MX2007016235A - New regimens for controlled drug delivery devices for contraception - Google Patents

Abstract

The subject invention provides for new regimens for contraceptive dosage forms.

Description

NEW REGIMES FOR CONTROLLED DRUG SUPPLY DEVICES FOR CONTRACEPTION Description of the Invention The present invention relates mainly to the field of female reproductive medicine, and particularly to the contraception of the female human. The present invention relates to new regimens for the administration of controlled drug delivery devices, for example, to obtain contraception or to treat and / or prevent other indications dependent on the hormonal cycle such as dysmenorrhea, menorrhagia, irregular menstruation, menstrual migraine and premenstrual syndrome (PMS, for its acronym in English). It is standard practice in the field of oral contraceptive regimens that the definition of cycle length is linked to a fixed number of days or weeks. This type of regimens evolved due to the need to pamper the menstrual cycle in the development of contraceptives. As a result, women begin a new cycle of contraception on a given day of the week, for example, Sunday, Monday, etc. Another result of the same is that the packages of patients with identical form and content (such as oral contraceptive strips with 21 or 28 tablets) can be produced which in turn ensure the economic production methods and help the user acquire habits for the consistent administration of the tablets for contraception. With the evolutive technology and new methods of drug supply, the cycle is no longer determined by the daily intake of active ingredients but by determinants of the drug delivery device or system itself. Controlled drug delivery devices are known in the art. For example, vaginal rings, implants, patches, hormonal intra-uterine devices (IUDs), aerosol devices, etc. are known in the art. used to obtain contraception. For example, a vaginal ring is a controlled drug delivery device for a complete cycle. European Patent 876 815 refers to the only commercially available vaginal ring (Nuvaring®) for contraception, which is designed for the simultaneous release of a progestogenic steroid compound and an estrogenic steroid compound. Nuvaring comprises 11.7 mg of etonogestrel (released at a frequency of 0.120 mg every 24 hours), 2.7 mg of estradiol ethinyl (released at a frequency of 0.015 mg every 24 hours) and ethylene vinyl acetate copolymer. The current regimen for this vaginal ring is that it is inserted for 21 days and then removed for a period of one week (7 days) to allow vaginal bleeding. After a week of allowing vaginal bleeding, a new ring is inserted into the vagina of the female to provide contraception in the next cycle or cycles of the female. The disadvantage of such a regime is that it requires the woman to remember many moments at a time. For each ring used, a woman should remember to take it off when the 21 days are over from the day of the placement and then remember to put a new ring when the 7 days are over. These crucial moments that must be remembered fall on different dates each time. For example, if a woman removed a ring on January 1, then a new ring should be placed on January 8 and removed again on January 29. A new ring should be placed on February 5, which ring should be removed later, on February 26, etc., etc. It is clear that it is difficult to keep those dates monitored. As a result some women forget to put on and / or remove their ring in due time, which results in unwanted pregnancies. Even if these devices are available to help the woman remember to start and remove her contraceptive (see for example, European patent 1257244), it would be desirable to have a regimen which maintains the effect of contraception and also automatically reminds the woman of the crucial dates, and in this way avoid the risk that the woman will forget to remove a ring (or other dosage form) or place a new ring (or other dosage form) and get pregnant. The reference invention now provides new regimens for the administration of contraceptive dosage forms (and for the administration of dosage forms to treat and / or prevent other cycle-dependent indications), which results in improved compliance while maintaining the efficacy of the contraceptive. This improved compliance is activated by the functional combination of at least two dosage forms as defined herein for at least two cycles. Compliance is activated with the administration of at least the second dosage form. Without at least the second dosage form, compliance should not be seen. And in this way, to obtain the effect of improved compliance, the functional combination of at least two dosage forms is a prerequisite. The new regimes of the present invention also result in women having only 12 periods per year as opposed to thirteen in standard regimens 21/7. Controlled drug delivery devices do not impose the contradictions of providing a fixed duration cycle. The present invention now experiences this new facility of providing regimes which are not limited to identical cycles of fixed implement duration to enable flexible cycle time. The reference invention has the important advantage of helping the consumer acquire habits, because the start and the elimination of a dosage form used in the scheme of the present invention is activated on fixed numerical days of the month. Thus, the invention provides a regimen for antisense with cycles of hormone administration for defined cycle durations, so that the cycle durations vary to correspond to the number of days of the month calendar in which the cycle begins. Both the "month" and the "calendar month" as used here mean any "month", i.e. January, February, March, April, May, June, July, August, September, October, November, or December. A "numeric date" as used here is any date of the month. For example, January has 31 numerical dates, January 1, January 2, January 3, etc., etc. February has 28 or 29 numerical dates; March has 31 numerical dates; April has 30 numerical dates, etc. "Cycle" as used in the reference invention is the duration of the number of days of the month in which the cycle begins. During the cycle there is a hormone-taking phase (or period or interval) and a hormone-free phase (or period or interval). For example, a cycle which starts in January is 31 days; a cycle which starts in February is 28 or 29 days depending on whether it is a bisinodic year or not; a cycle which starts in March has 31 days; a cycle which starts in April has 30 days, etc., etc. In addition, a reference cycle of the invention is a partial circle of events where the hormone levels in a woman increase or decrease due to the use of the dosage form. In order to complete the circle of events where hormone levels increase or decrease, increase again and decrease again, a woman must complete at least two cycles of the dosage form. "Begin", as used herein, means to apply or insert, or any form of contraceptive or pharmaceutical administration. For example, the patches are applied and the rings are inserted. "Remover", as used herein, means removing or removing or any form of eliminating a form of contraceptive or pharmaceutical dosage. For example, a vaginal ring is removed and a patch is torn. A dosage form, as used herein, means a controlled release drug delivery device such as a vaginal ring or a patch. A patch (a transdermal system), as used herein can be any patch (contraceptive) of any type, for example, matrix type, reserve type, a patch with multiple layers or a patch in which the drug is present in the adhesive while the patch that is used has sufficient active ingredient (s) for at least one cycle of contraception. The only commercially available contraceptive patch currently on the market is Evra®. The Evra® patch, however, contains enough active ingredients for only one week of contraception, i.e. not for an entire cycle as defined here. A vaginal ring, as used herein, can be any vaginal contraceptive ring such as Nuvaring® or vaginal rings such as described in WO 2004/103336, PCT / EP05 / 051189, U.S. Pat. 4,292,965, WO 97/02015, European Patent 887074. A dosage form useful in the reference invention may comprise an estrogen, a progestogen, or combinations thereof. Optionally it may also contain other active ingredients such as anti-microbial, folic acid, vitamins, etc. The progestogen as used herein can be any suitable progestogen, such as desogestrel, etonogestrel, levonorgestrel, norgestimate, norelgestromin, gestodene, nomegestrol acetate, dienogesto, drospirenone, or any other compound steroid or non-steroid with progestogenic activity. The estrogenic compound as used herein, can be any suitable estrogen (or salt thereof or ester thereof), such as estradiol, estriol, mestranol and ethinyl-estradiol or any other estrogenic steroid or non-steroid with oestrogenic activity. In a specific embodiment of the present invention, the progestogen is nomegestrol acetate.

In one embodiment of the present invention, estrogen is ethinyl estradiol. In another embodiment, the estrogen is estradiol or an ester thereof, or a salt thereof, such as estradiol hemi-hydrate. In a specific embodiment, the progestogen is etonogestrel and the estrogen is ethynyl estradiol or a salt thereof or an ester thereof. In another specific embodiment, the progestogen is nomegestrol acetate and the estrogen is estradiol or a salt thereof or an ester thereof. In a specific embodiment, the progestogen is etonogestrel and the estrogen is estradiol or a salt thereof or an ester thereof. In another specific embodiment, the progestogen is nomegestrol acetate and the estrogen is ethinyl estradiol. As used herein, both the "non-hormonal" and "hormone-free" phases are phases (or period or interval) during a cycle in which hormones are not administered. As used herein, "hormonal phase" is a phase (or period or interval) during a cycle in which hormones are administered.

A vaginal ring used in the reference invention may comprise one or more compartments. Each compartment may comprise one or more layers. Such a vaginal ring can be made of any suitable material to make these dosage forms. For example, a polymer can be used in the practice of the invention can in principle be any thermoplastic polymer or material suitable elastomer for pharmaceutical use, such as low density polyethylene, ethylene-vinylacetate copolymers, polysiloxane, polyurethane, polyacrylate and styrene-butadiene-styrene copolymers. In a specific embodiment, the ethylene-vinylacetate copolymer (poly-EVA) is used when it is commercially available under, for example, trade names; Elvax, Evatane, Lupolen, Movriton, Ultrathene, Ateva and Vestypar. In this way, improved compliance is activated using a method of human female contraception where the dosage form begins on the numerical date 'n + 3' of any month and removed on the numerical date 'n' of the next month where 'n' is the numeric date of one month from 1-25 regardless of the month and where the method is repeatedly carried out for at least two cycles. When this method is used, the non-hormonal phase is a period of no more than 4 days. This compliance improved is also activated using a method of contraception human female wherein the dosage form is started on numerical date 'm + 4' of any month and removed on numerical date 'm' of the following month wherein 'm 'is the numeric date of the month from 1-24 regardless of the month and where the method is repeatedly carried out for at least two cycles. When this method is used, the non-hormonal phase is a period no greater than days. This improved compliance is then enabled using a method of human female contraception where the dosage form begins on the numerical date 'y + 5' of any month and removed on the numerical date 'y' of the next month where 'y' is the numeric date of the month from 1-23 regardless of the month and where the method is repeatedly carried out for at least two cycles.When this method is used, the non-hormonal phase is a period no greater than 6 days. This improved compliance is additionally enabled using a method of human female contraception where the dosage form begins on a numerical date 'z + 6' of any month and removed on the numerical date 'z' of the next month where 'z' is the numeric date of the month from 1 to 22 regardless of the month and where the method is repeatedly carried out for at least two cycles. When this method is used, the non-hormonal phase is a period no greater than 7 days. The reference method of the invention can be used for any number of cells beginning with at least two cycles, Le. for two, three, four, five, six cycles, etc .; In a specific modality, the method is used by at least three cycles. In the methods of contraception of the present invention, the hormonal phase between months is not constant. The non-hormonal phase on the other hand is constant between calendar months. On the contrary, in all the modalities of the present invention, ovarian suppression (necessary to obtain contraception) is maintained and in some cases even improved. Compliance is thus activated by the fact that a woman can choose a particular numeric date of the month in which she finds an easy number to remember. On this day, the dosage form will always be removed. The effectiveness of contraception is maintained during the period of contraception independent of the fact that the hormonal phase is not constant between months, where the non-hormonal phase is constant between months. In this way, for example in a regime (n, n + 3), a woman can choose 'n' to be a numeric date between 1-25, regardless of the month. For example, the first of the month is in a large part an easy number to remember. In this example, in a regime (n, n + 3), a woman chooses 'n' to be 1, i.e. the first month. Then, the dosage form is inserted (started) every fourth day of the month ('n + 3' numerical date of the month). For example, the fourth of January, the fourth of February, the fourth of March, etc.

Etc. The dosage form is then removed on any first day of the month, for example, the first of January, the first of February, the first of March, etc. Etc. The woman now only has to remember the same two numeric dates each month, being the first and the fourth regardless of the month.

Even without limiting the reference invention, it is assumed that the dosage form is started on the fourth day of the month at the same time when it has been removed on the first day of the month, the duration of the hormonal phase is: -25 days in February -26 days in February in bisinodic year -27 days in April, June, September, November -28 days in January, March, May, July, August, October, December Within the same range, the duration of the hormone-free phase is constant and lasts 3 days. If the time of the day of insertion (beginning) is not the same time of the day of elimination then the hormone-free phase can not be longer, up to 4 days when for example, the woman removes the dosage form in 00.01 hours in the first month and insert (start) a new dosage form at 23.59 hours on the fourth day of the month. Thus, in the present example, the regimen (n, n + 3), the hormone-free interval is between 3-4 days but not longer at 4 days. For example, how much do we see a full year (non-bisinodic year) starting in January and assuming that the dosage form is inserted on the fourth day of each month at the same time as when it was withdrawn on the first day of the next month, then this regimen (n, n + 3) each month has a hormone-free period of 3 days and the days of hormone administration are as follows: The concept is similar for the regimens (m, m + 4), (y, y + 5) and (z, z + 6). In a regimen (m, m + 4), the hormone-free phase is at least 4 days but not longer than 5 days, in a regimen (y, y + 5), the hormone-free phase is at least 5 days but not longer than 6 days, and in a regimen (z, z + 6), the hormone-free phase is at least 6 days but not longer than 7 days. A regime of the reference invention has at least two advantages: The first, compliance is possible because it is much easier to remember, for a woman using a particular dosage form, that on a particular day of each month she is due withdraw (stop) the dosage form and 3, 4, 5, or 6 days later (depending on the regime that she chooses), it also results in a fixed numerical date of each month, she must insert (start) a form of dosage. Second, a regimen of the reference invention also maintains or improves the suppression of follicular development due to the long in-situ period of the dosage form and the shorter hormone-free period.; in other words, a regimen of the invention in reference maintains or in some cases still increases ovarian suppression. The reference invention also projects a contraceptive kit for the contraception of the human female which comprises at least two dosage forms, each dosage form for use in one or two sequential cycles, and each dosage form begins on a numerical date. n + 3 'of a month and removed on numerical date' n 'of the next month where' n 'is a numeric date of one month from 1-25. The present invention also provides a contraceptive kit for the contraception of the human female which comprises at least two dosage forms, each dosage form must be used in one or two sequential cells, and each dosage form should be started in a numeric date 'm + 4' of a month and removed on numerical date 'm' of the next month where 'm' is a numeric date of one month from 1-24. The reference invention involves a contraceptive kit for the contraception of the human female which comprises at least two dosage forms, each dosage form to be used in one or two sequential cycles, and each dosage form must be started on the date numerical 'y + 5' of a month and removed on a numerical date 'y' of the next month, where 'y' is a numeric date of one month from 1-23. The reference invention additionally provides a contraceptive kit for the antiseptic of the human female which comprises at least two dosage forms, each dosage form is used in one or two sequential cycles, and each dosage form must be started in a numerical date 'z + 6' of a month and removed on the numerical date 'z' of the next month, where 'z' is a numeric date of one month from 1-22. A reference contraceptive kit of the invention can be provided for any number of months starting with a kit for at least two months, i.e. a kit for two, three, four, five, six cycles, etc. If the kit, for example, is for three months, then of course each dosage form will be used in one or three sequential cycles; If the kit is for example for four months, then each dosage form will be used in one of the four cycles, etc. The reference invention also provides a reminder system for a dosage regimen comprising choosing a particular numeric date of the month from 1-25, regardless of the month, since a numerical date in which a dosage form is always removed and always A new dosage form begins three days later. The reference invention also projects a reminder system for the dosage regimen comprising choosing a particular numeric date of the month from 1-24, regardless of the month, since the numerical date in which the dosage form is always removed and always A new dosage form begins four days later. The invention of reference additionally involves a reminder system comprising choosing a particular numeric date of the month from 1-23, regardless of the month, since the numerical date on which a dosage form is always removed and always starts a new form of dosage five days later. The reference invention also provides a reminder system for a dosing regimen comprising selecting a particular numeric date of the month from 1-22, regardless of the month, since the numerical date on which the dosage form is always removed and always starting a new dosage form six days later. The reference invention also includes a contraceptive regimen for a dosage form of the reference invention wherein the hormones are administered for a defined duration, characterized in that the cycle lengths vary so as to correspond to the number of days on which it begins. the cycle. The defined duration can be any number of months starting at least two months, i.e. two, three, four, five, six months, etc. In a specific modality, the defined duration is three months. The present invention is further described in the following examples, which in no way tend to limit the scope of the invention as claimed.

EXAMPLE 1 Pharmacodynamic assay; n, n + 1 where n = 1 A comparative randomized, open-label pharmacodynamic trial conducted during the month of February, March and April with a commercially available contraceptive vaginal ring (Nuvaring®) on a monthly regimen of the reference invention where the ring is inserted every 4th of the month (n + 3) and then removed on the first day (n) of the next month compared to the standard 21/7 regime. This trial is carried out in healthy voluntary women to evaluate the effects of the vaginal ring in this monthly ovarian (pharmacodynamic) regimen compared to the effects on ovarian function in the standard 21/7 regimen. Forty (40) healthy pre-menopausal women between 18 and 40 years of age, at the time of monitoring participate in the trial for three cycles of treatment. The women are divided into two test groups, group A and group B. Trial group A uses the vaginal ring following the standard regimen where the rings are placed for 21 days followed by a ring-free period of 7 days. days. Group B uses the vaginal ring in a scheme of the reference invention where the ring is inserted every fourth day of the month and removed every first day of the following month.

Serum estradiol (E2), Progesterone (P), LH and FSH are measured three times a week and transvaginal ultrasound monitoring is carried out. A physical and gynecological examination is carried out in the monitoring and at the end of the treatment and cervical cytology is examined during the monitoring. EXAMPLE 2 Dynamic drug assay m, m + 4 where m = 1 A comparative dynamic, randomized open-label study essentially as described above in Example 1 is carried out in a lunar regime of the reference invention wherein the The ring is inserted every fifth day of the month (m + 4) and then removed on the first day (m) of the next month compared to the standard 21/7 regime. EXAMPLE 3 Dynamic drug test y, y + 5 where y = 1 A randomized, open-label, randomized study of the drug, essentially as described above in Example 1, is carried out in a monthly regimen of the reference invention wherein the Ring is inserted every 6th day of the month (y + 5) and then removed on the first day (y) of the next month compared to the standard 21/7 regimen. EXAMPLE 4 Dynamic drug assay z, z + 6 where z = 1 A comparative dynamic, open-label randomized study drug essentially as described above in Example 1 is carried out in a monthly regimen of the reference invention wherein the Ring is inserted every 7th day of the month (z + 6) and then removed on the first day (y) of the next month compared to the standard 21/7 regime. EXAMPLE 5 Exploratory Comparative Test A multicentre, open-label, five-group, randomized trial of comparative group with the regimens as described in Examples 1, 2, 3, and 4 compared to the standard 21/7 regimen is carried out with the same vaginal contraceptive ring commercially available to investigate different monthly regimens of the invention in reference in volunteers of healthy females. The efficacy of contraception, the characteristics of vaginal bleeding, safety, compliance and acceptability of these different monthly regimens is compared with the standard 21/7 regimen. Five hundred (500) healthy pre-menopausal women between 18 and 40 years of age at the time of monitoring participate in the trial for one year, i.e. for 12 months by the regimes of the reference invention or by 13 treatment cycles for the standard 21/7 regimen. Women are divided into five (5) groups: Test group A: standard regimen, 21 days of ring use, followed by a ring-free period for 7 days; The test group B; the monthly regimen of the reference invention wherein the ring is inserted on the 4th day of the month (n + 3) and removed on the first day of the following month (n); (3-4 days of free ring period); The test group C: the monthly regimen of the reference invention in which the ring is inserted on the 5th day of each month (m + 4) and removed the first day of the following month (m) (4-5 days of free period of ring); The test group D the monthly regimen of the reference invention wherein the ring is inserted on the 6th day of each month (and + 5) and removed on the first day of the following month (y) (5-6 days of free period of ring); The test group E: the monthly regimen of the reference invention wherein the ring is inserted on the 7th day of each month (z + 6) and removed the first day of the following month (z) (6-7 days of free period of ring). The evaluations are carried out in the monitoring (within a month before treatment) and in months 3, 6, 9 and 12 to a premature discontinuation. At the monitoring visit, the subjects provide the medical and gynecological history and undergo a physical and gynecological examination, including cervical cytology. The physical and gynecological exams are repeated on the last study visit. In addition, clinical safety laboratory tests are provided in the monitoring at the end of treatment. In all study visits, blood pressure and body weight are measured. A vaginal ultrasound for the evaluation of the endometrial thickness is elaborated in the monitoring and repeated after one year. Endometrial biopsies are taken if the endometrial thickness of the double layer is 10 mm or more. Urinary pregnancy tests are prepared by subjects before the start of the study treatment, at each study visit and if a pregnancy is suspected during the trial. The occurrence of adverse events and the use of concomitant medications are recorded through the trial. The patterns of vaginal bleeding and compliance are recorded on daily cards. EXAMPLE 6 Safety and efficacy test n, n + 3, where n = 1 A multicentre, open-label, two-group randomized trial of a comparative group is carried out to investigate the effectiveness of contraception, the characteristics of vaginal bleeding, compliance, safety and acceptability with the same vaginal ring as used in Examples 1-5 in the monthly regimen of the reference invention where the ring is inserted every 4th day (n + 3) of the month and removed every 1st day (n) of the next month compared to the standard 21/7 regime. One thousand three hundred and thirty healthy pre-menopausal women (1330) between 18 and 40 years of age at the time of monitoring participate in a trial for one year, i.e. for 12 months in regimens of the reference invention or for 13 treatment cycles for the standard 21/7 regimen.

Women are divided into two (2) groups: Trial group A: 330 women participate in a standard 21-day regimen of ring use, followed by a 7-day ring-free period (i.e. hormone-free); The test group B; 1000 women participate in a monthly scheme of reference invention where the ring is inserted the 4th day of each month (n + 3) and removed the first day of the following month (n) (3-4 days of the period without ring); The evaluations are carried out in the monitoring (within a month before the treatment) and in the months 3, 6, 9 and 12 or in a premature discontinuation. At the monitoring visit, the subjects provide the medical and gynecological history and undergo a physical and gynecological examination, including cervical cytology. The physical and gynecological exams are repeated on the last study visit. In addition, clinical safety laboratory tests are provided in the monitoring at the end of treatment. In all study visits, blood pressure and body weight are measured. Urinary pregnancy tests are prepared by subjects before the start of the study treatment, at each study visit and if a pregnancy is suspected during the trial. The occurrence of adverse events and the use of concomitant medications are recorded through the trial. The patterns of vaginal bleeding and compliance are recorded on daily cards. The investigated regimen is found to result in very high compliance compared to the standard 21/7 regimen. EXAMPLE 7 Safety and efficacy test m, m + 4, where m = 1 A multicentre, open-label, two-group, randomized trial of a comparative group as essentially described in Example 6 is carried out to investigate the efficacy of contraception, the characteristics of vaginal bleeding, compliance, safety and acceptability with the same vaginal ring as used in Examples 1-5 in the monthly regimen of the reference invention where the ring is inserted every 5th day (m + 4) of the month and removed every 1st day (m) of the following month against the standard 21/7 regime. The investigated regimen is found to result in very high compliance compared to the standard 21/7 regimen.

EXAMPLE 8 Assay of safety and efficacy y, y + 5, where y = 1 A multicentre, open-label, two-group, randomized trial of a comparative group as essentially described in Example 6 is carried out to investigate the efficacy of contraception, the characteristics of vaginal bleeding, compliance, safety and acceptability with the same vaginal ring as used in Examples 1-5 in the monthly regimen of the reference invention where the ring is inserted every 6th day (and + 5) of the month and removed every 1st day (and) of the following month against the standard 21/7 regime. The investigated regimen is found to result in very high compliance compared to the standard 21/7 regimen.

EXAMPLE 9 Safety and efficacy test z, z + 6, where z = 1 A multi-center, open-label randomized trial of comparative group as essentially described in Example 6 is carried out to investigate the efficacy of contraception, the characteristics of vaginal bleeding, compliance, safety and acceptability with the same vaginal ring as used in Examples 1-5 in the monthly regimen of the reference invention where the ring is inserted every 7th day (z + 6) of the month and removed every 1st day (z) of the next month compared to the standard 21/7 regimen. It was found that the investigated regime results in a very high compliance compared to the standard 21/7 regime.

Claims (36)

1. A method of contraception of human female which comprises starting a dosage form of numerical date 'n + 3' of a month and removing the dosage form on a numerical date 'n' of the following month, where 'n' is a numerical date of the month from 1-25 and where the method is repeatedly carried out for at least two cycles.

2. A method of contraception of human female which comprises starting a dosage form on a numerical date 'm + 4' of a month and removing the dosage form on a numerical date 'm' of the following month, where 'm 'is a numeric date of the month from 1-24 and where the method is repeatedly carried out for at least two cycles.

3. A method of contraception of human female which comprises starting a dosage form on a numerical date 'y + 5' of the month and removing the dosage form on a numerical date 'y' of the following month, where 'y' is a numeric date of one month from 1-23 and where the method is repeatedly carried out for at least two cycles.

4. A method of contraception which comprises starting a dosage form on a numerical date 'z + 6' of a month and removing the dosage form on a numerical date 'z' of the next month, where 'z' is a numeric date of one month from 1-22 and where the method is repeatedly carried out for at least two cycles.

5. A method according to claims 1-4 wherein the dosage form is a vaginal ring.

6. A method according to claims 1-4 wherein the start is administered intravaginally.

7. A method according to claims 1-4 wherein the dosage form is a patch.

8. A method according to claims 1-4 wherein the dosage form comprises an estrogen and a progestogen.

9. A method according to claim 8 wherein the progestogen is etonogestrel and the estrogen is estradiol or a salt thereof, or an ester thereof or the estrogen is estradiol ethinyl.

A method according to claim 8, wherein the progestogen is nomegestrol acetate and the estrogen is estradiol or a salt thereof, or an ester thereof or the estrogen is estradiol ethinyl.

11. A method according to claim 5, wherein the dosage form is made of thermoplastic material.

12. A method according to claim 5, wherein the dosage form comprises one or more compartments.

13. A method according to claim 12, wherein each compartment comprises one or more layers.

14. A contraceptive kit for contraception which comprises at least two dosage forms, each dose must be used in one or more sequential cycles and each dosage form must start at a numerical date 'n + 3' of a month and removed on a numerical date 'n' of the next month where 'n' is a numeric date of one month from 1-25.

15. A contraceptive kit for the contraception of the human female which comprises at least two dosage forms, each dosage form is used in one or two sequential cycles and each dosage form must be started on a numerical date 'm + 4 'one month and removed on a numerical date' m 'of the next month where' m 'is a numeric date of one month from 1-24.

16. A human female contraceptive contraceptive kit which comprises at least two dosage forms, each dosage form is used in one or two sequential cycles and each dosage form must start at a numerical date 'y + 5' of a month and removed on a numerical date 'and' of the next month, where 'y' is a numeric date of the month from 1-23.

17. A human female contraceptive contraceptive kit which comprises at least two dosage forms, each dosage form is used in one or two sequential cycles and each dosage form must start on a numerical date 'z + 6' of a month and removed on a numerical date 'z' of the following month, where 'z' is a numeric date of the month from 1-22.

18. A contraceptive kit according to claims 14-17 which comprises three dosage forms.

19. A kit according to claims 14-18, wherein the dosage form is a vaginal ring.

20. A kit according to claims 14-17, wherein the start is administered vaginally.

21. A kit according to claims 14-18 wherein the dosage form in a patch.

22. A kit according to claims 14-17 wherein the dosage form comprises estrogen and progestogen.

23. A kit according to claim 22, wherein the progestogen is etonogestrel and the estrogen is estradiol or a salt thereof, or an ester thereof, or the estrogen is estradiol ethinyl.

24. A kit according to claim 22, wherein the progestogen is nomogestrol acetate and the estrogen is estradiol or a salt thereof, or an ester thereof, or the estrogen is ethinyl estradiol.

25. A kit according to claim 19, wherein the dosage form is made of a thermoplastic material.

26. A kit according to claim 19, wherein the dosage form comprises one or more compartments.

27. A kit according to claim 26, wherein each compartment comprises one or more layers.

28. A reminder system for the dosing regimen comprising choosing a particular numeric date of one month from 1-25, regardless of the month, such as the numerical date on which the dosage form is always removed and beginning a new form of dosage three days later.

29. A reminder system for the dosing regimen comprising choosing a particular numeric date of one month from 1-24, regardless of the month, such as the numerical date on which the dosage form is always removed and beginning a new form of dosage four days later.

30. A reminder system for the dosing regimen comprising choosing a particular numeric date of one month from 1-23, regardless of the month, such as the numerical date on which the dosage form is always removed and starting a new one Dosage form five days later.

31. A reminder system for the dosing regimen comprising choosing a particular numeric date of one month from 1-22, regardless of the month, such as the numerical date on which the dosage form is always removed and starting a new form of dosage six days later.

32. A reminder system according to claims 28-31, wherein the dosage form is a vaginal ring.

33. A reminder system according to claims 28-31, wherein the start is administered intravaginally.

34. A reminder system according to claims 28-31 wherein the dosage form is a patch.

35. A contraceptive regimen in which the hormones are administered for a defined duration, characterized in that the duration of the cycle varies so as to correspond to the number of days of the month in which the cycle begins.

36. A contraceptive regimen according to claim 35, wherein a defined duration is at least three months.