NO327588B3 - Pharmaceutical composition and composition comprising ethinylostradiol and drospirenone for use as a contraceptive - Google Patents

Description

Field of the invention

The present invention relates to a tablet comprising drospirenone

and ethinyl estradiol as stated in claim 1 and a pharmaceutical preparation as stated in claim 4, as well as the use of drospirenone combined with ethinyl estradiol to produce a tablet for inhibiting ovulation as stated in claim 11.

Background and state of the art

Oral contraceptives containing a combination of a progestin and an estrogen component have been used since the 1960s. The earliest contraceptive preparations consisted of 21 tablets containing the combination of active agents, and 7 tablets containing no active agent, and the amount of each active agent was the same in each tablet (the so-called one-phase preparations). Subsequently, preparations were developed which consisted of tablets containing different amounts and ratios of the active agents during the administration cycle (the so-called multiphase preparations).

The reliability of the contraceptives is mainly provided by the progestin component. The daily dosage should be at least the minimum of what is necessary for the relevant progestin to effectively inhibit ovulation. The estrogen component works to increase the ovulatory inhibitory effect of the progestin and to ensure cycle stability. After the introduction of oral contraceptives, the daily dosage of progestin has been reduced through the development of new and more effective progestogens than those present in the early contraceptive preparations. It has also become possible to reduce the daily dosage of estrogen.

63.73; 153,16β-dimethyl-3-oxo-170-pregn-4-ene-21,17-carbolactone (drospirenone) is known from DE 26 52 761 where its use as a diuretic is described.

In DE 30 22 337 the progestagen-like activity of the compound and its consequent utility as a contraceptive is described at dosage levels of 0.5-50 mg drospirenone per day. It should also be noted that the mechanism of action of the compound is very similar to that of the natural corpus-luteum hormone progesterone, and that it does not give rise to increased blood pressure, and that it can thus be administered to women who have, or are susceptible to developing increased blood pressure It is further described that drospirenone can be administered together with ethinylestradiol in an amount of 0.03-0.05 mg per day.

DE 30 51 166 describes the use of drospirenone for treatment

of gynecological irregularities, and for impeding conception at a dosage level of 0.5-50 mg per day.

EP 398 460 describes the use of drospirenone for the treatment of androgen-induced disorders, aldosterone-induced disorders and hormonal irregularities, and likewise for fertility prevention at dosage levels of 0.5-50 mg, preferably 1-10 mg per day. Ethinylestradiol can be co-administered at a level of 0.02-0.04 mg per day.

US 5,756,490 describes pharmaceutical combination preparations comprising 23 or 24 dosage units containing a combination of a progestogen and an estrogen, and 4-10 dosage units containing estrogen alone. Drospirenone is mentioned as a possible but not preferred gestagenic compound, and ethinylestradiol is listed as a possible but not preferred estrogenic compound.

WO 98/04267 describes oral contraceptives containing 0.25-4 mg drospirenone and 10-20 µg ethinylestradiol. These doses are administered for 23-25 days beginning on day one of the menstrual cycle, and are followed by pure ethinylestradiol dosing (5-15 ug) for at least 3-5 days of the menstrual cycle. WO 98/04267 does not describe compositions which have rapid dissolution of drospirenone.

Oelkers et al. (Journal of Clinical Endocrinology and Metabolism, 1995; 80; 1816-1821) examined the effect of a combination of ethinylestradiol and dospirenone on, for example, body weight and blood pressure. Oelkers et al. does not describe compositions that have rapid dissolution

of drospirenone.

Kind et al. (Journal of Steroid Biochemistry, 1978; 9; 83-84) reported that the poor bioavailability of progesterone can be partially overcome by the addition of a cholesterol ester. Drospirenone is not mentioned by Kind et al.

Summary of the invention

In a first aspect, the present invention relates to a tablet comprising, as a first active agent drospirenone in an amount corresponding to a daily dosage, upon administration of the tablet of 3 mg, and as a second active agent ethinylestradiol in an amount corresponding to a daily dosage of from 0.015 mg to 0.03 mg, together with one or more pharmaceutically acceptable carriers or excipients, wherein at least 70% of said drospirenone is dissolved from the tablet within 30 minutes, as determined by USP XXIII "Paddle Method II", where the dissolution medium is 900 ml of water at 37 °C and the stirring speed is 50 rpm.

In another aspect, the invention relates to a pharmaceutical preparation consisting of a number of separately wrapped and individually removable tablets placed in a package unit, and intended for oral administration for a period of at least 21 consecutive days, wherein said tablets comprise a combination of drospirenone in an amount of 3 mg and ethinyl estradiol in an amount from 0.015 to 0.03 mg, in which at least 70% of said drospirenone is dissolved from the tablet within 30 minutes, as determined by USP XXIII "Paddle method II", where the dissolution medium is 900 ml of water at 37 ° C and the stirring speed is 50 rpm.

In a further aspect, the present invention relates to the use of drospirenone combined with ethinyl estradiol to produce a tablet for inhibiting ovulation in a mammal, especially a human, where the tablet comprises an amount of drospirenone corresponding to a daily dosage, upon administration of the tablet, of 3 mg , and comprising an amount of ethinylestradiol corresponding to a daily dosage, upon administration of the tablet, of from 0.015 to 0.03 mg, in which at least 70% of said drospirenone is dissolved from said tablet within 30 minutes, as determined by USP XXIII "Paddle method II ", where the dissolution medium is 900 ml of water at 37 °C and the stirring speed is 50 rpm.

Brief description of the figures

The present invention will be further described with

reference to the figures, in which:

Fig. 1 is a graph showing in vitro dissolution rate of drospirenone from tablet cores, where V1-V7 are batches containing micronized drospirenone, and where V8 is a batch containing macrocrystalline drospirenone. Fig. 2 is a graph showing the in vitro dissolution rate of drospirenone from tablet cores, where different lines represent different test batches. Fig. 3 is a graph showing the in vitro dissolution rate of drospirenone from film-coated tablets, where different lines represent different test batches. Fig. 4 is a graph showing the in vitro dissolution rate of ethinylestradiol from tablet cores, where different lines represent different test batches. Fig. 5 is a graph showing the in vitro dissolution rate of ethinylestradiol from film-coated tablets, where different lines represent different test batches.

Detailed description of the invention

Drospirenone, which can be prepared essentially as described in e.g. US 4,129,564 or WO 98/06738, is a poorly soluble substance in water and aqueous buffers at different pH values. Furthermore, drospirenone is converted to an inactive isomer under acidic conditions, and hydrolyzed under alkaline conditions. In order to ensure good bioavailability of the compound, it is therefore advantageous to provide it in a form that promotes rapid dissolution thereof.

It has surprisingly been found that if drospirenone is provided in a tablet which allows rapid dissolution of drospirenone, a high oral bioavailability is achieved ("rapid dissolution" is defined as dissolution of at least 70% within 30 minutes, and preferably at least 80% within 20 minutes, of drospirenone from a tablet preparation containing 3 mg of drospirenone in 900 ml of water at 37 °C as determined by USP XXIII "Paddle method" using a USP dissolution test apparatus 2 at 50 rpm). This can be achieved by providing drospirenone in micronised form (so that the particles of the active substance have a surface area of more than 10,000 cm<2>/g, and the following particle size distribution as determined under a microscope; no more than 2 particles in a given batch with a diameter of more than 30 µm, and preferably <20 particles with a diameter of >10 µm and <30 µm), or by dissolving it in a suitable solvent, e.g. methanol or ethyl acetate, and spraying it on the surface of inert carrier particles followed by an incorporation of the particles containing drospirenone on their surfaces in the tablet.

Without being bound by any particular theory, it appears that the in vitro dissolution rate of drospirenone is associated with the in vivo dissolution rate resulting in rapid absorption of drospirenone in vivo upon oral administration of the compound. This is an advantage because isomerization of the compound in the gastric environment and/or hydrolysis in the intestine is significantly reduced, which leads to a high bioavailability of the compound.

With regard to ethinyl estradiol which is also a poorly soluble substance, although this is less sensitive to degradation than drospirenone under conditions in the gastrointestinal system, it is advantageous to provide this in a micronized form, or that it is sprayed from a solution, e.g. .ex. in ethanol, on the surface of inert carrier particles. This has the further advantage of promoting a more homogeneous distribution of the ethinyl estradiol throughout the tablet, which may otherwise be difficult to achieve because ethinyl estradiol is incorporated in extremely small amounts. When ethinylestradiol is provided in micronized form, it preferably has the following particle size distribution as determined under a microscope; 100% of the particles have a diameter <15.0pm, 99% of the particles have a diameter <12.5pm, 95% of the particles have a diameter <10.0pm and 50% of the particles have a diameter <3.0pm. Furthermore, no particles are larger than 20 pm, and <10 particles have a diameter >15 pm and <20 pm.

In order to achieve a faster dissolution rate, it is preferred to include carriers or excipients that promote dissolution of both active substances. Examples of such carriers and excipients include substances that are easily dissolved in water, such as cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatinized starch, gelatin or polyvinylpyrrolidone. In particular, it appears that polyvinylpyrrolidone may be particularly useful in promoting dissolution.

The tablets according to the invention comprise drospirenone in an amount corresponding to a daily dosage of 3 mg. The amount of ethinylestradiol corresponds to a daily dosage of 0.015 mg to 0.03 mg.

In addition to its ability to inhibit ovulation, the tablet of the present invention has been found to possess extensive antiandrogenic properties. Furthermore, since drospirenone is an aldosterone antagonist, it has diuretic properties, and is therefore suitable to counteract the water-retaining properties of ethinylestradiol.

In a specific embodiment, the invention relates to a pharmaceutical preparation consisting of a number of separately wrapped and individually removable tablets placed in a packaging unit, and intended for oral administration for a period of at least 21 consecutive days, in which said tablets comprise a combination of drospirenone in an amount of 3 mg and ethinyl estradiol in an amount from 0.015 to 0.03 mg, and in which at least 70% of said drospirenone is dissolved from the tablet within 30 minutes, as determined by USP XXIII "Paddle method II", where the dissolution medium is 900 ml of water at 37 °C and the stirring speed is 50 rpm.

In one embodiment, the preparation comprises a further 7 or fewer tablets containing no active agent. Alternatively, it is possible to include in the dosing regimen a period of 7 days or less, during which no tablets are taken. For compliance reasons, however, it may be preferred to include a suitable number of blank days in the preparation, so that the total number of tablets in the preparation is at least 28. The inclusion of blank, or pill-free, days will then trigger withdrawal of bleeding.

The preparation can be a one-phase composition, i.e. a preparation where the amounts of each active agent remain constant throughout the at least 21-day period, or the amounts of either one or both active agents can be varied over the at least the entire 21-day period for to generate a multi-phase preparation, e.g. a 2- or 3-phase preparation, as is essentially described in e.g. EP 148 724.

In suitable embodiments of the present preparation, the number can

tablets that comprise the combination of drospirenone and ethinyl estradiol can be 21, 22, 23 or 24, and the number of tablets that do not contain an active agent can thus be 7, 6, 5 or 4. In a further embodiment of the present preparation, the number of tablets comprising the combination of drospirenone and ethinylestradiol be 28, or a multiple of 28, such as 2-4, especially 2 or 3, times 28.

In an alternative embodiment, the invention relates to a contraceptive preparation which consists of a number of separately wrapped and individually removable tablets placed in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, where at least 21 of said tablets comprise a combination of drospirenone in an amount of 3 mg and ethinylestradiol in an amount of from 0.015 to 0.03 mg, and where 7 or fewer of said tablets contain ethinyl-

estradiol alone in an amount from 0.01 to 0.05 mg.

By including a suitable number of tablets comprising only ethinylestradiol alone, a high contraceptive reliability, low follicular development and satisfactory cycle control with little or no intermenstrual bleeding can be achieved.

Also in this case, the preparation can be such that the amounts of each active agent remain constant for the entire period of at least 21 days (ie a 2-phase preparation), or the amounts of each, or both active agents can be varied over the period of at least 21 days for to generate a multiphase preparation, e.g. a 3- or 4-phase preparation, as is essentially described in e.g. EP 148 724.

In suitable embodiments of the present preparation, the number of tablets comprising the combination of drospirenone and ethinyl estradiol can be 21, 22, 23 or 24, and the number of tablets containing ethinyl estradiol alone can thus be 7, 6, 5 or 4.

In a further embodiment, the present invention relates to the use of drospirenone combined with ethinylestradiol to prepare a

tablet for inhibiting ovulation in a mammal, especially a human, wherein the tablet comprises an amount of drospirenone corresponding to a daily dosage, upon administration of the tablet, of 3 mg, and comprising an amount of ethinylestradiol corresponding to a daily dosage, upon administration of the tablet, from 0.015 to 0.03 mg, in which at least 70% of said drospirenone is dissolved from said tablet within 30 minutes, as determined by USP XXIII "Paddle method II", where the dissolution medium is 900 ml of water at 37 °C and the stirring speed is 50 rpm . In suitable embodiments, tablets comprising the combination of drospirenone and ethinyl estradiol may be administered for 21, 22, 23, or 24 consecutive days, and tablets containing no active agent may then be administered for 7, 6, 5, or 4 consecutive days, as appropriate. Furthermore, the tablets comprising the combination of drospirenone and ethinylestradiol can be administered for 28 consecutive days. In a variant of this embodiment, the tablets comprising the combination of drospirenone and ethinyl estradiol can be administered for 2-4, preferably 2 or 3, times 28 consecutive days, followed by administration of the tablets comprising the combination of drospirenone and ethinyl estradiol for 21, 22, 23 or 24 consecutive days and then administration of the tablets that do not contain active agent or

administration of no tablets, for 7, 6, 5 or 4 consecutive days.

Alternatively, a tablet comprising a combination of drospirenone in an amount of 3 mg and ethinylestradiol in an amount of from 0.015 to 0.05 mg may be administered daily for at least 21 consecutive days, followed by administration, each day for 7 or fewer consecutive days, of a tablet containing ethinylestradiol alone in an amount from 0.01 mg to 0.05 mg.

In this alternative embodiment, the tablets comprising the combination of drospirenone and ethinyl estradiol can conveniently be administered for 21, 22, 23 or 24 consecutive days, and where the tablets comprising ethinyl estradiol alone can then be administered for 7, 6, 5 or 4 consecutive days, as appropriate. In a further embodiment, the tablets comprising the combination of drospirenone and ethinyl estradiol can be administered for 2-4, preferably 2 or 3, times for 28 consecutive days, followed by administration of the tablets comprising the combination of drospirenone and ethinyl estradiol for 21 consecutive days and subsequent administration of the tablets which includes ethinylestradiol alone for 7 consecutive days.

For use in accordance with the invention, the pharmaceutical preparation can conveniently be in the form of a number of separately wrapped and individually removable tablets placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, each of said tablets comprising a combination of drospirenone in an amount of 3 mg, and ethinylestradiol in an amount of from 0.015 to 0.03 mg.

As indicated above, the preparation may further comprise 7 or fewer

tablets containing no active agent (or may contain 7 or fewer empty "spaces", e.g. in the form of empty blisters in a blister pack marking the days on which no tablets are to be administered).

Alternatively, the pharmaceutical preparation may be in the form of a number of separately wrapped and individually removable tablets placed in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, in which at least 21 of said tablets each comprise a combination of drospirenone in a amount of 3 mg and ethinyl estradiol in an amount of 0.015 to 0.03 mg, where the packaging unit further comprises 7 or fewer tablets comprising ethinyl estradiol alone in an amount of from 0.01 mg to 0.05 mg.

The tablet according to the invention can be formulated in any way known in the pharmaceutical field. In particular, as indicated above, can

the tablet is formulated by a method comprising providing drospirenone, and, if desired, ethinyl estradiol in micronized form in said tablets, or sprayed from a solution onto particles of an inert carrier in admixture with one or more pharmaceutically acceptable excipients which promote dissolution of drospirenone and ethinyl estradiol to promote rapid dissolution of drospirenone and preferably ethinyl estradiol by oral administration. Examples of such suitable excipients include fillers, e.g. sugars such as lactose, glucose or sucrose, sugar alcohols such as mannitol, sorbitol or xylitol, starches such as wheat, corn or potato starch, modified starch or sodium starch glycolate, lubricants such as talc, magnesium stearate, calcium stearate, colloidal silica or stearic acid, or binders such as polyvinyl pyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose or gelatin, to prepare tablets. Tablets can suitably be coated with a suitable film-forming agent, e.g. hydroxypropylmethylcellulose, hydroxypropylcellulose or ethylcellulose, to which suitable excipients can optionally be added, e.g. plasticizers such as glycerol, propylene glycol, diethyl phthalate or glycerol triacetate, fillers such as sucrose, sorbitol, xylitol, glucose or lactose, or a colorant such as titanium hydroxide, etc.

A package unit comprising the tablets described above can be prepared in a manner analogous to that found for the preparation of other oral contraceptives. This can e.g. be a conventional blister pack, or any other form known for this purpose, e.g. a package comprising the appropriate number of tablets (in this case at least 21, or for certain applications 28 or a multiple of 28) in sealed carrier packages with a cardboard, cardboard, foil or plastic, and wrapped in a suitable cover. Each bladder container can be appropriately numbered or otherwise marked, e.g. by starting from the first of at least 21 tablets containing the combination of drospirenone and ethinyl estradiol, possibly followed by the 7 or fewer empty blisters, or by the 7 or fewer tablets containing no active agent, or containing only ethinyl estradiol (even if the numbering may also start with the first of the 7 or fewer dosage units containing only ethinylestradiol).

The present invention is further described in the following examples.

EXPERIMENTAL PART

Example 1

Production of tablets containing drospirenone and ethinyl estradiol

Tablet cores of the following composition:

was prepared by filling a fluidized bed granulator with 31.68 kg corn starch, 21.12 modified starch, 6.60 micronized drospirenone, 0.066 kg micronized ethinylestradiol and 105.974 kg lactose monohydrate, and activating the fluidized bed. An aqueous solution of 8.80 kg of polyvinylpyrrolidone

25,000 in 46.20 kg of purified water was sprayed continuously on the fluidized bed, while the air stream from the fluidized bed was dried with heating. At the end of the process, 1.76 kg of magnesium stearate was sucked into the granulator and mixed with the granules while maintaining the fluidized bed. The resulting granules were compressed into tablet cores by compression using a rotary tablet press.

2.22464 kg of hydroxypropylmethylcellulose and 0.44528 macrogol 6000 were dissolved in 14.67 kg of purified water. 0.44528 kg of talc, 1.22430 kg of titanium dioxide and 0.06050 kg of ferric oxide pigment were suspended in 10.26 kg of purified water by stirring and homogenized. The solution and suspension were combined and used to coat tablet cores by continuous application of coating in the suspension in a coater.

Example 2

Dissolution of drospirenone from tablets

The dissolution rate of drospirenone from the tablets prepared in Example 1 was determined using the USP XXIII "Paddle Method" using the USP Dissolution Test Apparatus II including 6 coated glass shards and 6 paddles. The tablets were placed in 900 ml of water at a temperature of 37°C (±0.5°C) and stirred at 50 rpm.

The results appear from figures 1, 2 and 4. From fig. 1, it appears that the batch numbered V8 containing macrocrystalline drospirenone (but otherwise identical to the tablets prepared in Example 1) exhibits an extremely slow dissolution rate for drospirenone, while all the batches containing micronized drospirenone exhibit a dissolution rate greater than 70% within 30 minutes.

Fig. 2 and fig. 4 shows the results for dissolution of drospirenone from tablet cores and film-coated tablets, respectively. In both cases, more than 70% of the active agent is dissolved within 30 minutes. Thus, film coating did not significantly affect the dissolution rate.

Example 3

Dissolution Rate of Ethinyl Estradiol from Tablets in Vitro The dissolution rate of ethinyl estradiol from tablets prepared as described in Example 1 was determined in accordance with the USP "Paddle Method" as described in Example 2 for drospirenone. The results appear in Figures 3 and 5, which show dissolution rates from tablet cores and

film-coated tablets. In both cases, more than 70% of the active agent was dissolved within 30 minutes. Thus, the film coating did not significantly affect the dissolution rate.

Example 4

Bioavailability of drospirenone and ethinyl estradiol from tablets containing 3 mg drospirenone and 0.03 mg ethinyl estradiol

42 healthy women between 18 and 35 years of age were included in an open-label crossover trial after their informed consent was obtained. The purpose of the experiment was to investigate the relative bioavailability of drospirenone and ethinyl estradiol from a tablet formulation containing 3 mg drospirenone and 0.03 mg ethinyl estradiol with reference to an oral suspension containing 6 mg drospirenone and 0.06 mg ethinyl estradiol per ampoule.

Bioavailability was determined using serum concentrations of each active agent as parameters. Compared to the oral suspension, the relative bioavailability of drospirenone and ethinylestradiol from the tablets was 107% and 117%, respectively. It was therefore concluded that both drospirenone and ethinylestradiol are completely released from the tablets in vivo.

The absolute bioavailability of drospirenone was determined in 2 experiments to be 76% ± 13% after oral administration of 2 mg drospirenone to 8 young healthy women and 85% ± 24% after oral administration of a microcrystalline suspension containing 3.13 mg drospirenone to 6 post menopausal women.

The oral bioavailability of ethinylestradiol was determined in several trials, and average values from 36% to 59% were reported in the literature, indicating a first-pass effect.

Example 5

Antifertility efficacy of formulations containing drospirenone and ethinylestradiol

An open-label, randomized trial with 52 informed female volunteers aged 20-35 years included a pre-ossification cycle, 3 treatment cycles with 2 different tablets containing 2 mg and 3 mg drospirenone respectively, but otherwise corresponding to the tablets prepared in Example 1, and a follow-up phase. A washout phase of 1 month preceded the treatment.

At defined times, selected central and peripheral parameters were examined: LH, FSH, 17(3-estradiol, progesterone, cervical score, "spinnbarkeit", fern phenomenon. Ovarian function was checked with ultrasound. In addition, SHBG, CBG, prolactin, total testosterone, androstenedione, DHEA-S and selected metabolic parameters (serum glucose, triglycerides, cholesterol, HDL, LDL) were examined.Blood pressure, heart rate, body weight and cycle control were documented.

The results of the experiment showed by both LH and SFH were clearly suppressed with both test preparations. In accordance with this, secretion of estradiol and progesterone was greatly reduced in all 3 treatment cycles with the exception of the 3 volunteers who received the preparation with 2 mg drospirenone. This result was in principle confirmed by the accompanying ultrasound examination. Maturation of the follicle took place in several cases with both experimental preparations. Although 3 ovulations were diagnosed with the preparation containing 2 mg of drospirenone (one of which was described as "ambiguous" and the other as a "tablet ingestion error"), no differences were demonstrated statistically (p>0.05) between the two trial preparations with regard to to the hormones LH, FSH, estradiol and progesterone, and the parameter "ovulation during the treatment cycles". With regard to the hormones, cervical function was severely limited and the "spinnbarkeit" and crystallisability of the cervical mucus was greatly reduced with both test preparations. Prolactin increased minimally, and SHBG and CBG distinctively with both preparations. Triglycerides and HDL levels increased with both test preparations, while LDL levels decreased. Total cholesterol was essentially unchanged in both treatment groups. Oral glucose tolerance remained essentially unchanged or was slightly reduced. Testosterone, androstenedione and DHEA-S was minimally reduced.

The subjective and objective tolerance was good with both treatments. This was also the case for cycle control with the exception of the first cycle with 2 mg drospirenone. Blood pressure, heart rate and body weight remained constant in the majority of cases, or showed a slight tendency to decrease.

After 3 months of treatment, it was concluded:

The two trial preparations were equally good with regard to subjective and objective tolerance.

No negative metabolic effects were observed with any of the preparations. HDL was influenced positively in the sense of an increase.

The results confirmed the results from previous trials, namely that 2 mg drospirenone preparation was within the recommended threshold for inhibition of ovulation, while 3 mg drospirenone preparation had a demonstrable ovulation-inhibiting effect in all investigated cases.

Claims (12)

1. Tablet comprising, as a first active agent drospirenone in an amount corresponding to a daily dosage, when administering the tablet, of 3 mg, and as a second active agent ethinylestradiol in an amount corresponding to a daily dosage of from 0.015 mg to 0 .03 mg, together with one or more pharmaceutically acceptable carriers or excipients, in which at least 70% of said drospirenone is dissolved from the tablet within 30 minutes, as determined by USP XXIII "Paddle method II", where the dissolution medium is 900 ml of water at 37 ° C and the stirring speed is 50 rpm. 2. Tablet according to claim 1, wherein drospirenone is sprayed from a solution of drospirenone onto particles of an inert carrier. 3. Tablet according to claim 1 or 2, in which ethinylestradiol is in micronized form. 4. Pharmaceutical preparation consisting of a number of separately wrapped and individually removable tablets placed in a packaging unit, and intended for oral administration for a period of at least 21 consecutive days, in which said tablets comprise a combination of drospirenone in an amount of 3 mg and ethinylestradiol in an amount from 0.015 to 0.03 mg, in which at least 70% of said drospirenone is dissolved from the tablet within 30 minutes, as determined by USP XXIII "Paddle method II", where the dissolution medium is 900 ml of water at 37 °C and the stirring speed is 50 rpm. 5. Preparation according to claim 4, in which drospirenone is sprayed from a solution of drospirenone onto particles of an inert carrier. 6. Preparation according to claim 4, which further comprises 7 or fewer tablets containing no active agent intended for oral administration after the period of at least 21 consecutive days, the total number of tablets being at least 28. 7. Preparation according to claim 4, in which the number of tablets comprising the combination of drospirenone and ethinylestradiol is 21, 22, 23 or 24, and in which the number of tablets containing no active agent is 7, 6, 5 or 4. 8. Preparation according to claim 4, in which the number of tablets comprising the combination of drospirenone and ethinyl estradiol is 21, 22, 23 or 24, and in which the number of tablets comprising ethinyl estradiol alone is 7, 6, 5 or 4. 9. Preparation according to claim 4, in which the number of tablets comprising the combination of drospirenone and ethinylestradiol is 28, or a multiple of 28 such as 2-4, especially 2 or 3, times 28. 10. Preparation according to claim 4, in which the number of tablets intended for oral administration is for 2-4, preferably 2 or 3, times 28 consecutive days, followed by administration of the tablets comprising the combination of drospirenone and ethinylestradiol for 21, 22, 23 or 24 consecutive days and then administration of the tablets that do not contain active agent, or administration of no tablets for 7, 6, 5 or 4 consecutive days. 11. Use of drospirenone combined with ethinylestradiol to prepare a tablet for inhibiting ovulation in a mammal, especially a human, where the tablet comprises an amount of drospirenone corresponding to a daily dosage, by administration of the tablet, of 3 mg, and comprising an amount ethinylestradiol corresponding to a daily dosage, upon administration of the tablet, of from 0.015 to 0.03 mg, in which at least 70% of said drospirenone is dissolved from said tablet within 30 minutes, as determined by USP XXIII "Paddle Method II", where the dissolution medium is 900 ml of water at 37 °C and the stirring speed is 50 rpm. 12. Use according to claim 11, in which drospirenone is sprayed from a solution of drospirenone onto particles of an inert carrier.