Combined preparation for contraception, pharmaceutical packaging for contraception

 

(57) Abstract:

The invention relates to pharmaceutical industry and relates to a combined pharmaceutical preparation for contraception. The invention lies in the fact that the drug consists of the first stage, which contains a combination of three components, namely from biogenic estrogen, synthetic estrogen and progestogen and, if necessary, one or more further steps, which consist of pharmaceutically acceptable placeto, or biogenic or synthetic progestogen or estrogen, or from a combination of three components, or a combination of synthetic estrogen and progestogen, and consists of pharmaceutical packaging for contraception. The invention provides a new combination of substances for sequential reception, at which the total number of injected hormones clearly reduced. 2 S. and 6 C.p. f-crystals, 6 PL.

The invention relates to a combined pharmaceutical preparations for contraception during oral, endovaginal and percutaneous introduction.

Oral contraceptive drugs first became available in the early 60-ies. Due to incessant includestwo oral contraceptives with low-dose which consist mainly of the estrogenic component and gestagenna component. However, the imposition of hormones perform in various combinations and doses in the form of sequential /Stufen/ or phase of preparations for the 21st, respectively, for 28 days.

For gestagenna component as biologically active substances used are very different in chemical structure of steroids.

As the estrogenic component, preferably used are already known for more than 40 years ethinylestradiol or complex 3-methyl ether, mestranol. Mestranol is a prodrug and is metabolized in the body to ethinyl estradiol.

However, levonorgestrel has a number of disadvantages and side effects. Ethinylestradiol is bad and individually quite different absorbs in the gastrointestinal tract. It only leads to poor bioterrorist. In addition, ethinyl estradiol acts as a moderator of the "suicide" [Suizidaler Hemmer] on cytochrome P450-system. Due to this, come to the suppression own ways of destruction and metabolize. As the gestagen and many other biologically active substances enter into currency prophetic is riodic to the accumulation of biologically active substances in the body /W. Carol G. Klinger, W. Michels, J. Boer, Ch. Pocha; Untersuchungen zur Pharmakokinetik Kontrazeptiver Steroide unter den Bedingungen der Langzeitaufnahmen; Zent.-Bl. Gynakol., 113, S. 1298 - 1303; 1991/.

However, still could not find any alternative biologically active substances to ethinyl estradiol, respectively, mestranol to the field of oral contraceptives.

For example, in the patent Germany 32 29 612 describes what daily dose 0,020 - 0,040 ethinyl estradiol along with 0.3 mg to 0.8 mg norethindrone as gestagen need for reliable contraception.

Much more acceptable, autogenic [nutrient] estrogens, as 17-estradiol or estrone, for example, should be entered in micronized or conjugated form, for example, in the form of estradiolvalerate or astronought, oral or transdermal. However, only in very high doses more than 4 mg/day, achieved the required level in the blood, which guarantees sufficient proliferation of the endometrium and thus a good loop stability during reception /R. A. Lobo, and D. L. Cassident: Pharmacokinetics of oral 17-Estradiol, J. Reprod. Med. 37, S. 77 - 84/1992/ For this reason, the body's own estrogens are still not used to a greater extent for contraception.

When using estradiol, biogenic es is the amount of progestogen to achieve reliable contraception.

In several U.S. patents/4 530 839; 4 544 554; 4 628 051 and 4 921 843/ describes the various multi-phase oral contraceptive drugs, according to which during the whole cycle introduce a constant amount of ethinylestradiol and, for example, the 9th day of the cycle, a constant amount, respectively, of the increasing number of progestogen to improve the stability of the loop.

Task worthless invention is to provide a new combination of biologically active substances for sequential reception, at which the total number of injected hormones clearly reduced.

Another objective of the present invention is the development of a medicinal product in the form of daily dosage units, which are used for oral, endovaginal and transdermal introduction of a new combination of biologically active substances.

The present invention, then, is a creation of pharmaceutical packaging, which makes available a proposed according to the invention medicinal product in the required quantity and receive sequence of daily dosage units of individual stages.

The task according to the invention is solved by the fact that enter ethinyl estradiol and and or connections, chip off these estrogens in the body.

Proposed according to the invention combined preparation for contraception consists of one step, which contains a combination of three components, namely, biogenic estrogen, synthetic estrogen and progestogen, and if necessary one or more other steps which comprise pharmaceutically acceptable placebo or biogenic or synthetic progestogen or biogenic or synthetic estrogen or a combination of three components, namely, biogenic estrogen, synthetic estrogen and progestogen, or a combination of synthetic estrogen and progestogen.

Biogenic estrogen, according to the invention has at least one part of the group, including estradiol, estrone, estran, estriol and other biogenic estrogen, or at least one compound that quickly after taking otscheplaut one of the above component parts of the estrogen.

Synthetic estrogen, according to the invention has at least one part of the group, including levonorgestrel, mestranol and other synthetic estrogens, or at least one connection, cocorose invention has at least one part of the group, including levonorgestrel, desogestrel, progesterone, norethisterone, chlormadinone, gestodene, tsiproteronatsetat and other natural and/or synthetic progestogen, or at least one compound that quickly after taking it to one of the above parts progestogen.

It has been unexpectedly found that the simultaneous introduction of synthetic and biogenic estrogen leads to a synergistic effect. Dosage of synthetic and biogenic estrogen in particular and in General less than that required to achieve this effect, the appropriate dosage of the individual components. Additionally injected dose of progestogen is in the region of the compared drugs according to the prior art.

Contraceptive effective, proposed according to the invention the combination contains:

a) 0,005 - 0,010 mg/day of ethinyl estradiol or mestranol and

b) 1 mg/day of estradiol or estradiolvalerate or etranslate and

in) 0.125 mg/day of levonorgestrel or 0,150 mg/day desogestrel or 0.6 mg/day norethisterone or 2 mg/day dienoguesta or 2 mg/day of chlormadinone.

The introduction is carried out over a period of time the first 21 is integral with placebo or no impose any pharmaceutical drug.

With the simultaneous introduction of synthetic and autologous biogenic estrogen can significantly reduce the total number of biologically active substances. This leads to a reduction of side effects, which would otherwise be caused due to high dosages of synthetic or autogenous estrogen.

Another composition and daily sequence of use of proposed according to the invention a combination of biologically active substances provides, for the first 21 days of the cycle, the introduction of such biologically active substances in the same dosage, with only 22-day and 28-day cycle is injected autologous estrogens, such as 2 mg/day of estradiolvalerate or 1.5 mg/day etranslate.

The next step in the sequence of reception of the offer according to the invention a combination of biologically active substances is the introduction of 0.01 mg/day of ethinyl estradiol, respectively, an equivalent amount of mestranol, in combination with 1.0 mg/day of estradiolvalerate or etranslate, from the 1st to the 6th day of the cycle. From the 7th to the 21st day enter 0,005 mg/day of ethinyl estradiol with 1 mg/day of norethisterone, respectively, 3 mg/day dienoguesta or chlormadinone, or equivalent not take any pharmaceutical drug.

Further application of the proposed according to the invention a combination of biologically active substances in the form of a multi-stage combined drug is the introduction of 0.005 mg/day of ethinyl estradiol or an equivalent amount of mestranol with 1.5 mg/day autogenic estrogen - estradiolvalerate or etranslate together with 0.05 mg/day levonorgestrel or 0.8 mg/day dienoguesta or equivalent amount of other getragen, from the 1st until the 6th day of the cycle. From the 7th until the 12th day of the cycle introduces the combination of 0,0075 mg/day of ethinyl estradiol and 2 mg/day of estradiolvalerate or etranslate and 0.75 mg/day levonorgestrel or 12 mg/day dienoguesta or chlormadinone or an equivalent amount of another gestagen. From the 13th until the 21st day of the cycle take 0,005 mg/day of ethinyl estradiol and 1.5 mg/day of estradiolvalerate and 0.125 mg/day levonorgestrel or 2 mg/day dienoguesta or equivalent amount of other progestogen. In the remaining days of the cycle is injected pharmaceutically unquestioned placebo or not taking any pharmaceutical drug.

Proposed according to the invention a combination of biologically active substances administered in the form of oral, primeneniyu, pills or capsules with the medicine. Form compositions get itself known, when the conventional auxiliary agents and carriers, for example, described in "Remington''s Pharmaceutical Sciences Handbook, Hack. Pub. Co., New York, USA".

One possible application of the proposed according to the invention a combination of biologically active substances is an introduction in the form of vaginal suppositories and vaginal capsules. For this purpose, vaginal suppositories and vaginal capsules prepared by conventional means with the conventional auxiliary substances.

Proposed according to the invention a combination of biologically active substances, then you can enter in the form [TRANS] therapeutic system /TTS/. For this proposed according to the invention a combination of biologically active substances in itself known manner contribute in TTS. TTS can be based, for example, on the effects of iontophoresis or by diffusion or, if necessary, on the combination of these effects.

TTS is applied on suitable place on the body. The biologically active substance is then injected, transdermal, and the rate of infusion is adjusted to the size of the surface TTS and applied if necessary voltage.

The object of the present invention, therefore, are also pharmaceutical packaging, which differ in that they contain a dosing unit in a consistent sequence, and the sequence corresponds to the speed of daily nutrient intake.

Pharmaceutical packaging can be produced, for example, in the form globalwitness packaging. It is packaged, for example, 6 pills the first stage of [the combination of a gestagen and biogenic and synthetic estrogens], 6 drops of the second stage [pattern as in the first stage], 9 drops third stage [pattern as in the first degree] and 7 placebo, which can be removed, depending on the circumstances, daily, therefore, within 28 days. The packaging for the 21st day 7 runs without placebo. Changes relative to daily dosing, the execution of the forms of introduction, packing, etc. known to the specialist.

Example 1

Apply the vast ovulation tool, which contains twenty-one daily dosing unit, depending on the circumstances, with 0.01 mg of ethinyl estradiol, 1.0 mg of estradiolvalerate and 0.12 a very good contraceptive reliability it gives virtually no side effects, and bleeding come clearly less than the usual combination of 0.03 mg ethinylestradiol and 0.125 mg of levonorgestrel daily. There are no symptoms of side effects in relation to metabolic and circulatory heart. In contrast to conventional contraceptive drugs with a higher dose of levonorgestrel no influence on the exception of caffeine as a possible expression of negative damage to systems, destructive drug.

Example 2.

For inhibiting ovulation processing apply a two-step on the order of taking the drug, which contains 21 daily dosage unit, depending on the circumstances, with 0.005 mg ethinyl estradiol, 2 mg micronized 17-estradiol and 2 mg dienoguesta and 7 daily units, depending on the circumstances, with 2 mg micronized 17-estradiol. The tool used during the year. At high contraceptive reliability excellent kontrolowania cycle, i.e., compared to conventional contraceptive drugs not registered any intermediate bleeding. The duration and intensity of regular bleeding associated with a decrease in saralnuch hormonethe conventional contraceptive means with an increased dose of ethinyl estradiol, there is no impact on the metabolism and secretion of nifedipine as an expression of negative touching destructive drugs enzymes.

Example 3

For hormonal contraceptive use delaying ovulation means in the form of a two-stage preparation. During the first 6 days to introduce a combination of daily, 1.5 mg astroculture and 0.01 mg mestranola and then, in the days of the cycle 7-21, daily, take 1.0 mg of etranslate, 0.01 mg mestranola and 1.0 mg norethisterone. In the days of the cycle 22-28 do not take any drug. Tool taking for 8 months. Contraceptive reliability satisfactory, very good perceptibility. Women aged 30-38 years have reported on the effects of mood.

Example 4

For oral contraceptive use vast ovulation means in the form of a three-drug, which contains 6 daily units, depending on the circumstances, with 0.005 mg ethinyl estradiol, 1.0 mg of estradiolvalerate and 0.075 mg of desogestrel; the following 6 daily units, depending on the circumstances, with 0.005 mg of levonorgestrel, 1.5 mg of estradiolvalerate and 0.100 mg desogestrel, and, finally, 9 daily units with 0.005 mg ethinyl estradiol, 1.0 mg of estradiolvalerate is of 11 months. Contraceptive reliability is very good, the number of intermediate bleeding is relatively low. There was not a single test, which was interrupted by the drug.

Example 5

For inhibiting ovulation processing, use four contraceptive, which consists of 6 daily units, depending on the circumstances, with 0.01 mg of ethinyl estradiol, 1.0 mg of estradiolvalerate and 0.03 mg levonorgestrel; 6 daily units, depending on the circumstances, 0.01 mg of ethinyl estradiol, 1.0 mg of estradiolvalerate and 0.05 mg levonorgestrel; 9 daily units, depending on the circumstances, with 0.01 mg of ethinyl estradiol, 1.0 mg of estradiolvalerate and 0.100 mg of levonorgestrel, and, finally, 7 daily units, depending on the circumstances, with 2.0 mg of estradiolvalerate. The duration of treatment is 12 months. Contraceptive reliability corresponds to that of example 4, however, the control cycle is clearly better.

Example 6

For a contraceptive drug administration used the following combined treatment /treatment/: 21 daily unit, depending on the circumstances, with 0.015 mg mestranola and 0.05 mg of gestodene. Additionally, during the time between days 1 and 28 twice a week on the outer skin of the upper half of agogical 500 cycles. Contraceptive reliability corresponds to that of conventional contraceptives. There is no case of premenstrual complaints [malaise, feeling dizziness, hot flashes, causing the temperature rise, and so on].

Example 7

In the case of younger women with complaints about sexual life in the past year used the following contraceptive regimen: 21 daily unit, depending on the circumstances, with 0.005 mg ethinyl estradiol and 1.5 mg dienoguesta. Additionally on days 1-28 every 2 days using fast dissolving vaginal capsules, depending on the circumstances, with 10 mg of estriol. Contraceptive reliability of the same order of magnitude as conventional contraceptives. The vaginal epithelium, compared with the original condition, well krovosnabzhayutsya. Increased vaginal lubrication is perceived by patients as very pleasant, so the number of complaints about sexual activity is clearly reduced.

1. Combined drug concentration on the basis of estrogenic and gestagennogo component consisting of one or more further steps, characterized in that at least one of the degrees contains a combination of three components, namely biogenic estrogen, Sint is efticiency acceptable placebo or contain biogenic or synthetic gestagen, or contain biogenic or synthetic estrogen, or contain a combination of three components, namely biogenic estrogen, synthetic estrogen and progestogen, or contain a combination of synthetic estrogen and progestogen in an effective amount.

2. The drug under item 1, characterized in that the biogenic estrogen has at least one part of the group, including estradiol, estrone, estran, estriol or at least one compound, which after taking quick breaks one of the above component parts of the estrogen.

3. The drug PCP.1 and 2, characterized in that the synthetic estrogen has at least one part of the group, including levonorgestrel, mestranol or at least one compound, which after taking quick breaks one of the above component parts of the estrogen.

4. The drug PCP.1-3, wherein the gestagen is at least one compound of the group including levonorgestrel, desogestrel, progesterone, norethisterone, chlormadinone, gestodene, tsiproteronatsetat, or at least the connection that after taking quick breaks one of the above composite sustainainable application.

7. The drug PCP.1-6 for transdermal application.

8. Pharmaceutical packaging for concentration consisting of separate dosage units, characterized in that it contains up to 28 daily dosage units of a combined preparation of at least one of the above paragraphs.1-7 of the claims, and the number of daily dosage units of the first stage is 1-28, in the case of second-degree the number of daily dosage units for the second stage is 1-14 and in case there are other steps the number of daily dosage units for these further stages, depending on the circumstances, is from 1 to 7.

 

Same patents:

The invention relates to the field of medicine and relates to transdermal drug extended action with antiosteoporotic activity

The invention relates to the field of medicine and relates to transdermal compositions and tapes or dressings for transdermal delivery
The invention relates to medicine, namely to the dentist, and can be used for the treatment of gingivitis
The invention relates to medicine, in particular to the dentist, and can be used for the treatment of inflammatory periodontal diseases

The invention relates to the field of hygiene and sanitation, namely the composition for treatment of sanitary towels used to wipe the skin of the face, neck and other body parts
The invention relates to medicine , namely to wound dressings

The invention relates to chemical-pharmacological industry and relates to a method of obtaining pharmaceuticals and pharmaceuticals for oral administration and treatment of dermatological diseases

The invention relates to medicine and relates to methods of obtaining transdermal therapeutic agents
Patch // 2031648
The invention relates to the medical industry, namely, anti-inflammatory and analgesic drugs, in particular, compositions for the preparation of mustard

The invention relates to pharmaceutical industry and for the composition of the aerosol, in particular medicaments for injection

The invention relates to medicine, namely to pharmaceutical production, and for the creation of new dosage forms

The invention relates to medicine, namely to pharmaceutical production and for the creation of new dosage forms

The invention relates to medicine, namely to the pharmaceutical industry and relates to the creation of new dosage forms

The invention relates to the field of grinding pharmaceutical substances

The invention relates to medicine and relates to a method of obtaining emulsion based performancesin compounds able to carry oxygen and other gases, and can be used in the medical industry for the creation of artificial blood, radiopaque agents, and environments for the preservation of organs

The invention relates to medicine and relates to a method of obtaining emulsion based performancesin compounds able to carry oxygen and other gases, and can be used in the medical industry for the creation of artificial blood, radiopaque agents, and environments for the preservation of organs

The invention relates to the field of medicine and relates to transdermal drug extended action with antiosteoporotic activity
Up!