second hormonal component in each daily dosage unit contains quantity: 1,0 - 6,0 mg of 17-estradiol, a 0.002 - 0.04 mg ethinyl estradiol, 1.0 to 4.0 mg 17-estradiolvalerate.

5. Combination drug under item 4, characterized in that the second hormonal component in each daily dosage unit contains ethinylestradiol in an amount of 0.01 - 0,025 mg

6. Combined preparation according to one of paragraphs.1 to 5, characterized in that the total number of daily hormone units is 28.

 

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