ES2777886T3 - Pharmaceutical composition comprising drospirenone and contraceptive kit - Google Patents

Abstract

Contraceptive kit comprising one or more conditioning units, in which each conditioning unit comprises 21 to 28 daily active dosage units and in which (a) the amount of drospirenone in each daily active dosage unit is at least 2 mg, without any estrogen, and (b) each daily active dosage unit consists of a contraceptive composition suitable for oral administration comprising drospirenone, in which drospirenone has a d50 particle size ranging from 10 μm to 60 μm, so that: (i) no more than 50% of the drospirenone initially present in said daily active dosage unit dissolves within 30 minutes and (ii) at least 50% of said drospirenone dissolves in a range of time from 3 to 4 hours, when the daily active dosage unit is subjected to an in vitro dissolution test according to the paddle method of USP XXIII, the percentages of drospirenone with the amount of drospirenone initially present in said daily active dosage unit

Description

DESCRIPTION

Pharmaceutical composition comprising drospirenone and contraceptive kit

Field of the invention

The present invention relates to the field of contraceptive kits, compositions and methods.

Description of Related Prior Art

Several contraceptives that comprise synthetic progestogens and no estrogens are commercially available. These so-called “progestogen-only contraceptives” include implants, uterine delivery systems, and pills.

Progestin-only pills (PPS) have the advantage of avoiding combined estrogen administration compared to combined birth control pills.

However, PPS has several important disadvantages. Due to their low contraceptive reliability, PPS must be taken at the same time each day with no placebo interval or no pill.

Bleeding patterns for women taking PPS can also be severely altered compared to the natural menstrual cycle, as amenorrhea or unscheduled spotting or bleeding can occur. It turns out that despite their potential benefits, PPS is rarely used and is commonly indicated for women who cannot tolerate estrogens, for women in the postpartum period, and for women who are breastfeeding (Amy, Tripathi, 2009, BMJ, 339, 563-568; Mandisk, 2008, Obstetric Medicine, 1.78-87). Drospirenone (CAS: 67392-87-4; 6p, 7p, 15p, 16p-dimethylene-3-oxo-17a-pregn-4-en-21,17-carbo-lactone) is a synthetic progestogen with a very high pharmacological profile. closely related to that of natural progesterone.

Drospirenone (or DRSP) lacks androgenic, glucocorticoid, and antiglucocorticoid activity but has potent antimineralocorticoid and antiandrogenic properties. Oral daily doses of at least 3 mg of drospirenone were shown to inhibit ovulation over a single 21-day treatment cycle. The combination of 3 mg of drospirenone / 30 | ig of ethinyl estradiol provides a reasonable margin of contraceptive safety by inhibiting ovulation with a low frequency of follicular maturation (Rosenbaum et al., 2000, The European Journal of Contraception and Reproductive Health Care, 5 , 16-24).

Thus, drospirenone (DRSP) is an appropriate progestin component that can avoid the side effects that occur with conventional synthetic progestins such as weight gain and breast tension when combined with an estrogen for use as a contraceptive. DRSP is also likely to minimize fluid retention and have neutral effects on metabolic and vascular risks (Blode et al., 2000, The European Journal of Contraception and Reproductive Health Care, 5, 256-264; Sitruk-Ware, 2006 , Human Reproduction Update, 12, 169-178). Drospirenone has also been reported to be able to treat moderate acne thanks to its well-established antiandrogenic properties.

Drospirenone as a contraceptive component is available only in oral combination pills such as those marketed under the name Yasmin® (3 mg DRSP / 30 | ig ethinyl estradiol), Yaz® (3 mg DRSP / 20 | ig ethinylestradiol) and Yasminelle® (3 mg of DRSP / 20 | ig of ethinyl estradiol). These pills comprise ethinyl estradiol which acts to increase the ovulation inhibiting effect of drospirenone and to ensure contraception and cycle stability.

Patent application WO2008031631 describes combined oral contraceptives in which drospirenone is used as a progestative agent and ethinyl estradiol is replaced with the phytoestrogen 8-prenylnaringenin. These contraceptives may consist of modified release formulations of 8-prenylnaringenin and drospirenone that can deliver the active ingredients continuously for the gastrointestinal transit time of generally 12-16 hours.

The commercially available contraceptives Yasmin®, Yaz® and Yasminelle® comprise drospirenone in a micronized form that promotes its rapid dissolution in vitro and guarantees its good oral bioavailability. It is also the case for Angeliq® which is a hormone replacement drug that combines drospirenone and estradiol. However, such formulations are characterized by a high peak in plasma concentration for drospirenone after oral intake.

High plasma concentrations are not preferred in patients treated with drospirenone due to a correlation between a high Cmax and certain undesirable side effects as well as a general poor tolerance when hormone levels fluctuate too much every day.

There is still a need in the art for new contraceptive kits and for new pharmaceutical compositions comprising drospirenone.

Summary of the invention

The present invention relates to a contraceptive kit comprising one or more conditioning units, in which each conditioning unit comprises from 21 to 28 daily active dosage units and in which

(a) the amount of drospirenone in each daily active dosage unit is at least 2 mg, without any estrogen, and

(b) each daily active dosage unit consists of a contraceptive composition suitable for oral administration comprising drospirenone, in which drospirenone has a d50 particle size ranging from 10 µm to 60 µm, such that:

(i) no more than 50% of the drospirenone initially present in said daily active dosage unit dissolves within 30 minutes and

(ii) at least 50% of said drospirenone dissolves in a time interval from 3 to 4 hours, when the daily active dosage unit is subjected to an in vitro dissolution test according to the paddle method of USP XXIII , the percentages of drospirenone being related to the amount of drospirenone initially present in said daily active dosage unit.

The present invention further relates to a pharmaceutical composition suitable for oral administration comprising drospirenone, in which:

(a) a daily active dosage unit of said composition comprises an amount of drospirenone of at least 2 mg, without any estrogen, and

(b) said daily active dosage unit comprises drospirenone, and drospirenone has a d50 particle size ranging from 10 µm to 60 µm, so that:

(i) not more than 50% of the drospirenone initially present in said daily active dosage unit dissolves within 30 minutes, and

(ii) at least 50% of said drospirenone dissolves in a time interval from 3 to 4 hours, when the daily active dosage unit is subjected to an in vitro dissolution test according to the paddle method of USP XXIII , the percentages of drospirenone being related to the amount of drospirenone initially present in said daily active dosage unit,

for use as a contraceptive for a patient in need.

The present application describes a contraceptive kit comprising one or more conditioning units, in which each conditioning unit comprises from 21 to 28 daily active dosage units and in which, when administered fasting, one daily active dosage unit of said kit is adapted to provide a pharmacokinetic profile for drospirenone that has the following characteristics:

(i) a mean tmax of at least about 2.2 h and

(ii) a mean Cmax that is less than about 30 ng / ml,

A contraceptive method for a patient who needs it is also disclosed.

Brief description of the drawings

Figure 1: Particle size distribution

Figure 1 shows the cumulative distribution curve (cdf, solid diamonds) and the curve of the probability density function (pdf, solid squares) for the drospirenone lot (DRSP) 080053. The experimental distribution data were obtained using a laser diffraction method.

X axis: particle size (| im) in logarithmic scale. Left Y axis: cumulative distribution in percentage. Right Y-axis: probability density function.

Figure 2: In vitro dissolution profiles

Figure 2 shows the in vitro dissolution profiles for the tablet (A-3mg) obtained from the batch of DRSP 080053 as described in example 1 (of the invention, curve no. 2) and comparative tablets, specifically Yasminelle® (curve # 4), CO1-3mg tablets (curve # 3) and CO2-3mg tablets (curve # 1). Each tablet contains 3 mg of DRSP. In vitro dissolution profiles were determined by the paddle method of USP XXIII as described in Example 2.

X-axis: time in hours, Y-axis: average dissolution percentage of DRSP in relation to the initial amount of DRSP contained in the tablet under test.

Figure 3a and Figure 3b: Mean serum drospirenone concentration versus time curves

Figure 3a shows curves of DRSP mean plasma concentration versus time obtained after oral administration of a single reference product tablet, that is, Yasminelle® (open squares) or after oral administration of a single tablet obtained from DRSP lot 080053 as described in Example 1 (test product, solid squares). In both cases, the DRSP dosage was 3 mg. These clinical data were obtained during monocentric, open-label, randomized, single-dose, two-period crossover clinical trials conducted in 14 healthy volunteers as described in Example 3 part 1. Each volunteer randomly received a single oral dose. of 1 tablet of the test product or a tablet of Yasminelle® on two occasions, always on an empty stomach. The study periods were separated by a real drug rest phase of 7 days. In each study, blood samples were drawn prior to tablet administration (pre-dose, time 0) and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 5 : 00, 6:00, 8:00, 12:00, 24:00, 48:00 and 72:00 hours after dosing to test the plasma concentration of DRSP. X axis: time after oral administration of the tablet (in hours). Y-axis: mean plasma DRSP concentration in ng / ml (arithmetic mean).

Figure 3b shows curves of mean plasma DRSP concentration versus time obtained after oral administration of a single reference product tablet, that is, Yasminelle® (open squares) or after oral administration of a single CO1- tablet. 3mg (solid diamonds) or after oral administration of a single CO2-3mg tablet (solid squares) on an empty stomach (see example 3, part 2).

X axis: time after oral administration of the tablet (in hours). Y-axis: mean plasma DRSP concentration in ng / ml (arithmetic mean).

Figure 4a, 4b and 4c: Simulation based on pharmacokinetic results of the clinical trial described in example 3 Figure 4a and figure 4b show the experimental curves of mean plasma concentration of DRSP versus time obtained (i) for the oral administration of a single Yasminelle® tablet (comparative, solid squares) and (ii) for oral administration of a single tablet as described in example 1 (A-3mg, invention, hollow triangles). Both the Yasminelle® tablet and the A-3mg tablet contain 3 mg of DRSP. Figures 4a and 4b also show the predicted mean DRSP plasma concentration curve versus time (invention, hollow diamonds) obtained for oral administration of a tablet similar to that described in Example 1 but containing 4 mg of DRSP (tablet A -4mg). Such a curve was extrapolated from the experimental pharmacokinetic data obtained in the clinical trial described in example 3, part 1.

X axis: time after oral administration of the tablet (in hours). Y axis: mean plasma DRSP concentration in ng / ml.

Figure 4c shows mean DRSP plasma concentration versus time curves resulting from repeated administration of a Yasminelle® tablet (curve # 1), from that of an A-3mg tablet (curve # 3) and of an A-4mg tablet (curve # 2), every 24 hours. These curves were obtained by extrapolating experimental pharmacokinetic data obtained in the clinical trial described in Example 3.

X axis: time after oral administration of the first tablet (in hours). Y axis: mean plasma DRSP concentration in ng / ml.

Figure 5a and Figure 5b: In vitro dissolution profile and curve of mean serum drospirenone concentration versus time for a tablet comprising 4 mg of DRSP (B-4mg).

Figure 5a shows the mean in vitro dissolution profile for tablets obtained from DRSP lot # PR100003 as described in example 5 (see part 1). The tablet comprises 4 mg of DRSP.

X-axis: time in hours, Y-axis: average dissolution percentage of DRSP in relation to the initial amount of DRSP contained in the tablet under test.

Figure 5b shows curves of mean plasma concentration of DRSP versus time obtained after oral administration of a single reference product tablet, that is, Yasminelle® (open squares) or after oral administration of a single B- tablet. 4mg (solid squares) on an empty stomach (see example 5, part 2).

X axis: time after oral administration of the tablet (in hours). Y axis: mean plasma DRSP concentration in ng / ml.

Figures 6a and 6b: Individual plasma levels of progesterone and estradiol in patients during the treatment period and the follow-up period.

Figures 6a and 6b show the results of a clinical trial intended to illustrate the contraceptive efficacy of the contraceptive compositions according to the invention. The methodology of the clinical trial is described in Example 4. In summary, the treatment period comprises two treatment cycles in which the patients took a DRSP 4 mg pill (tablet B-4mg) from day 1 to day 24 and a placebo tablet from day 25 to day 28 of each treatment cycle at a fixed time. On day 5 and day 13 of the second cycle, taking the pill was delayed for 24 hours (i.e. no pills were taken on day 5 and day 13 and 2 pills were taken on day 6 and day 14, respectively). The entire study consisted of a treatment period of 56 days and a follow-up period 28 days after treatment. The pill corresponds to the B-4mg tablet.

Figure 6a shows the variation of individual plasma progesterone levels during the treatment period and the follow-up period. X axis: time in days after first taking the pill. Y axis: progesterone level in ng / ml.

Figure 6b shows the variation of individual plasma estradiol levels during the treatment period and the follow-up period. X axis: time in days after first taking the pill. Y axis: estradiol level in pg / ml.

Detailed description of the invention

The application discloses a contraceptive kit comprising a plurality of daily active dosage units. Each daily dosage unit consists of a pharmaceutical composition comprising drospirenone. In preferred embodiments, said pharmaceutical composition comprises drospirenone, without estrogen. In other words, the contraceptive kit is preferably a progestin-only contraceptive kit.

Drospirenone may be the only contraceptive agent present within the pharmaceutical composition.

Said daily active dosage unit makes it possible to prevent pregnancy when administered daily to a woman of childbearing age over a period of 21 to 28 consecutive days.

The number of daily active dosage units contained in the contraceptive kit may vary depending on the contraceptive method in which the contraceptive kit is intended to be used.

1. Pharmaceutical composition

Commercially available drospirenone-containing birth control pills comprise both ethinyl estradiol and micronized drospirenone. According to EP1214076, the micronized form of drospirenone promotes its rapid dissolution in vitro. This rapid dissolution in vitro is stated to be a necessary condition to obtain good bioavailability through the oral route. The rapid dissolution rate of drospirenone in vitro is evaluated to correlate with rapid in vivo absorption of DRSP that prevents its degradation by gastric or intestinal environments.

Several other patents and patent applications, such as WO2006128907 or WO2009138224, describe drospirenone compositions that exhibit rapid dissolution of drospirenone in vitro.

Accordingly, international application WO2006128907 teaches that surfactants can enhance the dissolution rate of non-micronized drospirenone having a specific surface area of less than 10,000 cm2 / g. International application WO2009138224 describes that the dissolution rate of drospirenone can be significantly improved by co-grinding drospirenone with an appropriate carrier to obtain drospirenone in amorphous state.

As mentioned in EP1214076, rapid dissolution of drospirenone in vitro generally means that at least 70% of drospirenone dissolves within 30 minutes when the composition is subjected to an in vitro dissolution test such as USP XXIII paddle method II.

Surprisingly, the applicant went against this prejudice and demonstrated, through in vivo pharmacokinetic tests , that a rapid dissolution of drospirenone in vitro is not required to obtain good oral bioavailability. In this regard, the applicant conceived compositions containing drospirenone with a dissolution rate in drospirenone slow vitro and having a value U ^c similar means (area under the curve, of the English Area Under the Curve) compared to Yasminelle® when administered orally to patients.

Furthermore, Applicant succeeded in devising compositions containing DRSP which also exhibit a significantly reduced mean Cmax value (maximum plasma concentration) associated with a delayed mean tmax value for drospirenone compared to Yasminelle®.

Lowering a DRSP Cmax is likely to improve the tolerance of the DRSP-containing composition by reducing or avoiding side effects, particularly those related to the plasma potassium level.

Drospirenone has an antimineralocorticoid property that leads to an increase in potassium excretion and also to an increase in the plasma potassium level. It has been suggested that the Cmax of drospirenone correlates with the Cmax of potassium released after administration of drospirenone. Such an increase in plasma potassium concentration after administration of drospirenone can lead to hyperkalaemia which is known to induce various disorders such as dizziness, palpitations, muscle weakness and even cardiac arrhythmia.

When administered orally, the DRSP-containing composition described herein induces a reduced plasma Cmax for drospirenone. A reduced Cmax for DRSP is expected to reduce plasma potassium release. Accordingly, in the case of the composition described herein, the tolerance for drospirenone can be improved especially for women who are predisposed to hyperkalemia, for women suffering from nephropathy, liver disease or adrenal diseases, and for women who are on daily treatment. long-term for a chronic state with drugs that predispose to hyperkalemia. Medications that predispose to hyperkalemia include, but are not limited to, non-steroidal anti-inflammatory drugs, potassium-sparing diuretics, potassium supplementation, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and heparin.

Accordingly, the DRSP-containing composition described herein may be particularly suitable for preparing any oral medicament in which the mean Cmax value for DRSP must be controlled in order to improve tolerance for drospirenone. For example, the composition can be used to prepare hormone replacement therapy (HRT) drugs.

Since the DRSP-containing composition described herein combined a reduced Cmax with a delayed tmax and a minimum AUCh-t to provide a contraceptive effect, such a composition may be suitable for use in progestogen-only pills.

As illustrated in Example 5, Part 3, Applicant demonstrated that the compositions described herein provide a stable and effective contraceptive drospirenone blood level when administered daily to a patient. Therefore, the co-administration of an estrogen is not required to guarantee contraception and cycle stability.

Since the mean Cmax value is significantly reduced, the contraceptive composition provides a more stable plasma concentration of drospirenone, that is, a plasma concentration of DRSP with low fluctuations between two consecutive administrations. Such a feature can further reduce the incidence of unscheduled spotting and bleeding and therefore can significantly improve the bleeding profile compared to conventional PPS.

As described in Example 5, the applicant also demonstrated that said composition remains contraceptive even when a placebo period is introduced into the contraceptive regimen and some daily pills are omitted. Thus, it is expected that such compositions will exhibit greater contraceptive reliability than other progestogen-only pills that will allow patients to comply somewhat less with treatment without risking unwanted pregnancy.

It was also expected that the contraceptive composition described herein, which does not contain estrogens, will be as effective as the combined oral pill without inducing estrogen-related side effects, in particular, without increasing the risk of cardiovascular events.

Therefore, in some embodiments, said pharmaceutical composition is suitable for use as an oral contraceptive. In some other specific embodiments, the pharmaceutical composition described herein is used as a progestin-only pill.

As used herein, "progestogen-only contraceptive" or "progestogen-only pill" means a pill or a contraceptive that comprises progestins as the sole contraceptive agents and does not comprise any estrogens.

By "composition having an improved pharmacokinetic profile for drospirenone" as used herein it is therefore meant that oral administration of a single daily dosage unit of said composition containing drospirenone provides a pharmacokinetic profile for drospirenone characterized by a delayed mean tmax and a reduced mean Cmax compared to the administration of a single daily dosage unit of Yasminelle®.

The pharmacokinetic profile of Yasminelle® is described above in Example 3.

In some aspect, the application provides a pharmaceutical composition containing DRSP characterized in that, when administered orally, a single daily dosage unit of said composition is adapted to provide a pharmacokinetic profile for DRSP that has a mean Cmax that is less 85% of the mean Cmax obtained after oral administration of a single dosage unit of Yasminelle®.

The pharmaceutical composition containing DSRP can be further characterized in that, when administered orally, a single daily dosage unit of said composition is adapted to provide a pharmacokinetic profile for DRSP that has a mean tmax that is at least 150% of the Mean tmax obtained after oral administration of a single Yasminelle® dosage unit.

It goes without saying that the administration of a single dosage unit of said composition provides an ultimate AUC which is sufficient to produce the pharmaceutical or biological effect sought by the administration of drospirenone. Said pharmaceutical or biological effect generally refers to a contraceptive effect.

When the composition as described herein is used as a contraceptive, it may further be required that the AUCüh-last mean obtained after administration of a single daily dosage unit of said composition is at least 70% of the AUCüh- tlast mean obtained in the case of Yasminelle®. In other words, the daily dosage unit of the pharmaceutical composition as described herein exhibits a combination of physical and / or chemical characteristics such that, when administered orally, said daily dosage unit is adapted to provide a pharmacokinetic profile that has the following characteristics:

- (i) a mean Cmax that is not more than 85% of the mean Cmax obtained after oral administration of a single dosage unit of Yasminelle® and

- (ii) a mean tmax that is at least 150% of the mean tmax obtained after oral administration of a single dosage unit of Yasminelle®

and, optionally, an AUCüh-last that is at least 70% of the mean AUCüh-last obtained after oral administration of a single dosage unit of Yasminelle®.

In some embodiments, the mean AUC ⁰ h-last is at least 85% of the mean AUC ⁰ h-last obtained after oral administration of a single Yasminelle® dosage unit.

In some embodiments, the pharmaceutical composition as described herein exhibits all of the pharmacokinetic characteristics mentioned above.

The AUC ⁰ h-last, C max, and t max are determined based on the curve of plasma drospirenone concentration versus time.

According to the present invention, for a given drospirenone-containing composition, the plasma drospirenone concentration versus time curve can be determined by following the plasma drospirenone concentration over a period of approximately 72 h after a single oral intake of a daily dosage unit. of said composition containing drospirenone.

The only oral administration of said composition containing drospirenone is preferably carried out on an empty stomach, that is, without food and not close to mealtime (that is, in general, about 6-10 hours after food) since the food intake can modify the rate of absorption of drospirenone from the tract gastrointestinal.

The Cmax and tmax values refer to the maximum plasma DRSP concentration and time to reach it, respectively, after oral administration of a single daily dosage unit of the DRSP-containing composition of interest.

In other words, tmax and Cmax refer to the characteristics of the peak plasma concentration of drospirenone observed after oral intake of a single daily dosage unit of the composition of interest.

The AUCüh-last corresponds to the area obtained by integrating the plasma concentration of drospirenone against time during the interval [0h-last], the point “0h” referring to the oral intake of a single daily dosage unit of the composition of of interest, and the "last" point refers to the last time for which the plasma concentration of DRSP can be quantified.

The plasma concentration of DRSP can be determined by well known prior art methods. For example, an appropriate method of quantification comprises the extraction of DRSP from human plasma and then its quantification using liquid chromatography coupled with tandem mass spectrometry.

In a preferred embodiment, the person skilled in the art can adapt the analytical method described by Kirk et al (Rapid Communication in Mass Spectrometry, 2006; 20: 1247-1252). One such method comprises a step of derivatization of drospirenone with Girard P's hydrazine solution in order to increase the DRSP response during subsequent MS analysis. This method is generally appropriate for quantifying DRSP in human plasma with EDTA over a concentration range of from about 0.25 to about 100 ng / ml.

As used herein, mean AUCh-last, mean Cmax, and mean tmax refer to arithmetic mean values determined from individual pharmacokinetic data obtained for a group of healthy, childbearing-age volunteers undergoing testing. a single oral administration of a daily dosage unit of a composition containing drospirenone.

The group of healthy volunteers may comprise enough women to provide statistically reliable pharmacokinetic results. Preferably, said group comprises at least ten healthy women of childbearing age.

As used herein, a healthy woman of childbearing age refers to a premenopausal Caucasian woman between the ages of 18 and 40, with a normal body weight and no health problems, in particular, without metabolic disorders, renal, hepatic or gynecological. A "normal body weight" refers to a body mass index (BMI) ranging from 18 to 29 kg / m2.

Preferably, such volunteers have not taken any hormone-containing composition within 3 months prior to testing to determine the pharmacokinetic parameters of interest.

The Cmax, tmax and AUCh-t last means for Yasminelle® and for the composition containing drospirenone according to the invention are determined for the same group of patients. Between the administration of the single daily dosage unit of Yasminelle® and that of the composition containing DRSP according to the invention, the volunteers can undergo a period of pharmacological rest of at least 7 days.

Mean Cmax, mean tmax and mean AUC ⁰ h-last for DRSP can be determined from raw individual pharmacokinetic data by well known statistical methods of the prior art. For example, all of the endpoints listed above can be determined independently of the model. The highest concentration actually measured and the time it was recorded after each dose in any given volunteer can be considered as the Cmax and tmax respectively according to the algorithm of the NC_PKP.sas program.

The daily dosage unit of the DRSP-containing composition comprises at least 2 mg of drospirenone. A daily amount of DRSP of from 3 mg to 4.5 mg may be preferred when the composition is used as a contraceptive.

As used herein, Yasminelle® is a combined oral pill sold by Bayer / Schering. The daily dosage unit for Yasminelle® is a coated tablet comprising 3 mg of micronized drospirenone and ethinyl estradiol, betadex clathrate, in an amount corresponding to 20 µg of ethinyl estradiol. The tablet further comprises lactose monohydrate, corn starch and magnesium stearate as main excipients. The tablet coating comprises hypromellose, talc, titanium oxide, and iron oxide red.

As used herein, Yasminelle® (marketed under the name Jasminelle® in France) refers to the pharmaceutical product covered by the French Marketing Authorization related to the CIS number (from French, Code d'Identification de Spécialité) 65052799 and revised September 17, 2009. In a preferred embodiment, the pharmacokinetic parameters (specifically Cmax, tmax, and AUCiih-last) are determined after the first oral administration of a single dosage unit of the DRSP-containing composition of interest. , said first oral administration occurring on an empty stomach.

In a more general aspect, the present application provides a pharmaceutical composition containing DRSP characterized in that, when administered orally, a single daily dosage unit of said composition is adapted to provide a pharmacokinetic profile for DRSP having an average Cmax that it is less than about 30 ng / ml. Said pharmaceutical composition containing DRSP can be further characterized in that, when administered orally, a single daily dosage unit of said composition is adapted to provide a pharmacokinetic profile for DRSP having a mean tmax that is at least about 2.2 h.

It goes without saying that the administration of a single dosage unit of such a composition provides an average AUChultimate which is sufficient to produce the pharmaceutical or biological effect sought by the administration of drospirenone.

When the composition as described herein is used as a contraceptive, it may further be required that the mean AUC ⁰ h-last obtained after the administration of a single daily dosage unit of said composition is at least about 300 ng * ml. / h.

In other words, in some embodiments, the daily dosage unit of the pharmaceutical composition exhibits a combination of physical and / or chemical characteristics such that, when administered orally, said daily dosage unit is tailored to provide a pharmacokinetic profile that has the following characteristics:

(i) a mean Cmax that is less than about 30 ng / ml

(ii) a mean tmax of at least about 2.2 h

and, optionally, a mean AUC ⁰ h-last of at least about 300 ng * h / ml.

In some embodiments, the pharmaceutical composition exhibits all of the aforementioned pharmacokinetic characteristics.

As used herein, the term "about" before a "specific value" defines a range from "the specific value minus 10% of the specific value" to "the specific value plus 10% of the specific value." . For example, "about 50" defines a range from 45 to 55.

A mean AUC ⁰ h-last of at least about 300 ng * h / ml includes a AUC ⁰ h-last of at least about 310 ng * h / ml, at least about 320 ng * h / ml, at least about 330 ng * h / ml, at least about 340 ng * h / ml, at least about 350 ng * h / ml, at least about 360 ng * h / ml, at least about 370 ng * h / ml, at least about 380 ng * h / ml, at least about 390 ng * h / ml, at least about 400 ng * h / ml, at least about 410 ng * h / ml, at least about 420 ng * h / ml, at least about 430 ng * h / ml.

In some embodiments, the mean AUC ⁰ h-last is at least about 350 ng * h / ml.

A mean tmax of at least about 2.2 hrs includes a mean tmax of at least about 2.5 hrs, of at least 3.0 hrs, of at least about 3.5 hrs, of at least 4 hrs.

In a preferred embodiment, the mean tmax does not exceed 6 hours in order not to significantly affect the bioavailability of DRSP. Therefore, the mean tmax preferably ranges from 2.2 h to 6 h.

In some embodiments, a tmax ranging from 3.0 h to 4.0 h is preferred.

A mean Cmax that is less than about 30 ng / mL includes a Cmax of less than about 28 ng / mL, less than about 26 ng / mL, less than about 24 ng / mL, less than about 22 ng / mL, less less than about 20 ng / mL, less than about 19 ng / mL, less than about 18 ng / mL, less than about 17 ng / mL, less than about 16 ng / mL, less than about 15 ng / mL, less than about 14 ng / ml.

In some embodiments, the mean Cmax ranges from 15 ng / ml to 30 ng / ml.

In other embodiments, the mean Cmax ranges from 15 ng / ml to 26 ng / ml.

In certain embodiments, the daily dosage unit of the pharmaceutical composition according to the invention is adapted to provide a pharmacokinetic profile having the following characteristics:

(i) a mean Cmax ranges from 15 ng / ml to 30 ng / ml,

(ii) a mean tmax ranges from 2.2 h to 6 h, and

(iii) optionally, a mean AUCoh-t of at least about 300 ng * h / ml,

when said daily dosage unit is administered on an empty stomach.

In a preferred embodiment, the pharmacokinetic parameters (specifically Cmax, tmax and AUC ⁰ h-last) are determined after the first oral administration of a single unit dosage of the DRSP-containing composition of interest, said first oral administration occurring in the fasted state.

The pharmaceutical composition as described herein is particularly suitable for use as a contraceptive, in particular as a progestogen-only contraceptive.

The pharmaceutical composition can also be used to prepare any other medicament for which improvement of DRSP tolerance is sought.

Such medications include, but are not limited to, HRT medication.

Without wishing to be bound by theory, Applicant believes that the dissolution rate of drospirenone in vitro correlates with its in vivo pharmacokinetic profile .

A composition exhibiting a pharmacokinetic profile for drospirenone as fully described above may show a slow in vitro dissolution rate of drospirenone such that no more than 50% of drospirenone initially present in said composition dissolves within 30 minutes.

In one aspect, the present application provides a pharmaceutical composition comprising drospirenone that is characterized by a slow in vitro dissolution rate of drospirenone.

As used herein, by "a slow in vitro dissolution rate of drospirenone" is meant that the release of drospirenone is such that no more than 50% of the drospirenone initially present in said composition dissolves within 30 minutes when said composition is subjected to a dissolution test.

As intended herein, no more than 50% of drospirenone comprises no more than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10 % of drospirenone initially present in the contraceptive composition.

In some embodiments, no more than 40% of the drospirenone initially present in the composition dissolves within 30 min.

As used herein, the percentage of drospirenone refers to the amount of drospirenone initially present in said contraceptive composition.

The dissolution rate of drospirenone in vitro can be evaluated by any of the well-known methods described in the prior art.

The dissolution rate of drospirenone in vitro is preferably evaluated by the paddle method of USP XXIII. Briefly, a tablet consisting of the contraceptive composition comprising drospirenone to be tested is placed in 900 ml of water at 37 ° C (± 0.5 ° C). The dissolution test is performed using a USP dissolution test apparatus 2 at a stirring speed of 50 rpm.

In some embodiments, the pharmaceutical composition is a contraceptive composition.

As used herein, by "contraceptive composition" is meant a composition that can prevent pregnancy when administered daily in an effective amount to a patient for a period of 21 to 28 consecutive days. The contraceptive composition can prevent pregnancy from occurring through various biological effects. For example, pregnancy can be prevented by inhibiting the ovulation, by thickening the cervical mucus (which reduces the viability and penetration of sperm) and / or preventing the implantation of the embryo.

The term "drospirenone" refers to drospirenone itself, that is, the chemical entity identified by CAS registry number 67392-87-4, drospirenone solvates, and drospirenone derivatives or prodrugs.

Drospirenone can be prepared by well known methods described in the prior art, for example described in US 4129564, WO9806738, EP11746101 or WO2006061309. The method described in WO2006061309 may be particularly suitable for preparing drospirenone.

It goes without saying that the method for preparing drospirenone can be performed to meet the requirements of Good Manufacturing Practice (GMP).

To ensure good bioavailability of drospirenone, a significant amount of the drospirenone initially comprised in the contraceptive composition has to be released in a reasonable time interval.

The applicant demonstrated that a good bioavailability of drospirenone was achieved in the case of compositions comprising drospirenone that had a dissolution rate of drospirenone in vitro such that at least 50% of the drospirenone initially present in said compositions dissolved in a range of time from 3 to 4 hours.

Accordingly, an object of the present invention is a contraceptive composition comprising drospirenone in which the in vitro dissolution rate of said drospirenone is such that no more than 50% of said drospirenone dissolves within 30 minutes and such that at least 50% of the drospirenone dissolves in a time interval of 3 to 4 hours.

A time range of from 3 hours to 4 hours encompasses a time range of from 3.25 hours to 3.5 hours, up to 3.75 hours, up to 4 hours.

At least 50% of drospirenone comprises at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, at least 88%, when less 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least the 98%, at least 99%, at least 99.5%.

In some embodiments, at least 60% of the DRSP initially present dissolves within a time interval of from 3 to 4 hours.

In some other embodiments, said contraceptive composition is further characterized in that at least 70% of the drospirenone dissolves within 6 hours.

The applicant has shown that the specific surface area of DRSP has a direct impact on the dissolution rate of drospirenone in vitro and its pharmacokinetic profile in vivo.

One way to obtain the DRSP-containing composition is to use drospirenone in a particle form having an appropriate specific surface area.

Drospirenone may be present in the pharmaceutical compositions described herein in non-micronized particulate form.

It has also been shown that drospirenone in particulate form having a specific surface area of from about 2000 cm2 / g to about 8500 cm2 / g may be suitable for obtaining contraceptive compositions. The specific surface area can be determined experimentally using the BET method (gas adsorption method).

In some embodiments, the contraceptive composition comprises drospirenone in a particulate form having a specific area of from about 2000 cm2 / g to about 8500 cm2 / g.

Such a specific area range includes values of about 2000 cm2 / g, 2500 cm2 / g, 3000 cm2 / g, 3500 cm2 / g, 4000 cm2 / g, 4500 cm2 / g, 5000 cm2 / g, 5500 cm2 / g, 6000 cm2 / g, 6100 cm2 / g, 6200 cm2 / g, 6300 cm2 / g, 6400 cm2 / g, 6500 cm2 / g, 6600 cm2 / g, 6700 cm2 / g, 6800 cm2 / g, 6900 cm2 / g, 7000 cm2 / g, 7500 cm2 / g, 8000 cm2 / g and 8500 cm2 / g.

Regarding the particle size distribution, drospirenone particles that have a diameter greater than 200 µm should be avoided in order not to drastically affect the in vitro dissolution rate and, therefore, the in vivo bioavailability since such particles they are not very soluble.

Drospirenone may preferably have a d50 of less than 70 µm. In a preferred embodiment, the d50 of the Drospirenone particles range from 10 µm to 60 µm.

A d50 ranges from about 10 | im to about 60 | im encompasses a d50 of 10 | im, 15 | im, 20 | im, 25 | im, 30 | im, 35 | im, 40 | im , 45 | im, 50 | im, 55 | im In some embodiments, the particle size distribution of the drospirenone present in the composition is characterized by:

(i) a d90 particle size of less than about 100 µm, and / or

(ii) a d50 particle size ranging from about 10 µm to about 60 µm and / or

(iii) a d10 particle size of greater than about 3 µm.

In some other embodiments, the d50 of drospirenone particles ranges from about 10 µm to about 30 µm. In such embodiments, the particle size distribution of the drospirenone present in the composition is characterized by at least one of the following characteristics:

(i) a d90 particle size of less than about 100 | im,

(ii) a d50 particle size ranging from about 10 µm to about 30 µm and

(iii) a d10 particle size of greater than about 3 µm.

As used herein, the term "about" before a "specific value" defines a range from "the specific value minus 10% of the specific value" to "the specific value plus 10% of the specific value." . For example, "about 50" defines a range from 45 to 55.

As used herein, by "d90 particle size" is meant that the particle size distribution is such that at least 90% of the particles have a particle size diameter of less than the specified value.

As used herein, by "d50 particle size" is meant that the particle size distribution is such that at least 50% of the particles have a particle size diameter of less than the specified value.

As used herein, by "particle size d10" is meant that the particle size distribution is such that at least 10% of the particles have a particle size diameter of less than the specified value.

D90 particle sizes of less than about 100 | im include d90 particle sizes of less than about 90 | im, 80 | im, 70 | im, 60 | im, 55 | im, 50 | im, 45 | im, 40 | im, 38 | im, 36 | im, 34 | im, 32 | im, 30 | im, 28 | im, 26 | im, 24 | im, 22 | im, 20 | im.

D50 particle size values ranging from about 10 | im to about 30 | im include values of about 10 | im, 11 | im, 12 | im, 13 | im, 14 | im, 15 | im, 16 | im , 18 | im, 19 | im, 20 | im, 21 | im, 22 | im, 23 | im, 24 | im, 25 | im, 26 | im, 27 | im, 28 | im, 29 | im, 30 | im.

D10 particle size values of more than about 3 | im include d10 particle size values of more than about 3 | im, 3.5 | im, 4.5 | im, 5 | im, 6 | im, 7 | im, 8 | im, 9 | im, 10 | im, 11 | im, 12 | im.

It goes without saying that a d10 particle size value is smaller than a d50 particle size value that is smaller than a d90 particle value.

The particle size distribution of drospirenone, in particular the d90, d10 and d50 values, can be determined by methods well known in the prior art such as sieve analysis, laser diffraction methods, photoanalysis or optical counting methods. Laser diffraction methods are particularly preferred. As illustrated in Example 1, the particle size distribution can be determined by wet scattering laser diffraction. The dispersing agent is preferably water.

In some embodiments, the pharmaceutical composition as described herein comprises drospirenone in a particle form having a particle size distribution that has a combination of two characteristics selected from:

(i) a d90 particle size of less than about 100 | im,

(ii) a d50 particle size ranging from about 10 µm to about 30 µm and (iii) a d10 particle size of greater than about 3 µm.

In other words, the DRSP particle size distribution exhibits a combination of features selected from feature (i) and feature (ii), feature (i) and feature (iii), and feature (ii) and characteristic (iii).

In some other embodiments, the pharmaceutical composition comprising drospirenone in non-micronized form having a particle size distribution is characterized in that:

(i) the particle size d90 is less than about 100 | im,

(ii) the particle size d50 ranges from about 10 µm to about 30 µm and

(iii) the d10 particle size is greater than about 3 µm.

In a preferred embodiment, the DRSP particle distribution is further characterized in that the d90 particle size value is less than 50 µm and that no particle is larger than 80 µm in size.

In some embodiments, the contraceptive composition comprises drospirenone in a particle form having a d90 particle size ranging from about 20 µm to about 40 µm, a d50 particle size ranging from about 10 µm to about 30 µm. im and a d10 ranging from about 3 µm to about 9 µm, and wherein no particle is larger than 80 µm, more preferably no particle is larger than 60 µm.

In some other embodiments, the contraceptive composition comprises drospirenone in a particulate form having

(i) a particle size d90 ranging from about 30 µm to about 40 µm,

(ii) a d50 particle size ranging from about 15 µm to about 25 µm and (iii) a d10 ranging from about 5 µm to about 9 µm and in which no particle is larger than 80 µm, more preferably no particle has a size greater than 60 µm.

For illustrative purposes, a suitable drospirenone particle size distribution according to the invention is shown in Figure 1.

In some other embodiments, the contraceptive composition as described herein comprises drospirenone in a particle form having a specific surface area of from about 2000 cm2 / g to about 8000 cm2 / g and having a particle size d50 that ranges from 10 | im to 60 | im.

To obtain drospirenone in particle form having the specific surface area and / or the particle size distribution as described above, the skilled artisan can use well known prior art methods such as optionally combined milling process with sieve procedure.

For example, drospirenone, obtained by any of the synthesis methods described in the prior art, can be subjected to a ball milling or hammer milling step optionally followed by a vibrating screen step. Subsequent vibrating screen steps can remove the finest and largest drospirenone particles that would affect the pharmacokinetic profile and dissolution profile of drospirenone in vitro. One skilled in the art can adjust the parameters of the milling and sieving steps by routine experiments to obtain the appropriate drospirenone particle shape. Appropriate mills that can be used include fluid power mill, ball mill or rod mill, hammer mill, shear mill, and oscillating granulator.

An appropriate drospirenone particle form can also be prepared by a crystallization or precipitation process optionally combined with a sieving step in order to fully control the size of the drospirenone particles. The precipitation process may comprise the steps of (i) dissolving drospirenone in a water-miscible solvent and then (ii) dispersing the solution resulting in cold water with stirring to induce precipitation of drospirenone. The drospirenone particles can then be recovered by a filtration procedure.

The water miscible solvents can be a solvent commonly used in a crystallization or precipitation process such as methanol, ethanol, isopropanol, dimethylformamide, tetrahydrofuran, dioxane, or dimethylsulfoxide, dimethylacetamide, or acetone.

Such a process makes it possible to obtain drospirenone essentially in crystallized form.

Through routine experiments, one of skill in the art can determine the parameters of the precipitation procedure to be used to obtain the appropriate form of drospirenone.

One skilled in the art can adjust the parameters of said precipitation procedure (such as the amounts of solvent, water and optionally those of surfactant to be used) by routine experiments.

As described above, when the pharmaceutical composition is a contraceptive composition, said composition can provide a pharmacokinetic profile of drospirenone such that the presence of an estrogenic compound is not required to ensure the contraceptive efficacy of said compositions.

Accordingly, in preferred embodiments, the contraceptive composition as described herein does not comprise an estrogen, including phytoestrogen. As used herein, the term "estrogen" refers to compounds, such as ethinyl estradiol, mestranol, or the phytoestrogen 8-prenylnaringenin, that can bind to and activate estrogen receptors. In other words, the DRSP is present in the estrogen-free contraceptive composition, which means that the DRSP is not associated with or combined with an estrogen as in the case of the combined oral pill.

In some preferred embodiments, drospirenone is the only contraceptive component comprised in the contraceptive compositions, that is, the only active ingredient that can prevent pregnancy when administered to a patient of childbearing age.

However, in some specific embodiments, drospirenone can be combined with one or more progestogens.

The term "progestin", as used herein, refers to any compound that binds to and activates the progesterone receptor.

Progestins include, but are not limited to, 17-hydroxyprogesterone esters, 19-nor-17-hydroxyprogesterone esters, 17a-ethynyltestosterone and derivatives thereof, 17a-ethynyl-19-nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, ethinylodiacetate, dydrogesterone, medroxyprogesterone acetate, norethindrel, allystrenol, linoestrenol, fuingestanol acetate, medrogestone, norgestrienone, dimethiderome, ethinisterone, norgeston-cyproterone acetate, levon-13-acetate, oxygestrelone -ethyl-17a-aetinyl-gon-4-en-3-one, cyproterone acetate, gestiondene, desogestrel, etonorgestrel, norgestimate, norelgestromin, chlormadione and dienogest.

In some other embodiments, drospirenone can be combined with one or more active ingredients that do not have contraceptive activities. Such active ingredients include, but are not limited to, antiemetic agents, vitamins such as folic acid, vitamin B12, vitamin D, minerals, and trace elements such as iron, iodine, selenium, and others. The contraceptive composition as described herein comprises drospirenone in an amount corresponding to a daily dosage that prevents pregnancy when said contraceptive composition is administered to a woman during a single treatment period of 21 to 28 days.

As described in Example 3 in connection with a clinical trial, the Applicant demonstrated that the oral administration of a single daily dosage unit of a composition according to the invention and comprising 3 mg of DRSP makes it possible to obtain a value of AUCüh-last of 368 ng * h / ml, which corresponds to 88% of the AUCüh-last mean resulting from the oral administration of a single dose of Yasminelle®.

In a preferred embodiment, the pharmaceutical composition is a contraceptive composition comprising drospirenone in an amount corresponding to a daily dose of at least 2 mg of drospirenone. At least 2 mg of drospirenone encompasses at least 3 mg of drospirenone, at least 3.5 mg of drospirenone, at least 4 mg of drospirenone.

In some embodiments, the daily active dosage unit consisting of the contraceptive composition as described above may comprise an amount of DRSP ranging from about 2 mg to about 6 mg.

A daily dose ranging from about 2 mg to about 6 mg encompasses daily doses of 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6 mg.

In a preferred embodiment, the contraceptive composition comprises DRSP in an amount corresponding to a daily dosage that ensures the inhibition of ovulation when said contraceptive composition is administered to a woman during a single treatment period of 21 to 28 days.

Preferably, the daily dose of drospirenone ranges from about 3 mg to about 6 mg, more preferably from 3 mg to 4.5 mg. In some embodiments, the amount of drospirenone corresponds to a daily dose of about 4.0 mg.

However, the daily dose of drospirenone to be administered to a patient in need can also be adjusted according to individual factors such as the age, body weight, general health, and diet of the patient. Said daily dose can also vary according to the interaction that can occur between drugs. Said daily dose may also vary according to the additional biological effect (s), other than the prevention of pregnancy, which can be sought by the administration of DRSP.

The daily dose of drospirenone to be administered daily to a patient may be lower or higher than the previously mentioned doses. For example, a patient in perimenopause may require a higher or lower daily dosage of drospirenone, in order to improve her general conditions and, for example, in order to improve the regularity of her menstrual cycles.

Adjustment of the daily dose can be determined routinely by clinicians.

In a preferred embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

The pharmaceutical composition can be formulated according to conventional methods such as those described in Remington: The Science and Practice of Pharmacy (Lippincott Williams &Wilkins; Twenty-First Edition, 2005) Pharmaceutically acceptable excipients that can be used to formulate the contraceptive composition are described, in particular, in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association (Pharmaceutical Press; 6th revised edition, 2009).

Examples of suitable excipients include, but are not limited to, fillers, carriers, diluents, binders, anti-caking agents, plasticizers, disintegrants, lubricants, flavors, buffering agents, stabilizers, colorants, dyes, antioxidants, non-stick agents, softeners, preservatives, and glidants. .

In some embodiments, the contraceptive composition comprises one or more excipients selected from the group of binders, fillers, glidants, and lubricants.

Examples of fillers include, but are not limited to, anhydrous lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, dibasic calcium phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, lactose, dextrose, sucrose, mannitol and sorbitol and combinations thereof.

Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, talc, propylene glycol, PEG, stearic acid, vegetable oil, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium monostearate. mineral oil polyoxyethylene and combinations thereof.

Examples of binders include, but are not limited to, starches, for example, potato starch, wheat starch, corn starch; gums, such as gum tragacanth, acacia, and gelatin; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose; polyvinylpyrrolidone and combinations thereof.

Examples of glidants include silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

In a preferred embodiment, the pharmaceutical composition does not comprise a significant amount of surfactant. A significant amount of a surfactant can affect the dissolution profile of DRSP in vitro by increasing its initial dissolution rate. Surfactants include nonionic surfactants such as polyoexyethylene sorbitan fatty acid esters and ionic surfactants such as sodium lauryl sulfate.

In some embodiments, the pharmaceutical composition comprises drospirenone, at least one binder, and at least one filler, wherein:

(i) the amount of drospirenone represents 1% to 10% by weight

(ii) the amount of the at least one binder represents 50% to 65% by weight and

(iii) the amount of the at least one filler represents 25% to 35% by weight,

the percentages by weight being related to the total weight of said contraceptive composition.

In some embodiments, said contraceptive composition further comprises at least one slipper and at least one lubricant, wherein:

(iv) the amount of the at least one glidant represents 0.2% to 6% by weight and

(v) the amount of the at least one lubricant represents 0.2% to 0.6% by weight

the percentages by weight being related to the total weight of said contraceptive composition.

It goes without saying that the drospirenone to be used can be in the form of a particle having the specific surface area and / or particle sizes d90, d10 and d50 which are fully described in the present specification.

Said contraceptive composition can optionally comprise additional excipients that can represent from about 0.1% to 10% by weight.

In some other embodiments, the contraceptive composition comprises drospirenone, at least one binder, at least one filler, at least one glider, and at least one lubricant, wherein:

(i) the at least one binder is microcrystalline cellulose

(ii) the at least one charge is anhydrous lactose

(iii) the at least one glidant is silicon dioxide and

(iv) the at least one lubricant is magnesium stearate.

The contraceptive composition as described herein can be formulated in a galenic form suitable for oral administration. Such forms include, but are not limited to, tablets, caplets, granules, pills, capsules, powders, and suspension.

In preferred embodiments, the contraceptive composition is formulated in a solid form for oral administration such as tablets, capsules, granules, caplets, and pills.

Such solid forms are particularly suitable for use as a daily active dosage unit in the contraceptive kit as described herein.

When the pharmaceutical composition is formulated in solid forms such as tablets or pills, said solid forms may be conveniently coated with a suitable film-forming agent such as hydroxypropylmethylcellulose, hydroxypropylcellulose or ethylcellulose, to which a suitable excipient may optionally be added, for example, a softener such as glycerol, propylene glycol, diethyl phthalate, or glycerol triacetate, a filler such as sucrose, sorbitol, xylitol, glucose or lactose, or a colorant such as titanium hydroxide, etc.

The pharmaceutical composition in the form of tablets, pills or granules can be prepared by conventional methods such as direct compression, dry granulation and wet granulation.

In some embodiments, the solid shapes are obtained by direct compression.

The application also describes a method for preparing the contraceptive composition as described herein which comprises the steps consisting of:

(i) providing drospirenone in particulate form as fully described previously herein

(ii) provide one or more pharmaceutically acceptable excipients; and

(iii) mixing the drospirenone provided in step (i) with the one or more excipients provided in step (ii).

As fully described above, Applicant provides technical guidance for obtaining a composition comprising DRSP in such a form that:

(i) no more than 50% of the drospirenone initially present in said composition dissolves within 30 minutes and

(ii) at least 50% of said drospirenone dissolves in a time interval of 3 to 4 hours, when the composition is subjected to an in vitro dissolution test , the percentages of drospirenone being related to the amount of drospirenone present initially in said composition.

A composition containing DRSP with such an in vitro dissolution profile or the in vivo pharmacokinetic profile fully described above can be achieved in other ways.

Through routine experiments and in view of his general knowledge, the person skilled in the art can modify (i) the particle size distribution of DRSP and (ii) the amounts and the nature of the excipients in order to obtain other alternative compositions. exhibiting the in vitro dissolution profile and in vivo pharmacokinetic profile described in the present application.

For example, the person skilled in the art can devise a composition comprising (i) micronized DRSP together with (ii) a slow release agent in order to decrease the dissolution rate of said DRSP.

The person skilled in the art may also contemplate (i) combining large DRSP particles together with (ii) a surfactant and / or a wetting agent in order to ensure dissolution of said DRSP.

In a general aspect, DRSP in non-micronized and essentially crystallized form is preferably used to prepare the pharmaceutical composition described herein.

2. Contraceptive methods

When administered orally, the pharmaceutical composition provides a significantly improved pharmacokinetic profile for drospirenone characterized by a similar AUC [ ⁰ h-last], a delayed tmax and a reduced Cmax compared to that obtained with Yasminelle®.

In order to conceive a contraceptive based on said pharmaceutical composition, the presence of an estrogen such as ethinyl estradiol or 8-prenylnaringenin is not required to guarantee ovulation inhibition and cycle stability.

Furthermore, such compositions are expected to be more reliable than the PPS described in the prior art.

Contraceptive compositions as described herein that do not comprise an estrogen are therefore particularly suitable for use as a progestin-only contraceptive.

Accordingly, another object of the present invention is the use of the pharmaceutical composition as described herein to prepare a progestin-only contraceptive pill or to prepare a contraceptive kit.

A further object of the present invention is to provide an oral contraceptive method for a patient in need, characterized in that it comprises the step of administering daily active dosage units consisting of a pharmaceutical composition as fully described herein to said patient during a period of several consecutive days preferably over a period of 21 to 28 days.

As used herein, a contraceptive method refers to a method of preventing pregnancy.

As used herein, "a daily active dosage unit" means a dosage unit that can prevent pregnancy when administered daily to a patient for a selected period of periods of 21 to 28 consecutive days.

In preferred embodiments, the daily active dosage unit can inhibit ovulation when administered daily to a patient for a selected period of periods of 21 to 28 consecutive days.

As used herein, a "patient" refers to a woman of childbearing age, i.e., from puberty to menopause. Women of childbearing age also include perimenopausal women.

In a preferred embodiment, said daily dosage units do not comprise an estrogen.

In some embodiments, drospirenone is the only contraceptive component comprised in said contraceptive composition.

The contraceptive method as described herein is generally performed for a period of time corresponding to the average duration of a menstrual cycle, i.e. 28 days, and can be repeated for several consecutive months, even for several years.

In some embodiments, the contraceptive method is to "continuously" administer daily dosage units as described herein. Such a method does not comprise a contraceptive-free period, that is, a period in which no contraceptive is administered.

In other embodiments, the contraceptive method comprises two consecutive phases:

- a first phase in which daily active dosage units that do not comprise estrogen are administered to the patient for a period of 21 to 27 consecutive days and

- a second phase in which no contraceptive composition is administered to the patient for a period of 1 to 7 consecutive days.

As used herein, a period of 1 to 7 consecutive days includes periods of 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, and 7 consecutive days.

As used herein, a period of 21 to 27 consecutive days includes periods of 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, and of 27 consecutive days.

As mentioned above, the duration of the first phase plus the second phase is preferably 28 days.

In the first phase, the composition of daily active dose units can remain constant, in particular with respect to the daily amount of drospirenone.

In some other embodiments, the composition of the daily active dose units may vary, in particular with respect to the daily amount of drospirenone.

The second phase is a contraceptive-free period, that is, a phase during which no contraceptive components are administered to the patient. During said second phase, daily placebo dosage units can be administered to the patient. In some other cases, no pills are given to the patient. Such a second phase can allow regular menstrual bleeding to occur and thus can allow you to mimic the natural menstrual cycle.

Furthermore, it is believed that said second phase allows endogenous estradiol secretion which may have some benefits on the patient's bone metabolism.

As used herein, the term "daily active dosage unit" refers to physically separate units suitable as a unit dosage consisting of a contraceptive composition as fully described hereinbefore. As previously mentioned, the daily active dosage unit may generally comprise an amount of drospirenone from about 3.0 mg to about 6.0 mg, more preferably, from about 3.5 mg to about 4.5 mg.

In some embodiments, the first phase of the contraceptive method lasts for 21 to 24 consecutive days and the second phase of the contraceptive method lasts for 4 to 7 consecutive days.

In some embodiments, the first phase of the contraceptive method lasts for 24 consecutive days and the second phase of the contraceptive method lasts for 4 consecutive days.

The contraceptive method can provide high contraceptive efficacy without the disadvantages (i.e. spotting, irregular bleeding ...) seen for progestogen-only contraceptive methods marketed such as Cerazette®.

Such a contraceptive method may be more reliable than other progestogen-only methods of contraception by allowing patients to comply somewhat less with treatment (i.e. allowing them to skip episodic pills) without risking an unwanted pregnancy (see example 4 below).

The contraceptive method is suitable for women of childbearing age.

It should be noted that the contraceptive method may be suitable for women whose health conditions are not compatible with high peaks in the plasma concentration of drospirenone. Such women include, but are not limited to, patients with renal dysfunction, women predisposed to hyperkalemia, and patients taking potassium-sparing drugs concomitantly.

The contraceptive method is also particularly suitable for women for whom estrogen administration is not recommended. Such women include, but are not limited to, women predisposed to cardiovascular disorders, women who smoke, and women who are breastfeeding.

3. Contraceptive kits

The present application also provides a contraceptive kit based on the contraceptive compositions as fully described in the present application. Such a kit is particularly suitable for use in contraceptive methods as described above.

Said contraceptive kit comprises one or more conditioning units.

One or more conditioning units include, but are not limited to, 1 conditioning unit, 2 conditioning units, 3 conditioning units, 4 conditioning units, 5 conditioning units, and 6 conditioning units.

Each conditioning unit comprises from 21 to 28 daily active dosage units. As fully described above, each daily active dosage unit consists of a contraceptive composition as described herein.

In some embodiments, the contraceptive kit comprises one or more conditioning units wherein each conditioning unit comprises from 21 to 28 daily active dosage units and wherein each daily active dosage unit comprises drospirenone in non-micronized particulate form of so that:

(i) no more than 50% of the drospirenone initially present in said daily active dosage unit dissolves within 30 minutes and

(ii) at least 50% of said drospirenone dissolves in a time interval of 3 to 4 hours, when the daily active dosage unit is subjected to an in vitro dissolution test , the percentages of drospirenone being related to the amount of drospirenone initially present in said daily active dosage unit.

In other embodiments, the contraceptive kit comprises one or more packaging units wherein each conditioning unit comprises 21 to 28 daily active dosage units and wherein oral administration of a daily active dosage unit provides a pharmacokinetic profile for DRSP characterized by the following characteristics:

(i) a mean tmax of at least about 2.2 h and

(ii) a mean Cmax that is less than about 30 ng / ml.

In some embodiments, oral administration of said daily active dosage unit provides a pharmacokinetic profile further characterized by an AUCh-ultimate of at least 300 ng * ml / h, more preferably of at least 350 ng * ml / h.

As fully described above, the daily active dosage units preferably do not comprise any estrogen or estrogen derivative such as ethinyl estradiol, mestranol or 8-prenylnaringenin. In other words, DRSP is preferably present in daily active dosage units without estrogen. In more preferred embodiments, DRSP is the only contraceptive component comprised within the daily active dosage units.

In some other embodiments, the contraceptive kit comprises one or more conditioning units wherein each conditioning unit comprises 21 to 28 daily active dosage units and wherein:

(a) the amount of drospirenone in each daily active dosage unit is at least 2 mg, without estrogen, and

(b) Oral administration of a daily active dosage unit provides a pharmacokinetic profile for DRSP characterized by the following characteristics:

(i) a mean tmax ranging from 2.2 h to 6 h and

(ii) a mean Cmax that is less than about 30 ng / ml.

In other embodiments, the contraceptive kit comprises one or more conditioning units wherein each conditioning unit comprises 21 to 28 daily active dosage units and wherein

(a) the amount of drospirenone in each daily active dosage unit is at least 2 mg without estrogen, and (b) each daily active dosage unit comprises drospirenone in a form such that:

(i) no more than 50% of the drospirenone initially present in said daily active dosage unit dissolves within 30 minutes and

(ii) at least 50% of said drospirenone dissolves in a time interval from 3 to 4 hours, when the daily active dosage unit is subjected to an in vitro dissolution test according to the paddle method of USP XXIII , the percentages of drospirenone being related to the amount of drospirenone initially present in said daily active dosage unit.

Each conditioning unit optionally comprises from 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.

In some embodiments, the contraceptive kit is characterized in that each packaging unit comprises 28 daily dosage units and no daily dosage units of a pharmaceutically acceptable placebo. Such a contraceptive kit is particularly suitable for the contraceptive method that consists of administering DRSP “continuously” without a contraceptive-free period (see paragraph 2 above). In other embodiments, each conditioning unit comprises:

- from 21 to 27 daily active dosage units consisting of a contraceptive composition as fully described in the present application and

- optionally, 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.

A contraceptive kit of this type is particularly suitable for carrying out the contraceptive method described in the present document which comprises

- a first phase in which daily active dosage units that do not comprise estrogen are administered to the patient for a period of 21 to 27 consecutive days followed by

- a second phase in which no contraceptive composition is administered to the patient for a period of 1 to 7 consecutive days.

In some other embodiments, each kit packaging unit comprises 24 daily dosage units comprising an effective amount of a contraceptive composition as described herein and, optionally, 4 daily dosage units of a pharmaceutically acceptable placebo.

The conditioning unit as described above may have one of the conventional forms commonly used for oral contraceptives.

For example, the packaging unit may be a conventional blister pack comprising the appropriate number of dosage units in a blister pack sealed with a cardboard, card, foil or plastic backing and enclosed in a suitable covering. Each blister pack can be conveniently numbered or marked to facilitate compliance.

The conditioning unit may contain daily dosage units in the order in which they are to be taken, ie, starting with the first of the at least 21 dosage units containing the drospirenone combination optionally followed by 7 or fewer empty blisters or by 7 or fewer dosage units comprising a pharmaceutically acceptable placebo.

The kit may comprise other appropriate components such as instructions for use.

The following examples are illustrative and are not intended to limit the scope of the invention as claimed.

Examples

Example 1: Preparation of tablets

to. Preparation of drospirenone

Drospirenone was prepared according to a procedure similar to that described in WO2006 / 061309. In order to obtain DRSP with an appropriate particle size distribution, the DRSP was subjected to a further precipitation procedure as mentioned in the present application.

Five batches of DRSP were prepared by variants of the above mentioned precipitation procedure.

The analysis of the particle size distribution of each batch was carried out by means of a wet scattering laser diffraction method (Helos sensor, Sympatec with the Quixel wet disperser). The dispersing agent used was water. Complete particle dispersion was guaranteed by ultrasonication.

The specific area was determined by a BET method. The results obtained are shown in Table 1. Table 1: Particle size distribution parameters and specific area of DRSP batches

The cumulative distribution function and the probability density function for lot 080053 are shown in Figure 1.

b. Preparation of tablets according to the present invention

Tablets are prepared by direct compression. The composition of tablets is described below.

Table 2: composition of tablets (A-3mg, of the invention)

Example 2: In vitro dissolution profiles

to. Comparison of A-3mg tablets ( of the invention) with Yasminelle® ( comparative)

The dissolution rate of drospirenone of the tablets prepared in Example 1 (A-3mg) was determined by the paddle method of USP XXIII using a USP dissolution test apparatus 2 including 6 covered glass containers and 6 paddles.

The tablets were placed in 900 ml of water at a temperature of 37 ° C (± 0.5 ° C) and shaken at 50 rpm. The amount of drospirenone released into water was measured over several hours. The mean percentages of DRSP released (which were related to the amount of drospirenone initially present in each tablet) were calculated and plotted against time in order to provide the dissolution profile of DRSP in vitro.

The in vitro dissolution profile of A-3mg tablets (of the invention) is shown in Figure 2 (see curve # 2).

Figure 2 also provides the dissolution profile obtained for Yasminelle® tablets comprising micronized DRSP (comparative) (see curve # 4).

It appears that the initial dissolution rate for the tablets obtained in Example 1 (A-3mg) was significantly reduced compared to that of the Yasminelle® tablet since only approximately 22% of the DRSP initially present in the tablets was released in the term 30 min (compared to almost 100% for Yasminelle® in 30 min). The final dissolution percentage of DRSP of the tablets obtained in Example 1 was more than 80%. As described in example 3, part 1, such an in vitro dissolution profile correlates with an improved pharmacokinetic profile compared to Yasminelle®.

b. Examples of other in vitro dissolution profiles

In order to illustrate the correlation between the dissolution profile of drospirenone in vitro and its pharmacokinetic profile after oral administration, two other types of tablets containing DRSP (comparative) were prepared. The composition of these tablets is different from that of the A-3 mg tablet. Each tablet contains 3 mg of DRSP in non-micronized form.

The first type of tablet (CO1-3mg) provides rapid dissolution in vitro since approximately 60% of the DRSP initially present in the tablets was released within 30 min according to the paddle method of USP XXIII (see curve No. 3, Figure 2).

The second type of tablet (CO2-3mg) has a very low in vitro dissolution rate of DRSP. No more than 5% of the DRSP initially present in the tablets was released within 30 min and no more than about 40% of said DRSP dissolved within 4 hours (see curve # 1, Figure 2 ).

Example 3: Pharmacokinetic studies

Part 1: Evaluation of the pharmacokinetic parameters for the composition according to the invention (tablet A-3mg) in comparison with Yasminelle®

Goals:

The main objective of the present test was to evaluate the bioavailability of an oral test preparation containing 3.0 mg of drospirenone (tablets described in Example 1 obtained from batch 080053 (i.e. A-3mg), hereinafter referred to as "product of test ”) compared to a conventional product on the market (YASMINELLE®, Schering AG, hereinafter referred to as“ reference product ”) after oral administration of a single dose of 3.0 mg of drospirenone in the fasted state in two different periods, 7 days apart. Yasminelle® comprises 3.0 mg of DRSP in micronized form and 0.030 mg of ethinyl estradiol.

In order to investigate the relative bioavailability of the products, the 90% confidence intervals were determined for the intra-individual ratios (test vs. reference) for the endpoint (s) (last AUCü. And Cmax of drospirenone) .

The secondary objective of the present trial was to investigate the safety of both preparations based on laboratory and clinical safety examinations (at the beginning and at the end of the trial) and the recording of adverse events and / or adverse drug reactions.

Methodology:

The study was conducted as a single-dose, single-dose, open-label, two-period, crossover, monocentric trial in healthy volunteers, with a duration of hospitalization of approximately 12 h - 13 h after dosing on day 1 and with a real drug rest period of 7 days.

Patients (planned and analyzed): - planned for completion: 10

- registered: 19

- only screened: 5

- randomized: 14

- dropouts: 0

-Finished according to the protocol: 14

- data set for pharmacokinetic analysis: 14

- data set for statistical analysis: 14

- data set for safety analysis: 14

Diagnosis and main criteria

for inclusion: [1] Caucasian female

[2] age between 18 and 40 years

[3] physically and mentally healthy as judged by a gynecological, conventional laboratory, and medical examination

[4] non-smokers for at least 6 months (confirmed by urine cotinine test)

[5] use of effective non-hormonal contraception

List of accepted contraceptive methods

- combination of two barrier methods (female / male condoms, diaphragms, spermicides)

- intrauterine device (inert or copper releasing IUD)

- existing sterilization (female tubal occlusion)

Treatment duration:

Each volunteer randomly received a single oral dose of 1 tablet of the test product or 1 of the reference drug on two unique occasions, always fasting.

Both study periods were separated by a real drug rest phase of at least 7 days.

Blood sampling points in each study period:

Previous dose and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 24:00, 48:00 and 72:00 hours after dosing with plasma separation.

For each endpoint, plasma DRSP quantification was performed according to an analytical method adapted from Kirk et al., Rapid Communications in mass Spectrometry, 2006, 20: 1247-1252.

Briefly, drospirenone was extracted from human plasma with EDTA using a solid phase extraction procedure with HLB 60 mg Oasis cartridges and after that it was derivatized with Girard-P solution, then injected into a liquid chromatograph equipped with a tandem mass spectrometry detector. This method allows the determination of drospirenone in human plasma with EDTA over a range of 0.25 to 100.40 ng / ml.

Criteria for evaluation:

Pharmacokinetics:

Primary endpoints: drospirenone AUCü. Last and Cmax

Secondary endpoint: drospirenone tmax

Additional endpoints: not provided

Security

Adverse events, laboratory and clinical screening parameters.

Statistical methods:

For pharmacokinetic endpoints:

• parametric method (ANOVA-log) for AUC0-tultimate and Cmax of drospirenone

• covariates in the model: sequence, treatment, period, voluntary within the sequence

• non-parametric method (Hauschke et al. 1990) tmax of drospirenone

• 90% confidence interval for the ratios (test vs. reference) for drospirenone AUC0-th and Cmax

For safety assessment:

• descriptive statistical evaluation only.

Bioavailability:

The 90% confidence intervals of logarithmically transformed values were calculated for the test versus reference intra-individual ratio for AUC0-tultimate and Cmax of drospirenone a then they were only interpreted descriptively and were not compared with the usual acceptance intervals for the respective parameters (CPMP / EWP / QWP / 1401/98, July 2001) since the current trial was not intended to provide bioequivalence). The 90% confidence interval was calculated for the intra-individual ratio for the difference in tmax (test-reference) and it was evaluated descriptively.

Results

Pharmacokinetics:

A total number of 14 volunteers completed the trial according to the protocol. Samples from 14 volunteers were analyzed and 14 volunteers were subjected to statistical evaluation. Drospirenone assay endpoints after a single oral dose of 1 tablet (= 3.0 mg drospirenone) of the test preparation or 1 film-coated tablet (= 0.03 mg / 3 mg ethinylestradiol and drospirenone ) of the reference product from the 14 volunteers who underwent pharmacokinetic and statistical evaluation are summarized in Table 3 below.

Table 3: Pharmacokinetic endpoints (primary, secondary and additional) of drospirenone for the test product (TEST) and the reference product (REFERENCE).

The 90% confidence intervals for the intra-individual (test / reference) ratios for drospirenone AUCo-thymus and Cmax, as well as differences (test-reference) for drospirenone tmax are presented in Table 4 below.

Table 4: Drospirenone 90% Confidence Intervals

The concentration versus time curves of drospirenone after the administration of a single oral dose of 1 tablet of the test preparation and tablet of the reference product are found in Figure 3a for both preparations (arithmetic means).

Assessment of the bioavailability of the primary endpoints AUC0-last and Cmax of drospirenone was based on a parametric method (ANOVA-log).

The 90% confidence interval calculated by log-ANOVA for the first primary endpoint, intra-individual ratio (T / R) of AUC ^0- last, was between 0.8081 and 0.9380. The 90% confidence interval calculated using ANOVAlog for the second primary endpoint, intra-individual ratio (T / R) of Cmax for drospirenone, was between 0.3930 and 0.5658.

For the secondary endpoint tmax, the 90% confidence interval for intra-individual differences was between 1.5000 and 2.5000 hours. The point estimator for the difference in tmax of drospirenone was 106 minutes (the concentration maxima after administration of the test preparation are observed below).

It is well known in the art that drospirenone isomerized into a biologically inactive isomer under acidic conditions, including the acidic conditions found in the human stomach.

When conducting the present pharmacokinetic study, assays have been performed to detect the eventual presence of the inactive isomer of drospirenone in the plasma of treated women. Results have shown that the amount of the inactive isomer of drospirenone in plasma samples collected from patients undergoing clinical tests was below the detectable level (<1 ng / ml), which means that the pharmaceutical composition that has been used it is adapted to release the full amount of drospirenone in its biologically active form to the target organs.

Security:

The test formulation and the reference drug were well tolerated. Seventeen non-serious adverse events (AA) were recorded in 11 patients over the course of the trial:

• Nine AAs were observed in 8 patients after administration of the test product

• Eight AAs were observed in 7 patients after administration of the reference drug.

All adverse events were assessed as non-serious. The investigator assessed all adverse events as possibly related. All AEs resolved completely within a relatively short period of time. The results of the laboratory screening gave no indication of adverse events or adverse drug reactions.

Conclusions

Based on the AUCO-t latest of drospirenone, the degree of absorption of the test product is similar to that of the reference product but the rate of absorption is significantly delayed resulting in an increased tmax and a decreased Cmax. The tolerability of the test product and the reference product was equally good.

Part 2: Evaluation of other comparative tablets CO1-3mg and CO2-3mg compared to Yasminelle®

The main objective of this second trial was to further illustrate the correlation between the pharmacokinetic parameters and the in vitro dissolution profile for oral tablets comprising DRSP.

The oral test tablets were the CO1-3mg tablet and the CO2-3mg tablet which showed a fast in vitro dissolution rate for DRSP and a very slow dissolution rate for DRSP, respectively (see example 2b).

The reference product was Yasminelle®. The methodology for this second trial was similar to that of the trial described in part 1 above.

In summary, the bioavailability of two oral test preparations (specifically CO1-3mg and CO2-3mg) compared to that of the conventional product on the market (JASMINELLE, Schering AG) was evaluated after oral administration of a single tablet in each case. (corresponding to 3 mg of DRSP) fasting in three different periods, 7 days apart. In order to investigate the relative bioavailability of the products, the 90% confidence intervals were determined for the intra-individual ratios (CO1-3mg vs reference product and CO2-3mg vs reference product) for the criterion (s) ( s) titer (AUCü-tultimate and Cmax of drospirenone).

The study was conducted as a single-dose, three-period, open-label, randomized, monocentric trial with crossover groups in healthy volunteers, with a duration of hospitalization of approximately 12h - 13h after dosing.

Each volunteer randomly received a single oral dose of 3.0 mg of drospirenone (either 1 CO1-3mg test tablet or 1 CO2-3mg test tablet or 1 Yasminelle® film-coated tablet) in single three sometimes fasting.

The three study periods were separated by a real drug rest phase of between 7 days and 10 days.

Patients (planned and analyzed): - planned for completion: 10

- registered: 18

- only screened: 4

- randomized: 14

- dropouts: 0

-Finished according to the protocol: 14

- data set for pharmacokinetic analysis: 14

- data set for statistical analysis: 14

- data set for safety analysis: 14

Results

The concentration versus time curves of drospirenone after the administration of a single oral dose of 1 tablet of each product (specifically, CO1-3mg, CO2-3mg and Yasminelle®) are shown in Figure 3b (arithmetic means).

For the rest, CO1-3mg presented a rapid dissolution rate for DRSP in vitro (approximately 60% within 30 min). As expected, the pharmacokinetic profile obtained for CO1-3mg is very close to that of Yasminelle® except for Cmax. Interestingly, the mean Cmax for CO1-3mg was 30 ng / ml versus 36 ng / ml for Yasminelle®. The last AUCh-t for CO1-3mg was similar to that of Yasminelle® (410.58 ng * h / ml vs 440.14 ng * h / ml).

On the other hand, CO2-3 mg has a very low dissolution rate of DRSP in vitro since no more than 5% of the DRSP initially present in the tablets was released within 30 min and no more than approximately 40% of said DRSP dissolved within 4 hours. As expected, said composition exhibits a reduced Cmax and a delayed tmax compared to Yasminelle®. However, the mean AUC of that composition it was low. Such a composition may not be suitable for use as a progestogen-only pill since it may provide poor contraceptive reliability.

These pharmacokinetic results combined with the in vitro results described in Example 2 illustrate the correlation between the in vitro dissolution rate of DRSP and its pharmacokinetic profile (in particular for Cmax and tmax), after oral administration.

Example 4: Simulation curves based on experimental data obtained in the clinical trial described in example 3, part 1.

The curves of mean plasma DRSP concentration versus time, expected to be obtained from the oral administration of a tablet described in Table 2 but containing 4 mg of DRSP from batch 80053 (specifically, A-4mg), were extrapolated based on experimental data obtained in the clinical trial described in example 3 with the assumption that the plasma concentration of DRSP is proportional to the oral amount of DRSP administered.

The resulting curve for the A-4mg tablet is shown in Figure 3a and Figure 4a and was compared with that obtained with Yasminelle® and with the A-3mg tablet described in Table 2.

As illustrated in figure 4a and 4b, it is expected that increasing the amount of DRSP from 3 mg to 4 mg in the tablet described in table 2 does not modify the tmax which can remain significantly delayed compared to that of Yasminelle® . Cmax is expected to increase but remain significantly lower than that of Yasminelle® (no more than 60% of that of Yasminelle®). Interestingly, the mean plasma concentration is expected to be higher than that of Yasminelle® after peak concentration.

Figure 4c shows the DRSP plasma concentration curves versus the time expected to result from the repeated administration every 24 hours of a Yasminelle® tablet (curve No. 1), that of an A-3mg tablet (curve No. . ° 3) and that of an A-4mg tablet (curve No. 2).

The curves obtained for the compositions of the invention (specifically curves No. 3 and No. 2) show less difference between the mean Cmax and the mean Cmin (minimum DRSP concentration) than the Yasminelle® composition. Therefore, repeated administration of the compositions of the invention is expected to provide a more stable plasma DRSP concentration with a lower Cmax than Yasminelle®. Such a fact is expected to improve the bleeding profile and reduce the side effects of DRSP when the compositions of the invention are used as a contraceptive.

In the case of the A-4mg tablet, it should be noted that the mean plasma concentration is expected to be higher than that obtained from Yasminelle® during the period of time between the tmax and the time of taking the next tablet, which provides greater reliability. contraceptive.

Therefore, the A-4mg tablet is expected to be suitable for use as a progestin-only pill. Example 5: Another example of a composition according to the invention

Part 1: In vitro dissolution profile

Tablets (B-4mg) were prepared as described in Example 1 from DRSP lot # PR100003. Each tablet comprises 4.0 mg of DRSP and excipients in an amount similar to that described in Table 1. The tablets (B-4mg) were further coated with a suitable film-forming agent, as described in the specification. .

The resulting tablets were subjected to an in vitro dissolution test as described in Example 2. The mean in vitro dissolution profile of said tablets is shown in Figure 5a.

The initial dissolution rate for DRSP was significantly reduced compared to Yasminelle® as only approximately 22% of the DRSP initially present in the tablets was released within 30 min. However, approximately 66% and approximately 77% of the DRSP initially present in the tablets was released within 4 h and 6 h, respectively.

The in vitro dissolution profile for the B-4mg tablets was similar to that of the A-3mg tablet (see Example 1). Such a fact illustrates that the specific area of DRSP does not significantly affect its dissolution in vitro if said DRSP has appropriate d50, d90 and d10.

Part 2: Evaluation of the pharmacokinetic parameters for the composition according to the invention (tablet B-4mg) in comparison with Yasminelle®

to. Methodology

The pharmacokinetic parameters for the B-4mg tablet were determined as described in Example 1, part 1.

In summary, the bioavailability of the test preparation (specifically B-4mg) was evaluated in comparison with that of the conventional product on the market (JASMINELLE, Schering AG) after oral administration of a single tablet in each case on an empty stomach in three periods. different, 7 days apart.

The oral dose of DRSP was 3 mg for Yasminelle® versus 4 mg for the B-4mg tablet (of the invention).

In order to investigate the relative bioavailability of the products, the 90% confidence intervals were determined for the intra-individual ratios (B-4mg vs Yasminelle®) for the endpoint (s) (AUCü. Last and Cmax drospirenone).

The study was conducted as a single-dose, three-period, open-label, randomized, monocentric trial with crossover groups in healthy volunteers, with a duration of hospitalization of approximately 12h - 13h after dosing.

Each volunteer randomly received a single oral dose of drospirenone (either a test B-4mg tablet or a Yasminelle® tablet) on only two fasting occasions.

Both study periods were separated by a phase of real pharmacological rest of between 7 days and 10 days.

Patients (planned and analyzed): - planned for completion: 10

- registered: 15

- only screened: 5

- randomized: 10

- dropouts: 0

-Finished according to the protocol: 10

- data set for pharmacokinetic analysis: 10

- data set for statistical analysis: 10

- data set for safety analysis: 10

b. Results

All patients tolerated Yasminelle® and the test product well.

The concentration versus time curves of drospirenone after the administration of a single oral dose of 1 tablet of each product (specifically, tablet B-4mg and Yasminelle®) are shown in Figure 5b (arithmetic means). The results of such a test are further shown in Table 5 below.

Table 5: Pharmacokinetic endpoints for the B-4mg tablet (TEST) and Yasminelle® (REFERENCE).

The pharmacokinetic profile for DRSP obtained after oral administration of a B-4mg tablet was correlated with the expected DRSP pharmacokinetic profile based on the simulations (see Example 4). As expected, the mean tmax for the B-4mg tablet was significantly delayed compared to that of Yasminelle® (3.9 h vs. 1.7 h). Furthermore, the mean Cmax obtained for the B-4mg tablet was significantly lower than that of Yasminelle® (19.8 vs 32.9 ng * h / ml).

The mean Cmax for tablet B-4mg corresponded to approximately 58% of the Cmax for Yasminelle® while, in Example 1, the mean Cmax for tablet A-3mg corresponded to 49% of that for Yasminelle®: the increase The dose of DRSP in the tablets did not induce any significant change in Cmax values. On the other hand, increasing the DRSP dose significantly improved the last mean AUCüh since the last mean AUCüh for the B-4mg tablet was 111% that of Yasminelle. In Example 1, the mean AUCh-t for tablet A-3mg was only 86% of that for Yaminelle®.

In other words, the present results clearly show that the compositions of the invention make it possible to obtain a high mean AUCh-t-last value in combination with a low mean Cmax and a delayed mean tmax for DRSP compared to Yasminelle®.

Repeated administration of B-4mg tablets every 24 hours will certainly provide a DRSP plasma concentration profile similar to that expected for tablet A-4mg (see Figure 4C, curve # 2). To conclude, the pharmaceutical tablets of the invention, such as tablet A-4mg and tablet B-4mg, are likely to be suitable for use as contraceptive only pills. Such contraceptives are expected to have a good tolerance and avoid the occurrence of side effects related to high and fluctuating plasma DSRP concentrations.

Part 3: Evaluation of the contraceptive efficacy of the pharmaceutical composition according to the invention

The aim of the study is to illustrate that a contraceptive pill according to the invention comprising DRSP as the sole contraceptive agent and administered in a 24/4 regimen enables ovulation to be inhibited even in the event of an episodic delay of the pill.

The contraceptive pill consists of 24 B-4mg tablets as defined in Example 5, part 2 above and 4 placebo tablets.

to. Methodology

The study was an open-label, single-center trial.

The patients eligible for the study were between the ages of 20-30 years, had a body mass index <30 kg / m2, had regular menstrual cycles (at least 4 regular cycles in the last 6 months) and were willing to use a condom throughout the duration of the study. Patients with a (suspected) pregnancy, past or active thromboembolic disorder, past or present severe liver disease, endometrial carcinoma or other suspected or known estrogen-dependent neoplasia, undiagnosed vaginal bleeding, use of liver enzyme-inducing drugs and other drugs were excluded. .

A total of 20 women were enrolled in this trial and performed the two treatment cycles and the follow-up cycle.

Table 6: Enrolled Patient Parameters

Patients received daily treatment with tablets containing 4 mg of DRSP on a 24/4 regimen for two cycles. Patients began treatment on the first day of the cycle (ie, the first day of vaginal bleeding onset) after the screening visit. Patients took one DRSP 4 mg tablet from day 1 to day 24, and a placebo tablet from day 25 to day 28 of each treatment cycle at a fixed time, with the exception of day 5 and day 13 of the second cycle. On these two days, tablet-taking was delayed for 24 hours (i.e. no pills were taken on day 5 or day 13, and 2 tablets were taken on day 6 and day 14, respectively ). The entire study consisted of a treatment period of 56 days and a follow-up period after treatment of 28 days. After obtaining informed consent, the patients underwent a gynecological examination and a general medical examination, laboratory tests of urinalysis, biochemistry, hematology, and lead 12 ECG. After compliance with the selection criteria was confirmed , and after performing a negative urine pregnancy test on the first day of vaginal bleeding onset, the patient was enrolled in the study and began taking the study drug.

Blood samples were taken for hormonal determination (progesterone, 17-beta-estradiol, FSH and LH) every 3 days from day 1 to day 84 and weight, blood pressure and heart rate evaluations were performed at each visit . Serum progesterone, 17-beta-estradiol, FSH and LH concentrations were measured with validated commercial in vitro diagnostic kits (VIDAS, ELFA Biomerieux). Internal controls were included in each set of samples.

Two urine pregnancy tests were performed during the study:

■ at the visit on day 1 of the first cycle in order to verify the exclusion criterion "pregnant woman" just before starting study treatment: the patient was excluded if this test was positive

■ at the visit on day 7 of the follow-up cycle.

Ovulation during treatment was determined based on serum progesterone concentration, using the criteria of Landgren et al. Therefore, ovulation was considered to have occurred in the case of progesterone concentrations> 5.04 ng / ml, maintained for at least 2 consecutive progesterone samples.

b. Results

Figures 6a and 6b show individual values plotted for plasma progesterone levels and plasma estradiol levels, respectively.

For all women, progesterone level values were consistently less than 5.04 ng / ml throughout the treatment period (including the placebo period). The maximum progesterone value was observed to be 3 ng / ml for a single woman and for only once during the treatment periods (including the placebo period).

These results show that during the 2 cycles, ovulation did not occur. In contrast, after cessation of treatment, during the 28-day follow-up cycle, progesterone levels increased above 5.04 ng / ml in 17 of 20 women who showed a recurrence of ovulation. The minimum time until the first progesterone level was above 5.04 ng / ml was on day 15 after the last placebo tablet.

During the 2 cycles on treatment, the mean estradiol levels were significantly lower compared to those measured during the follow-up cycle.

Notably, estradiol secretion is not totally inhibited during the treatment period.

To conclude, these data confirm that the composition of the invention, when used as PPS in a 24/4 regimen, provided reliable ovulation inhibition even in the presence of the placebo period. This inhibition of ovulation was maintained even if tablet-taking was delayed for 24 hours at two different times within a cycle.

In view of these experimental data, the progestogen-only contraceptive of the invention is expected to exhibit similar reliability and efficacy to the traditional combination pill such as Yasmine® with fewer side effects on the cardiovascular system.

Example 6: Another example composition according to the invention

Tablets comprising 4 mg of drospirenone (C-4mg) are prepared by direct compression. The composition of tablets is described below.

Table 7: Composition of the tablets (C-4mg, of the invention)

Material mg / tablet

The DRSP PR100311 batch is characterized by a specific area of 0.66 m2 / g.

The in vitro dissolution rate and the pharmacokinetic parameters for these tablets were determined as described in Example 2 and Example 3, respectively.

Table 8: In vitro DRSP dissolution rate and DRSP pharmacokinetic profile for C-4mg tablets

Claims (15)

i. Contraceptive kit comprising one or more conditioning units, in which each conditioning unit comprises 21 to 28 daily active dosage units and in which (a) the amount of drospirenone in each daily active dosage unit is at least 2 mg, without any estrogen, and (b) each daily active dosage unit consists of a contraceptive composition suitable for oral administration comprising drospirenone, in which drospirenone has a d50 particle size ranging from 10 µm to 60 µm, such that: (i) no more than 50% of the drospirenone initially present in said daily active dosage unit dissolves within 30 minutes and (ii) at least 50% of said drospirenone dissolves in a time interval of 3 to 4 hours, when the daily active dosage unit is subjected to an in vitro dissolution test according to the paddle method of USP XXIII, the percentages of drospirenone being related to the amount of drospirenone initially present in said daily active dosage unit. 2. The contraceptive kit according to claim 1, in which drospirenone has a particle size distribution characterized by: (i) a d90 particle size of less than 100 µm; (ii) a d50 particle size ranging from 10 µm to 60 µm; and (iii) a d10 particle size of more than 3 µm. 3. The contraceptive kit according to any one of claims 1 or 2, in which drospirenone is the only contraceptive component. A contraceptive kit according to any one of claims 1 to 3, wherein the amount of drospirenone in each daily active unit dosage ranges from about 2.0 mg to about 6.0 mg, preferably from about 3.0 mg to about 4.5 mg, more preferably about 4 mg. Contraceptive kit according to any one of claims 1 to 4, wherein the one or more conditioning units further comprise from 1 to 7 daily dosage units of a pharmaceutically acceptable placebo. Contraceptive kit according to any one of claims 1 to 5, in which each conditioning unit comprises 24 daily active dosage units. A contraceptive kit according to claim 6, further comprising 4 daily placebo dosage units. A contraceptive kit according to any one of claims 1 to 7, wherein said contraceptive composition comprises: - drospirenone in an amount representing 1% to 10% by weight, - at least one binder representing 50% to 65% by weight, - at least one filler representing 25% to 35% by weight, - at least one slipper representing 0.2% to 6% by weight, and - at least one lubricant representing 0.2% to 0.6% by weight, the percentages by weight being related to the total weight of said contraceptive composition. Contraceptive kit according to any one of claims 1 to 8, wherein said contraceptive composition comprises drospirenone, at least one binder, at least one filler, at least one sliding and at least one lubricant, in which: (i) the at least one binder is microcrystalline cellulose, (ii) the at least one filler is anhydrous lactose, (iii) the at least one glidant is silicon dioxide, and (iv) the at least one lubricant is magnesium stearate. 10. Pharmaceutical composition suitable for oral administration comprising drospirenone, wherein: (a) a daily active dosage unit of said composition comprises an amount of drospirenone of at least 2 mg, without any estrogen, and (b) said daily active dosage unit comprises drospirenone, and drospirenone has a d50 particle size ranging from 10 µm to 60 µm, so that: (i) not more than 50% of the drospirenone initially present in said daily active dosage unit dissolves within 30 minutes, and (ii) at least 50% of said drospirenone dissolves in a time interval of 3 to 4 hours, when the daily active dosage unit is subjected to an in vitro dissolution test according to the paddle method of USP XXIII, the percentages of drospirenone being related to the amount of drospirenone initially present in said daily active dosage unit, for its use as a contraceptive for a patient in need. 11. Pharmaceutical composition for use according to claim 10, wherein said composition is according to any one of claims 1 to 4, 8 or 9. 12. Pharmaceutical composition for use according to either of claims 10 or 11, wherein the daily dosage units of the composition are administered to said patient for a period of 21 to 28 consecutive days. 13. Pharmaceutical composition for use according to any of claims 10 to 12, wherein the daily dosage units of the composition are administered comprising two phases: ■ a first phase in which daily active dosage units are administered to the patient for a period of 21 to 27 consecutive days, followed by a second phase in which the patient is not given contraception for a period of 1 to 7 consecutive days. 14. Pharmaceutical composition for use according to claim 13, wherein daily placebo dosage units are administered during said second phase. 15. Pharmaceutical composition for use according to any of claims 13 or 14, wherein the first phase lasts 24 consecutive days and the second phase lasts 4 consecutive days.