OA18512A

OA18512A - Drospirenone-based contraceptive for a female patient affected with excess weight.

Info

Publication number: OA18512A
Application number: OA1201700509
Authority: OA
Inventors: Philippe Perrin; Dominique Drouin; Cécile Boyer-Joubert
Original assignee: Laboratorios Leon Farma Sa
Priority date: 2015-06-23
Filing date: 2016-06-23
Publication date: 2018-12-04

Abstract

Drospirenone as the sole contraceptive ingredient comprised in a daily active dosage unit in an amount of at least 3 mg for use as a contraceptive for a female patient affected with obesity.

Description

· The présent invention relates to the field of contraceptive compositions and methods, în particular for a female patient affected with excess weight, which encompasses a female patient affected with overweight or obesity.

BACKGROUND OF THE INVENTION

Excess weight among adults, i.e. overweight and obesity, highly increases with time in the general population.

The World Health Organization (WHO) has established weight standard status categories based on a body mass index (BMI), which range for adults are as follows:

- an underweight status is featured by a BMI below 18.5 kg/m²;

- a normal weight status is featured by a BMI ranging from 18.5 kg/m² to

24.9 kg/m²;

- an overweight status is featured by a BMI ranging from 25.0 kg/m² to

29.9 kg/m²; and

- an obesity status is featured by a BMI of 30.0 kg/m² or greater.

Based on the latest OECD Health Statîstics report, the majority of adults (53%) are overweight or obese in EU countries with obese adults representîng about 17% of the adult population (OECD/European Union (2014), “Overweight and obesity among 25 adults”, in Health at a Glance: Europe 2014, OECD Publishing.). In the United States, 64% of women are affected with overweight or obesity, among which 36% are obese (Flegal et al., Journal of the American Medical Association. 2012; 307(5):491-97). Obesity is a known risk factor for numerous health problems, including hypertension, high cholestérol, diabètes, cardiovascular diseases, and some forms of cancer.

The prevalence of unintended pregnancy rivais that of overweight or obesity.

About 40% of ail pregnancîes worldwide were unintended, with 43% in Europe and 51% in North America (Sedgh G. et al. Studies in Family Planning 2014; 45 (3):301-314).

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Obese women and especially those with comorbidities are at higher risk of pregnancyrelated complications. Thus, avoidance of unintended pregnancy în these women is especially important (Cedergren MI. Obstet. Gynecol. 2004;103:219-24).

The best way to prevent unintended pregnancies is to provide appropriate contraception with safe and well-tolerated options.

Hormonal contraceptives are one of the most widely used contraceptive methods in the world and hâve the widest géographie distribution of any method. Hormonal contraceptives are also the most popular form of réversible female contraception in the developed world (United Nations. Department of Economie and Social Affairs - Population Division. World Contraceptive Patterns 2013.). Among hormonal contraceptives, one may cite combined contraceptives (pills, vaginal rings or transdermal patches) or progestin-only contraceptives (progestin-only pills, injections, implants).

Combined hormonal contraceptives comprise a combination of a progestîn and of an estrogen component.

A number of pharmacologie effects contribute to the contraceptive effects of progestins. These include inhibiting ovulation by suppressing the function of the hypothalamic-pituitary-ovarian axis; modifying the subséquent pituitary surge of Iuteinizing hormone and follicle-stimulating hormone. It includes also slowing transport of the ovum through the fallopian tubes, which limits the time available for fertilization; thickening cervical mucus, which impedes sperm transit; and inhibiting the activation of spermatic enzymes required for ovum pénétration. The primary aim of the estrogen is to provide adéquate cycle (bleeding) control; it also inhibits the release of follicle stimulating hormone and consequently prevents follicle development.

One of the adverse effects of combined oral contraceptives is the increased risk of venous thromboembolism (VTE) into two clinicai characteristics: deep vein thrombosis or pulmonary embolism. Every year 10,000 women of childbearing âge sufîer a venous thromboembolie disease and this incidence is increased threefold to fîvefold in women who use combined hormonal contraceptives. In women at fertile âge, combined hormonal contraception remains the most important factor for the development of VTE and remains in most cases the only factor that triggers the disease (Blanco-Molina MA et » >

al., Progestin-only contraception and venous thromboembolism. Thrombosis Research.2012;129:e257-e262).

Obesity is an independent risk factor for the development of venous thromboembolism (VTE). (Abdollahi M. et al. Thromb. Haemost. 2003 ;89 (3):493-498). Use of combined oral contraceptive is associated with increased risk of VTE in obese patients. A population-based case-control study performed in the Netherlands has revealed this increased risk. Among women who did not use oral contraceptives, the risk increased 2.5-fold for overweight women and 3.0-fold for obese women compared to normal weight women who do not use oral contraceptives. Relative to non-users having a normal BMI, oral contraceptive users who were overweight had an 11.6-fold increased risk of VTE and those who were obese had a 23.8-fold increased risk of VTE. (Murthy AS. Semin Reprod Med. 2010 Mar;28(2): 156-63 ; Pomp ER et al. Br J Haematol 2007;139:289-296.).

The estrogen component of contraceptive formulations was consîdered to be mainly responsable for the prothrombotic effect of combined hormonal contraception.

According to guidelines from the World Health Organization and US Centers for Disease Control and Prévention (Guidelines on “Medical eligibility criteria for contraceptive use.”), the use of combined oral contraceptives is discouraged by women of 35 years âge and older, who arc obese, hypertonie, smoke or hâve diabètes. Ail modes of progestin-only contraception are advocated, even for higher VTE risk women such as those with hereditary thrombophilia, history of estrogen induced venous thromboembolism, or history of récurrent venous thromboembolism (Centers for Disease Control and Prévention. US medical eligibility criteria for contraceptive use. MMWR Early Release 2010;59:1-86. Department of Reproductive Health WHO. Medical eligibility criteria for contraceptive use . 4th ed. WHO Press, 2009).

It is recalled that progestin-only contraception (POC) relies upon maintaining a high level of progestérone in the female body, hence inhibiting the sécrétion of the follicle stimulating hormone and the luteinizing hormone. POC treatment results in the absence of development of any new egg follicles.

In POC contraceptive formulations, one may cite numerous progestogen molécules, such as norethindrone, ethynodiol diacetate, levonorgestrel, desogestrel, lynestrenol, drospirenone or depot medroxyprogesterone acetate (DMPA) that hâve been proven efficient as contraceptive active ingrédients.

*

Regarding progestin-only contraception, a systematic revîew and metaanalysis from Mantha evaluating the risk of VTE in progestin-only contraceptives users did not identify a significant risk of venous thromboembolism associated with use of progestin-only contraception. (Mantha S et al. BMJ 20l2;345:e4944). In a recent study, Lidegaard analyzed more than 29 000 women years for a third génération progestin-only pill (desogestrel) and failed to show any increased VTE risk associated with its use (adjusted venous thromboembolie event rate 0.64 (95% confidence interval 0.29 to 1.42)) (Lidegaard O. et al., 2001 -9. BMJ 2011 ;343:d6423).

Consequently, progestin-only contraceptives should be the best option for women at risk of VTE and thus should be a safe option for overweight or obese women.

However the main known disadvantage of progestin-only contraceptives is the alteration of the bleeding profile, resulting in breakthrough bleeding or spotting during the hormonal treatment.

It is well-known that bleeding irregularities are one of the prominent reasons for discontinuation of contraception, which increases risk of unintended pregnancy. Women discontînuing oral contraceptives often fail to substitute another contraceptive or adopt a less effective method. Indeed, a study has shown that among 6% of users who discontinued oral contraceptives because of irregular bleeding, 23% had unintended pregnancy (Rosenberg MJ et al.. J Reprod. Med. 1995;40(5);355-360).

The prevalence of breakthrough bleeding în overweight or obese women using hormonal contraception is unknown. A rétrospective analysis of data from a study evaluating 2893 women (613 were overweight or obese) using two different formulations of a low-dose oral contraceptive found that rates of breakthrough bleeding were not different across weight categories (Hampton RM et al., Contraception 2008;77(6):415419). Another study showed that during the use of the contraceptive vagina! ring Nuvaring (etonogestrel/ethînyl estradiol), there was overall no différence in the total number of bleeding or spotting days reported by the group of normal BMI women and obese women (normal BMI: 8.7 ± SD 7.3 days, obese: 7.7 ± SD 6.0 days p= 0.64) (Dragoman M. et al., Contraception. 2013 Apr; 87(4): 432-436).

Irregularities in amount and frequency of menstrual fiow and weight gain are wel! documented side effects of POC therapy, such as DMPA, a long acting réversible progestin-only contraceptive birth control drug that is injected every 3 months (Harel Z et al. Adolescents’ reasons for and expérience after discontinuation of the long-acting contraceptives Depo-Provera and Norplant. J Adolesc Health 1996;19(2): 118—23; Kaunitz

AM. Injectable depot medroxyprogesterone acetate contraception: an update for U.S.

clinicians. Int J Fertil Womens Med I998;43(2):73-83; Keder LM et al. Compliance with depot medroxyprogesterone acetate: a randomized, controlled trial of intensive remînders.

Am J Obstet Gynecol 1998; 179(3 Pt 1):583-5; Fraser IS et al.. Depo-Provera use in an Australien metropolitan practice. Med J Australia 1994; 160(9):553-6; Nutley T et al. Treatment of bleeding problems associated with progestin-only contraceptives: survey results. Adv Contracept 1997; 13(4):419-28; Hill DA. Gynecology case challenge: vaginal 10 bleeding in a woman taking an injectable contraceptive. Medscape Womens Health

I998;3(I):4).

Sole one experimental study relating to DMPA-based POC contraception seemed to show a lower risk of excessive bleeding in overweight women (Connor et al.; J. Am. Borad Fam. Pract, ; 2002, vol. 15(1): 7-10) or obese women (Belsey et al.;

Contraception. 1988 Aug;38(2):243-57). Connor et al. (2002) showed that women presenting excessive weight or obesity, when under POC treatment with DMPA, showed a lower risk of increased or excessive bleeding compared with height-weight proportional counterparts. Connor et al. (2002) focused on physiological effects encompassing excessive flow, excessive bleeding, continuous bleeding and continuous flow (globally termed “excessive bleeding” therein) altogether with effects encompassing increased spotting, increased flow, heavier menses and increased duration of menses (globally termed “increased bleeding” therein). The comparative results disclosed by Connor et al. (2002) concem exclusively a unique and global bleeding parameter encompassing both “excessive bleeding” and “increased bleeding”.

However, Connor et al. were silent on the possible effect of DMPA on the duration of the bleeding events, and especially on the number of days for which the bleeding or spotting occurs.

Nevertheless, it flows from the study of Connor et al. that women presenting excessive weight or obesity still présent unwanted spotting and bleeding.

Still further, it may also be referred to a study published by Casey et al. (2013,

Contraception, Vol. 87 : 370-374) relating to etonogestrel-based POC contraceptive under the form ofa subdermal implant (ESI). Casey et al. (2013) showed that obese women were ί ,Α * less likely to hâve the ESI Implant removed for bleeding îrregularities compared to nonobese women.

It flows from the prior art knowledge discussed above that each known progestogen candidate molécule aimed at formulating POC contraceptive formulations adapted to spécifie administration regimen may behave differently, including regarding their effect on various kinds of bleeding events.

Finally, it is generally known in the art that POC treatment is also often correlated with a weight gain, which may become challenging for women with excess weight, in particular overweight women, and especially for obese women, which weight gain effect may enhance the occurrence of diseases linked to overweight and/or obesity, such as, e.g., coronary heart diseases, high blood pressure, stroke, type 2 diabètes, abnormal blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea, obesity hypoventilation syndrome, infertility, gallstones, goût.

Specifically, a systematic review from Curtis, looking at the use of progestinonly contraceptives in obese women, suggested that adolescent DMPA users who are obese or overweight will gain more weight than normal weight users (Curtis KM. et al. Progestogen-only contraceptive use in obese women. Contraception 2009;80(4):346-354). Women often blâme contraception for their weight gain. Many women will discontinue their contraception because of this perceived side effect. Indeed, studies of oral contraceptive users hâve found that a perceived weight gain is one of the leading reasons for discontinuation in US women (Rosenberg M. Weight change with oral contraceptive use and during the menstrual cycle: results of daily measurements. Contraception 1998;58:345-9)

Therefore, due to the drawbacks mentioned above, occurrence of unwanted bleeding or spotting, weight gain, women with excess weight, in particular overweight women, and especially obese women, are more likely to drop off POC treatment, hence increasing their chances of unintended pregnancy.

Therefore, there is a need to provide women with excess weight, which encompass overweight and obese women, with safe and efficient contraceptive formulations, especially with better-tolerated contraceptive formulations showing improved patient compliance.

SUMMARY OF THE INVENTION

This invention relates to drospirenone (DRSP) as the sole contraceptive ingrédient comprised in a daily active dosage unit in an amount of at least 3 mg for use as a contraceptive for a female patient affected with excess weight, which encompasses a female patient affected with overweight as well as a female patient affected with obesity.

This invention also pertains to the use of drospirenone as the sole contraceptive ingrédient for manufacturing a contraceptive composition for a female patient affected with excess weight, which encompasses a female patient affected with overweight as well as a female patient affected with obesity.

This invention also relates to the use of drospirenone in the manufacture of a contraceptive formulation which leads to a réduction in the number of days with bleeding events in female patients affected with excess weight, which includes overweight female patients and obese female patients. The general and substantiel réduction in the number of days with bleeding events, as compared with female patients who are not affected with 15 excess weight, is disclosed throughout the présent spécification. The said contraceptive formulation, which contains drospirenone as the sole contraceptive ingrédient, is described in detail and in its various embodiments throughout the présent spécification.

In another aspect, the invention also relates to a method comprising administering a pharmaceutical composition comprising drospirenone in an amount of at 20 least 3 mg to a female patient affected with excess weight, which encompasses a female patient affected with overweight as well as a female patient affected with obesity.

This invention pertains to a method comprising administering a pharmaceutical composition comprising drospirenone in an amount of at least 3 mg to a female patient affected with excess weight, which encompasses a female patient affected 25 with overweight as well as a female patient affected with obesity, wherein said pharmaceutical composition allows for a 28 day daily dosing regimen, and wherein after initial administration of said drospirenone has established its contraceptive effect in a patient, said patient may skip up to 4 doses within 28 day daily dosing regimen period.

This invention also concems the use of drospirenone in the manufacture of a contraceptive formulation which leads to a general substantial réduction of the number of days with bleeding events in female patients, and especially female patients affected with excess weight, which encompasses female patients affected with obesity. The general and

I substantial réduction in the number of days with bleeding events, as compared with female patients who are not affected with excess weight, is disclosed throughout the présent spécification, The said contraceptive formulation, which contains drospirenone as the sole contraceptive ingrédient, is described in detail and in its various embodiments throughout the présent spécification.

This invention also pertains to the use of drospirenone in the manufacture of a contraceptive kit which leads to a general substantial réduction of the number of days with bleeding events în female patients, wherein said contraceptive kit comprises one or more packaging units wherein each packaging unit comprises 21 to 28 daily active dosage units and wherein:

a) each daily active dosage unît comprises drospirenone in an amount of at least 3 mg, without estrogen, and

b) a single daily active dosage unit, when orally administered under fastîng conditions, is adapted to provide a pharmacokinetic profile for drospirenone having:

(î) a mean tmax ranges from 2.2h to 6h and (ii) a mean Cmax which is less than about 30 ng/ml, and (iii) optionally a mean AUCOh-tlast of at least about 300 ng*h/ml..

The Cmax and tmax values refer to the maximum DRSP plasma concentration and the time to reach it, respectively, after the oral administration of a single daily dosage unit of the DRSP-contaîning composition ofinterest. In other words, Cmax and t_max refer to the characteristics of drospirenone plasma concentration peak observed after the oral intake of a single daily dosage unit of the composition of interest.

The AUCoh-tiast corresponds to the area obtained by intégration of the drospirenone plasma concentration versus time over the interva] [Oh-tlast], the point “0h” referring to the oral intake of a single daily dosage unit of the composition of interest and the point “tlast” refers to the last time for which plasma concentration of DRSP can be quantifiable.

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

In an embodiment, one skilled in the art may adapt the analytical method described by Kirk et al (Rapid Communication in Mass Spectrometry, 2006; 20:12471252). Such a method comprises a step of derivatization of drospirenone with Girard P hydrazine solution in order to increase the response of DRSP during the subséquent MS analysis. This method is generally appropriate to quantify DRSP in human EDTA plasma over a concentration range from about 0.25 to about 100 ng/ml.

As used herein, the mean AUCoh-tiast, the mean Cmax and the mean tmax refer to arithmetic mean values determined from individual pharmacokinetic data obtained for a group of healthy female volunteers of child-age bearing subjected to a single oral administration of one daily dosage unit of a drospirenone-containing composition. The group of healthy female volunteers may comprise enough women to provide statistically confident pharmacokinetic results. Preferably, the said group comprises at least ten healthy women of child-bearing âge.

As used herein, a healthy woman of child-bearing âge refers to a premenopause Caucasien female between 18 and 40 years, with normal body weight and with no health problem, in particular, with no metabolism, rénal, liver or gynécologie disorders.

This invention also concems the use of drospirenone in the manufacture of a contraceptive kit which leads to a réduction of the number of days with bleeding events in female patients, wherein said contraceptive kit comprises one or more packaging units wherein each packaging 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 3 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 présent in the said daily active dosage unit is dissolved within 30 minutes and (ii) at least 50% of said drospirenone is dissolved in a time range from 3 hours to 4 hours, when the daily active dosage is subjected to an in vitro dissolution test according to USP XXIII Paddle Method, the percentages of drospirenone being related to the amount of drospirenone initially présent in the said daily active dosage unit.

LEGEND OF THE FIGURES

Figure 1: plot illustrating the corrélation between the body mass index (BMI) of women undertaking a DRSP-based contraceptive treatment with respect to the change in weight (kg). Change of weight is measured by subtracting the weight at visit 6 (day

24±2 of the 13^Λ cycle) from the weight at screening. Any négative resuit is indicative of a weight loss. Women with a BMI lower than 30 kg/m² (left) do not présent any average weight change, whereas women with a BMI of 30 kg/m² or greater (right) do présent a slight but significant change in weight during the course ofthe contraceptive treatment.

Figure 2: plot illustrating the corrélation between the body mass index (BMI) of women undertaking a DRSP-based contraceptive treatment with respect to the change in heart rate. Change in heart rate is measured by subtracting the heart rate at visit 6 (day 24±2 of the 13^Λ cycle) from the heart rate at screening. Any positive resuit is indicative of a higher heart rate during the course of the contraceptive treatment. Women with a BMI lower than 30 kg/m² (left) do présent a slight but significant increase in the heart rate during the course of the contraceptive treatment, whereas women with a BMI of 30 kg/m²or greater (right) do not présent any change în the heart rate during the course of the contraceptive treatment.

DETAILED DESCRIPTION OF THE INVENTION

The in vent ors hâve recently developed a new contraceptive kit and a new contraceptive pharmaceutical composition based on drospirenone (DRSP) in a CTystallized and non-micronized form (WO 2012/000981). DRSP is a fourth génération of progestogen, which dérivés from spironolactone and has a pharmacological profile that mimics natural progestérone.

DRSP is devoid of androgénie, glucocorticoid and anti-glucocorticoid activity but does possess potent anti-mineralocorticoid and anti-androgenic propertîes. It was shown that oral daily doses of at least 3 mg of DRSP are able to inhibit ovulation over a single treatment cycle of 21 days. The combination of 3 mg DRSP /30 pg ethinylestradiol provides a reasonable contraceptive safety margin by inhibiting ovulation with a low frequency of follicular maturation (Rosenbaum et al., 2000, The Européen Journal of Contraception and Reproductive Health Care, 5,16-24).

π

Contrarily to other DRSP-based contraceptive formulations available on the market, DRSP-based contraceptive formulation according to WO 2012/000981 relies upon a slow dissolution rate of DRSP in vitro.

Moreover, the DRSP-based contraceptive formulation according to WO 2012/000981 displays a peculiar pharmacokinetic profile. In particular, a single daily active dosage unit comprising DRSP in an amount of at least 3 mg, when orally administered under fasting conditions, is adapted to provide a pharmacokinetic profile for DRSP having:

- a mean t_max ranging from 2.2 h to 6h and

- a mean Cmax which is less than about 30 ng/ml.

The contraceptive pharmaceutical composition based on drospirenone (DRSP) in a crystallized and non-micronized form disclosed in WO 2012/000981 has been suggested being suitably administered to female patients having a BMI lower than 30 kg/m².

Within the scope of the following terminology is being used for a standardized description of bleeding and/or spotting in female patients under contraceptive treatment (Mishell et al., 2007, Contraception, 75(1):11).

The term “bleeding” or the expression “bleeding event” is intended to refer to a blood loss that requires the use of a tampon, pad or panty liner.

The term “spotting” or the expression “spotting event” is intended to refer to a minimal blood loss that does not require use of any type of protection.

The expression “épisode of bleeding and/or spotting” is intended to refer to bleeding and/or spotting days bounded on either end by two days of no bleeding or spotting.

In some embodiment, the term “bleeding” may also encompass “spotting”.

As it is shown in the examples herein, the number of days with bleeding events per treatment cycle in women with excess weight, i.e. in women having a BMI of 25 kg/m² or more, who are treated with the DRSP-based POC formulation described herein (i) is reduced by about 22.5% as compared with non-overweight women subjected to the same contraceptive treatment, i.e. women having a BMI of 24.9 kg/m² or less, during the treatment cycles 2 to 4, (ii) is reduced by about 27.7% as compared with nonoverweight women subjected to the same contraceptive treatment, i.e. women having a i s

BMI of 24.9 kg/m² or less, during the treatment cycles 2 to 6, (iii) is reduced by about 30.8% as compared with non-overweight women subjected to the same contraceptive treatment, i.e. women having a BMI of 24.9 kg/m² or less, during the treatment cycles 2 to 9, (iv) is reduced by about 23.1% as compared with non-overweight women subjected to 5 the same contraceptive treatment, i.e. women having a BMI of 24.9 kg/m² or less, during the treatment cycles 5 to 7 and (v) is reduced by about 22.5% as compared with nonoverweight women subjected to the same contraceptive treatment, i.e. women having a BMI of 24.9 kg/m² or less, during the treatment cycles 7 to 9. The différence observed is statistically significant (p<0.01 ) using the Wilcoxon-rank sum test.

As it is further shown in the examples herein, the average number of days of bleeding events în women with excess weight, i.e. in women having a BMI of 25 kg/m² or more, (i) does not exceed 13% per treatment cycle, during the treatment cycles 2 to 4; (ii) does not exceed 11% per treatment cycle during the treatment cycles 2 to 6; (iii) does not exceed 10% per treatment cycle, during the treatment cycles 2 to 9, during the treatment ! 5 cycles 5 to 7, or during the treatment cycles 7 to 9.

As used herein, “a treatment cycle” encompasses a 28 days period of treatment, wherein said treatment comprises the administration of 21 to 28 consecutive daily doses of the active test product tablets and may comprise at most the administration of 7 daily doses of placebo tablets.

In a preferred embodiment, the treatment cycle comprise the administration of consecutive daily doses of the active test product tablets and subsequently 4 consecutive days of administration of placebo tablets.

As used herein, “the number of days with bleeding events per treatment cycle” encompasses the number of days with one or more bleeding épisode during a cycle of 25 treatment, irrespective the time period of the cycle, i.e. active test product or placebo.

As shown in the examples herein, the number of days with bleeding events per treatment cycle in women with excess weight, i.e. in women having a BMI of 25 kg/m² or more, who are treated with the DRSP-based POC formulation described herein is always reduced by at least 5.0% as compared with women with no excess weight subjected to the 30 same contraceptive treatment, i.e. women having a BMI of 24.9 kg/m² or less, during any cycle of the treatment cycles studied.

*+^r *

As used herein, a réduction of the number of days with bleeding events per treatment cycle by “at least 5%” encompasses a réduction by at least 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% and 30%.

For example, the mean percentage of réduction of the number of days with bleeding events per treatment cycle in women with excess weight treated with the DRSPbased POC formulation as compared with women with no excess weight subjected to the same contraceptive treatment, may be evaluated for 3 consecutive cycles of treatment and may range from 15% to 30%, preferably from 20% to 25%, more preferably from 22% to 24%.

It is to be understood that the percentage of réduction of the number of days with bleeding events per treatment cycle in women with excess weight may be submitted to variations, depending on parameters such as e.g. initial weight, âge, time elapsed from the beginning of the treatment.

As it is further shown in the examples herein, the number of days with bleeding events per treatment cycle in obese women, i.e. in women having a BMI of 30 kg/m² or more, who are treated with the DRSP-based POC formulation described herein (i) is reduced by about 60.1% as compared with non-obese women subjected to the same contraceptive treatment, i.e. women having a BMI of 29.9 kg/m² or less, during the treatment cycles 2 to 4, (ii) is reduced by about 67.9% as compared with non-obese women subjected to the same contraceptive treatment, i.e. women having a BMI of 29.9 kg/m² or less, during the treatment cycles 2 to 6, (iii) is reduced by about 69.7% as compared with non-obese women subjected to the same contraceptive treatment, i.e. women having a BMI of 29.9 kg/m² or less, during the treatment cycles 2 to 9, (iv) is reduced by about 48.1% as compared with non-obese women subjected to the same contraceptive treatment, i.e. women having a BMI of 29.9 kg/m² or less, during the treatment cycles 5 to 7 and (v) is reduced by about 62.0% as compared with non-obese women subjected to the same contraceptive treatment, i.e. women having a BMI of 29.9 kg/m² or less, during the treatment cycles 7 to 9.

The différence observed is statistically significant (p<0.05) using the

Wilcoxon-rank sum test.

ι

As it is further shown in the examples herein, the average number of days of bleeding events in obese women, i.e. in women having a BMI of 30 kg/m² or more, (i) does not exceed about 7% during the treatment cycles 2 to 4, during the treatment cycles 5 to 7; (ii) does not exceed about 5% during the treatment cycles 2 to 6, during the treatment cycles 2 to 9, during the treatment cycles 7 to 9.

In addition, as it is further shown in the examples herein, as compared to other POC-based contraceptive composition, the drospirenone-based composition may benefit obese women, since a significant decrease în the number of bleeding or spotting events during the period cycles was observed.

Thus, as shown in the examples herein, the number of days with bleeding events per treatment cycle in obese women, i.e. in women having a BMI of 30 kg/m² or more, who are treated with the DRSP-based POC formulation described herein is always reduced by about 10.0% or more as compared with non-obese women subjected to the same contraceptive treatment, i.e. women having a BMI of 29.9 kg/m² or less, during any cycle of the treatment cycles studied.

As used herein, a réduction of the number of days with bleeding events per treatment cycle by “at least 10%” encompasses a réduction by at least 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 20 44%, 45%, 46%, 47%, 48%, 49% and 50%.

The mean percentage of réduction of the number of days with bleeding events per treatment cycle in obese women treated with the DRSP-based POC formulation as compared with non-obese women subjected to the same contraceptive treatment, may further be evaluated for 3 consecutive cycles of treatment and may range from 30% to 25 75%, preferably from 40% to 75%, more preferably from 45% to 65%.

The réduction in the number of days with bleeding or spotting that is shown by the inventors may benefit to women with excess weight, which includes overweight and obese women, and amelîorate considerably their living comfort, while providing a compilant contraceptive treatment, and thus an increased efficiency in the contraceptive 30 treatment.

In addition to the réduction of the number of days with bleeding or spotting, oral administration of a DRSP-based POC treatment according to WO 2012/000981 to »

women with excess weight, in particular overweight women, and especially to obese women, may also provide a benefit on the weight change together with a benefit on the restîng heart rate change, as shown in the examples herein.

These surprising observations could not hâve been expected from the previous clinical évaluation disclosed in WO 2012/000981.

Indeed, such DRSP-based contraceptive composition, when administered to women with excess weight, in particular overweight women, and especially to obese women, results in an average significant weight loss, and no change to the resting heart rate as compared to women from the general population, for which, no effect on weight change and a slight significant increase of the resting heart rate is observed during the course of this treatment.

Therefore, the DRSP-based contraceptive treatment according to the invention allows women with excess weight, including women affected with obesity, which encompasses women having a body mass index (BMI) of 30 kg/m² or greater, to better comply with the prescribed contraceptive treatment, thereby reducing the risks of dropping off the said contraceptive treatment and therefore increasing the risks of unintended pregnancy.

Thus, in some embodiments, the présent invention relates to drospirenone as the sole active ingrédient comprised in a daily active dosage unit in an amount of 3 mg or more, and especially in an amount ranging from 3 to 6 mg, for use as a contraceptive for reducing the number of days with bleeding events in overweight women by 5% or more, and preferably by 10% or more, as compared with non-overweight women subjected to the same contraceptive treatment.

Further, the experimental data disclosed herein show that the effect of réduction of the number of days with bleeding events per treatment cycle tends to increase with the duration of the contraceptive treatment with the DRSP-POC formulation, to reach a réduction of 15% or more. As disclosed in the examples herein, a réduction of more than 30% of the days with bleeding events per treatment cycle occurs in overweight women during the time period of the treatment cycles 2 to 9.

Stîll further, the présent invention relates to drospirenone as the sole active ingrédient comprised in a daily active dosage unit in an amount of 3 mg or more, and especially in an amount ranging from 3 to 6 mg, for use as a contraceptive for reducing the

4 number of days with bleeding events in obese women by 10% or more as compared with non-obese women subjected to the same contraceptive treatment. As disclosed in the examples herein, a réduction of more than 45% of the days with bleeding events occurs in obese women during the time period of the treatment cycles 2 to 9.

As it is further shown in the examples herein, the number of days of bleeding events in an overweight or obese patient does not exceed about 20%, 15%, 10%, S%, or 5% in any treatment cycle subséquent to an initial treatment cycle.

1- Daily active dosage of drosnirenone

In one aspect, the invention relates to DRSP as the sole contraceptive ingrédient comprised in a daily active dosage unit in an amount of at least 3 mg for use as a contraceptive for a female patient affected with excess weight, which encompasses a female patient affected with overweight and a female patient affected with obesity.

In one particular embodiment, the invention relates to DRSP as the sole contraceptive ingrédient comprised in a daily active dosage unit in an amount of at least 3 mg for use as a contraceptive for a female patient affected with obesity.

In certain embodiments, the invention relates to DRSP as the sole contraceptive ingrédient comprised in a daily active dosage unit in an amount of at least 3 mg for use as a contraceptive for a female patient a BMI of 30 kg/m² or greater.

As used herein, by “contraceptive ingrédient is meant an ingrédient that may prevent pregnancy when daily administered in an effective amount to a female patient over a period of 21 to 28 consecutive days. The contraceptive ingrédient may prevent pregnancy to occur by various biological effects. For example, the pregnancy may be prevented by the inhibition of ovulation, by the thickening of cervical mucus (which reduces the sperm viability and pénétration) and/ or by prevent embryo implantation.

As used herein, the expression “sole contraceptive ingrédient” is intended to mean that DRSP îs the unique ingrédient that promûtes contraception. In other words, the contraceptive ingrédient does not comprise an estrogen.

Drospirenone or DRSP, namely 6p, 7p,15p, 16p-dimethylen-3-oxo-17apregn4-ene-21,17-carbo-lactone, and further îdentified by the CAS registry Number 67392-87-4, is a synthetic progestogen with a pharmacological profile very closely related to that of natural progestérone.

a /

As used therein, the term “drospirenone” refers to drospirenone itself, a solvaté of drospirenone, and a derivate or prodrug of drospirenone.

DRSP may be prepared by well-known methods described in the prior art, for example, described in US 4129564, WO9806738, EPI 1746101 or W02006061309. The method described in W02006061309 may be particularly suitable for preparing DRSP.

It goes without saying that the method for preparing DRSP may be performed so as to meet the Good manufacturing practice (GMP) requirements.

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

A good bioavailability of DRSP may be achieved in the case of compositions comprising DRSP which had an in vitro dissolution rate of DRSP such that at least 50% of the DRSP initially présent in the said compositions was dissolved in a time range from 3 hours to 4 hours.

As used herein, “an active daily dosage unit” means a dosage unit which is able to prevent pregnancy when daily administered to a female patient. In preferred embodiments, the active daily dosage unît is able to inhibit ovulation.

As used herein, a “female patient” refers to a female individual of childbearing âge i.e. from the puberty to the ménopausé. Female individual of child-bearing âge also include women in peri-menopause.

Body mass index (BMI) is a simple index of weîght-for-height that is commonly used to classify overweight and obesity in adults. It is defined as a person's weight in kilograms divided by the square of his height in meters (kg/m²).

The WHO (World Health Organization) accepted weight standard status categories associated with BMI ranges for adults are as follows:

- a BMI below 18.5 kg/m² îs indicative of an underweight status;

- a BMI ranging from 18.5 kg/m² to 24.9 kg/m² is indicative of a normal weight status;

- a BMI ranging from 25.0 kg/m² to 29.9 kg/m² is indicative of an overweight status; and

- a BMI of 30.0 kg/m² or greater is indicative of an obesity status.

As used herein, a female patient affected with excess weight, encompasses a female patient having a BMI of 25.0 kg/m² or more, which includes an overweight female patient and an obese female patient.

As used herein, an overweight female patient includes a female patient having a BMI ranging from 25.0 kg/m² to 29.9 kg/m².

As used herein, an obese female patient, or a female patient affected with obesity, encompasses a female patient having a BMI of 30.0 kg/m² or more.

In certain embodiments, the female patient has a BMI of 25.0 kg/m² or greater.

In certain preferred embodiments, the female patient has a BMI of 30.0 kg/m²10 or greater.

In certain embodiments, the said daily active dosage unit is comprised within a contraceptive kit comprising one or more packaging units wherein each packaging unit comprises 21 to 28 daily active dosage units and wherein:

(a) the amount of DRSP in each daily active dosage unit is at least 3 mg without 15 estrogen, and

0ï) each daily active dosage unit comprises DRSP in a form such that:

(i) no more than 50% of the DRSP initially présent in the said daily active dosage unît is dissolved within 30 minutes and (ii) at least 50% of the said DRSP is dissolved in a time range from 3 hours to 4 20 hours, when the daily active dosage unit is subjected to an in vitro dissolution test according to the USP XXIII Paddle Method, the percentages of DRSP being related to the amount of DRSP initially présent in the said daily active dosage unit.

The daily active dosage unit comprising DRSP is characterized by a slow dissolution rate of DRSP in vitro.

As used herein, by “a slow dissolution rate of DRSP in vitro is meant that the release of DRSP is such that no more than 50% of DRSP initially présent in the said daily active dosage unit is dissolved within 30 minutes when the said daily active dosage unit is 30 subjected to a dissolution test.

« »

As intended herein, no more than 50% of the DRSP encompasses no more than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% ofthe DRSP initially présent in the daily active dosage unit.

In some embodiments, no more than 40% of the DRSP initially présent in the daily active dosage unit is dissolved within 30 min.

As used herein, the percentage of DRSP is related to the amount of DRSP initially présent in the said daily active dosage unit.

The in vitro dissolution rate of DRSP may be assessed by anyone of wellknown methods described in the prior art.

The in vitro dissolution rate of DRSP is preferably assessed by the USP ΧΧΠΙ Paddle Method. Briefly, a tablet consisting of the contraceptive composition comprising DRSP 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 rate of 50 rpm.

In a preferred embodiment, amount of DRSP in each daily active unit dosage is at least 3 mg of DRSP. At least 3 mg of DRSP encompasses at least 3.5 mg, at least 4 mg of DRSP, at least 4.5 mg of DRSP, at least 5 mg or at least 5.5 mg of DRSP.

In some embodiments, the active daily dosage unit which consists of the contraceptive composition as describes above may comprise a DRSP amount ranging from about 3 mg to about 6 mg. A daily dose ranging from about 3 mg to about 6 mg encompasses daily doses of 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg and 6 mg.

In certain embodiments, the amount of DRSP in each daily active unit dosage ranges from about 3.5 mg to 4.5 mg.

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

In certain embodiments, the one or more packaging units further comprise from 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.

Within the scope of the instant invention, the term “placebo” is intended to mean a pharmacologically inert or innocuous substance.

In certain embodiments, each packaging unit comprises 24 daily active dosage units.

t

In certain embodiments, each packaging unit comprises 4 daily placebo dosage units.

In certain embodiments, DRSP is in a crystalline form.

In certain embodiments, DRSP is in a non-micronized form.

As mentioned already, DRSP in a crystalline and non-micronized form allows for a slow dissolution rate of DRSP in vitro.

One way to obtain the DRSP-containing composition of the invention is to use DRSP in a particle form, such as a non-micronized particle form, having an appropriate spécifie surface area. It has been also shown that DRSP in a particle form having a 10 spécifie surface area from about 2000 cm²/g to about 8500 cm²/g may be suitable for obtaining the contraceptive compositions of the invention. The spécifie surface area may be experimentally determined using the BET method (gas adsorption method).

In certain embodiments, DRSP in a particle form has a spécifie surface area from about 2,000 cm²/g to about 8,500 cm²/g.

Such a spécifie area range which 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 cmVg and 8500 cm²/g.

Conceming the size particle distribution, DRSP particles having a diameter 20 greater than 200 pm shall be avoided in order to not drastically impair the in vitro dissolution rate and, thus, the in vivo bioavaîlability since such particles are poorly soluble.

In certain embodiments, DRSP has a dso of less than 70 pm.

ln certain preferred embodiments, the dso of the DRSP particles ranges from

10 pm to 60 pm. A dso ranges from about 10 pm to about 60 pm encompasses a dso of 10 pm, of 15 pm, of20 pm, of 25 pm, of30 pm, of35 pm, of40 pm, of45 pm, of50 pm, of 55 pm and of 60 pm.

In some embodiments, the particle size distribution of the DRSP présent in the composition according to the invention is characterized by:

(i) a doo particle size less than about 100 pm, and/or (ii) a dso particle size ranging from about 10 pm to about 60 pm and/or (iii) a dio particle size more than about 3 pm.

t

In some other embodiments, the djo of DRSP particles ranges from about 10 gm to about 30 gm. In such embodiments, the particle size distribution of the DRSP présent in the composition according to the invention is characterized by at least one of the following characteristics:

(i) a dço particle size less than about 100 gm, (ii) a dso particle size ranging from about 10 gm to about 30 gm and (iii) a dio particle size more than about 3 gm.

As used herein, by “dw particle size” is meant that the particle size distribution is such that at least 90% of the particles hâve a particle size diameter of less than the specified value. ·

As used herein, by “dso particle size” is meant that the particle size distribution is such that at least 50% of the particles hâve a particle size diameter of less than the specified value.

As used herein, by “dio particle size” is meant that the particle size distribution is such that at least 10% of the particles hâve a particle size diameter of less than the specified value.

d90 particle size less than about 100 gm include d<?o particle sizes less than about 90 gm, 80 gm, 70 gm, 60 gm, 55 gm, 50 gm, 45 gm, 40 gm, 38 gm, 36 gm, 34 gm, 32 gm, 30 gm, 28 gm, 26 gm, 24 gm, 22 gm, 20 gm.

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

The dio particle size values more than about 3 gm include dlO particle size values more than about 3 gm, 3.5 gm 4.5 gm, 5 gm, 6 gm, 7 gm, 8 gm, 9 gm, 10 gm, 11 gm, 12 gm.

It goes without saying that dio particle size value is smaller than djo particle size value which is smaller than dw particle value.

The DRSP particle size distribution, in particular doo, dio and dso values, may be determined by well-known methods of the prior art such as sieve analysis, laser diffraction methods, photo-analysis or optical counting methods. Laser diffraction methods are particularly preferred. The particle size distribution may be determined by laser diffraction in wet dispersion. The dispersant is preferably water.

In some embodiments, the pharmaceutical composition of the invention comprises DRSP in a particle form having a particle size distribution having a combination of two characteristics selected from:

(i) a dço particle size less than about 100 pm, (ii) a dso particle size ranging from about 10 pm to about 30 pm and (iii) a dio particle size more than about 3 pm.

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

In some other embodiments, the pharmaceutical composition of the invention comprising DRSP in a non-micronized form having a particle size distribution 15 characterized in that:

(i) doo particle size is less than about 100 pm, (ii) dso particle size ranging from about 10 pm to about 30 pm and (iii) dio particle size is more than about 3 pm

In a preferred embodiment, the DRSP particle distribution is further characterized in that doo particle size value is less than 50 pm and in that no particle has a size greater than 80 pm.

In some embodiments, the contraceptive composition of the invention comprises DRSP in a particle form having a doo particle size which ranges from about 20 25 pm to about 40 pm, a dso particle size which ranges from about 10 pm to about 30 pm and a dlO which ranges from about 3 pm to about 9 pm and wherein no particle has a size greater than 80 pm, more preferably no particle has a size greater than 60 pm.

In some other embodiments, the contraceptive composition of the invention comprises drospirenone in a particle form having (i) a doo particle size which ranges from about 30 pm to about 40 pm, (ii) a dso particle size which ranges from about 15 pm to about 25 pm and (iii) a dio which ranges from about 5 pm to about 9 pm and wherein no particle has a size greater than 80 pm, more preferably no particle has a size greater than 60 pm.

In some other embodiments, the contraceptive ingrédient of the invention is represented by DRSP in a particle form having a spécifie surface area from about 2000 cm²/g to about 8000 cm²/g and having a dso particle size ranges from 10 pm to 60 pm.

To obtain DRSP in a particle form having the spécifie surface area and/or the particle size distribution as described above, the one skilied in the art may use well-known 10 methods of the prior art such as milling process optionally combined with sieve process.

For example, DRSP, obtained by anyone of the synthesis methods described in the prior art, may be subjected to bail mill or hammer mill step optionally followed by a vibrating sieve steps. The subséquent vibrating sieve steps may remove finest and biggest particles of DRSP which would impair the pharmacokinetic profile and the in vitro 15 dissolution profile of DRSP.

The one skilied in the art may adjust the parameters of the milling and sieve steps by routine experiments to obtain the appropriate particle form of DRSP. Appropriate mills which may be used include fluid energy mill, bail mill or rod mill, hammer mill, cutting mill and oscillating granulator.

An appropriate particle form of DRSP may be also prepared by crystallisation or précipitation process optionally combined with a sieve step in order to fully control the size of DRSP particles. The précipitation process may comprise the steps of (i) dissolving DRSP in a water-miscible solvent and then (ii) dispersing the resulting solution in cold water under stirring so that to induce the précipitation of DRSP. The DRSP particles may 25 be then recovered by a filtration process.

The water-miscible solvents may be a solvent commonly used in crystallisation or précipitation process such as methanol, éthanol, isopropanol, dimethylformamide, tetrahydrofuran, dioxane or dimethyl sulfoxide, dimethylacetamide or acetone.

Such a process enables to obtain DRSP essentially in crystallized form.

«

By routine experiments, the one skilled in the art may détermine the parameters of the précipitation process to be used so as to obtain the appropriate form of DRSP.

The one skilled in the art may adjust the parameters of the said précipitation process (such as the amounts of solvent, of water and optionally that of surfactant to be used) by routine experiments.

2- Contraceptive method

The invention also relates to a method comprising administering a pharmaceutical composition comprising DRSP tn an amount of at least 3 mg to a female patient affected with excess weight, wherein said pharmaceutical composition allows for a 28 day daily dosing regimen, and wherein after initial administration of said DRSP has established its contraceptive effect in a patient, said patient may skip up to 4 doses within 28 day daily dosing regimen period.

In some embodiments, the invention also relates to a method comprising administering a pharmaceutical composition comprising DRSP in an amount of at least 3 mg to a female patient affected with obesity, wherein said pharmaceutical composition allows for a 28 day daily dosing regimen, and wherein after initial administration of said DRSP has established its contraceptive effect in a patient, said patient may skîp up to 4 doses within 28 day daily dosing regimen period.

In some other embodiments, the invention also relates to a method comprising administering a pharmaceutical composition comprising DRSP in an amount of at least 3 mg to a female patient having a BMI of 30 kg/m² or greater, wherein said pharmaceutical composition allows for a 28 day daily dosing regimen, and wherein after initial administration of said DRSP has established its contraceptive effect in a patient, said patient may skip up to 4 doses within 28 day daily dosing regimen period.

In some embodiments of the method above, the said female patient has a BMI of 25 kg/m² or greater.

In some embodiments of the method above, the said female patient is affected with obesity.

In certain embodiments, the female patient is having a BMI of 30 kg/m² or greater.

As used herein, “daily dosing regimen” means that the contraceptive method for a female patient affected with obesity comprises the step of administering active daily dosage units consisting of a pharmaceutical composition as fully-described herein to the said female patient over a period of several consecutive days over a period of 28 days, i.e.

a period corresponding to the average length of a menstrual cycle.

As used herein, “an active daily dosage unit” means a dosage unit which is able to prevent pregnancy when daily administered to a female patient over a period of 28 consecutive days.

After DRSP has established its contraceptive effect, the method may comprise a second phase that is a free-contraceptive period i.e. a phase during which no contraceptive ingrédients is administered to the female patient. During the said second phase, daily placebo dosage units may be administered to the female patient. In some other cases, no pill is administered to the female patient.

By “daily placebo dosage unit” it is understood that the ingrédient comprised in said dosage unit is pharmaceutically inert or innocuous. In other words, the daily placebo dosage unit does not contain any contraceptive ingrédient, as defined herein.

Such a second phase may enable regular menstrual bleedings to occur and thus may enable to mimic the naturel menstrual cycle.

Moreover, the said second phase is believed to enable the sécrétion of 20 endogenous estradiol which may hâve some benefits on bone metabolism of the female patient.

In certain embodiments, said pharmaceutical composition further allows during said 28 days daily dosing regimen for said patient to skip up to two nonconsecutive days of said DRSP, provided said DRSP skipped dose is taken within about 25 24 hrs after said up to two skipped non-consecutive days.

In certain embodiments, said skipped up to 4 doses are on non-consecutive days.

In certain embodiments, said skipped up to 4 doses are on consecutive days.

In a general aspect, non-micronized and crystallized form DRSP is preferably used for preparing the pharmaceutical composition of the invention.

The daily dosing regimen of DRSP to be administered to a female patient affected with obesity may also be adjusted depending on individual factors such as the âge, the body weight, the general health and the diet of the female patient. The said daily dosing regimen may also vary upon the drug interaction which may occur. The said daily dosing regimen may also vary upon the additional biologîcal effect(s), other than the prévention of pregnancy, which may be sought through the administration of DRSP.

The daily dosing regimen of DRSP to be daily administered to a female patient may be lower or higher than the doses previously mentioned. For example, a female patient in peri-menopause may require a higher or lower daily dosage of DRSP, in order to improve her general conditions and, for example, in order to improve the regularity of her menstrual cycles.

The adjustment of the daily dosing regimen may be routinely determined by practitioners.

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

The pharmaceutical composition of (he invention may be formulated according to standard methods such as those described in Remîngton: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins; Twenty first Edition, 2005)

Pharmaceutically acceptable excipients that may be used to formulate the contraceptive composition of the invention are, in particular, described in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association (Pharmaceutical Press; 6^,h Revised édition, 2009).

Examples of appropriate excipients include, but are not limited to, fïllers, carriers, diluents, binders, anti-caking agents, plasticizers, disintegrants, lubricants, flavors, bufïering agents, stabîlizers, colorants, dyes, anti-oxîdants, anti-adherents, softeners, preservatives and glidants.

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

Examples of fïllers include, without being limited to, lactose anhydrous, microcrystalline cellulose, starch, pregelatinized starch, modified starch, dibasic calcium phosphate dihydrate, calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, lactose, dextrose, sucrose, mannitol and sorbitol and combinations thereof.

Examples of lubricants include, without being limited to, magnésium stéarate, calcium stéarate, zinc stéarate, talc, propylene glycol, PEG, stearic acid, vegetable oil, sodium benzoate, sodium lauryl sulfate, magnésium lauryl sulfate, minerai oil polyoxyethylene monostearate and combinations thereof.

Examples of binders include, without being limited to, starches, e.g., potato starch, wheat starch, com starch; gums, such as gum tragacanth, acacia gum and gelatin; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose; polyvinyl pyrrolidone and combinations thereof.

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

In a preferred embodiment, the pharmaceutical composition according to the invention does not comprise a sîgnificant amount of surfactant agent. A sîgnificant amount of a surfactant agent may impair the irt vitro dissolution profile of DRSP by increasing its initial rate of dissolution. Surfactant agents include non-ionic surfactants such as polyoxyethylene sorbitan fatty acid esters and ionic surfactants such as sodium lauryl sulphate.

It goes without sayîng that the DRSP to bc used may be in a particle form having the spécifie surface area and/or the dw, dio and dso particle sizes which are fullydescribed in the présent spécification.

The said contraceptive composition may optionally comprise additional excipients which may accounts for about 0.1 % to 10% by weight.

The contraceptive composition according to the invention may be formulated in a galenic form suitable for oral administration. Such forms include, without being 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 appropriate to be used as daily active dosage unit in the contraceptive kit according to the présent invention.

When the pharmaceutical composition is formulated in solid forms such as tablets or pills, the said solid forms may be conveniently coated with a suitable filmforming agent such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose or ethyl cellulose, to which a suitable excipient may optionally be added, e. g. a softener such as glycerol, propylene glycol, diethylphthalate 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 may be prepared by conventional methods such as direct compression, dry granulation and wet granulation.

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

A further object of the invention is to provide a method for preparing the contraceptive composition as described herein which comprises the steps consisting of:

(i) providing DRSP in a particle form as fully-described previously in the présent spécification (ii) providing one or more pharmaceutically acceptable excipients; and (iii) mixing the DRSP provided in step (i) with the one or more excipients provided in step (ii).

As fully-described above, the Applicant provides technical guidelines to obtain a composition comprising DRSP in a form such that:

(i) no more than 50% of the DRSP inîtially présent in the said composition is dissolved within 30 minutes and (ii) at least 50% of the said DRSP is dissolved in a time range from 3 hours to hours, when the composition is subjected to an in vitro dissolution test, the percentages of DRSP being related to the amount of DRSP inîtially présent in the said composition.

A DRSP containing composition with such an In vitro dissolution profile or the in vivo pharmacokinetic profile fully-described above may be achieved by various other ways.

By routine experiments and in view of his general knowledge, the one skilled in the art may modify (i) the particle size distribution of DRSP and (ii) the amounts and the nature of excipients in order to obtain other alternative compositions displaying the in vitro dissolution profile and the in vivo pharmacokinetic profile described in the présent application.

For example, the one skilled in the art may conceive a composition comprising (i) micronized DRSP together with (ii) a slow release agent in order to diminish the dissolution rate of said DRSP.

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

In certain embodiments, said pharmaceutical composition comprises a contraceptive kit comprising one or more packaging units wherein each packaging unit comprises 21 to 28 daily active dosage units and wherein:

(i) no more than 50% of the drospirenone initially présent in the said daily active dosage unit is dissolved within 30 minutes and (ii) at least 50% of the said drospirenone is dissolved in a time range from 3 hours to 4 hours, when the daily active dosage unit is subjected to an in vitro dissolution test according to the USP XXIII Paddle Method, the percentages of drospirenone being related to the amount of drospirenone initially présent in the said daily active dosage unit.

The said contraceptive kit comprises one or more packaging units.

One or more packaging units includes, without being limited to, 1 packaging unit, 2 packaging units, 3 packaging units, 4 packaging units, 5 packaging units and 6 packaging units.

Each packaging unit comprises from 21 to 28 daily active dosage units. As fully described above, each daily active dosage unit consists of a contraceptive composition of the invention.

As fully described above, the daily active dosage units preferably do not comprise any estrogen or estrogen dérivative such as ethinyl estradiol, mestranol or 8prenylnaringenin. In other words, the DRSP is preferably présent în the daily active dosage units without estrogen.

In more preferred embodiments, DRSP is the sole contraceptive ingrédient comprised within the daily active dosage units.

Each packaging 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 unit of a pharmaceutically acceptable placebo. Such a contraceptive kit is particularly appropriate to perform the contraceptive method of the invention which consists in administering “continuously” DRSP without free-contraceptive period.

In other embodiments each packaging unit comprises:

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

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

Such a contraceptive kit is particularly appropriate to perform the contraceptive method of the invention which comprises:

- a first phase wherein active daily dosage units of the invention which do not comprise estrogen are administered to the female patient affected with obesity over a period of 21 to 27 consecutive days followed by;

- a second phase wherein no contraceptive composition is administered to the female patient over a period of 1 to 7 consecutive days.

In some other embodiments, each packaging unit of the kit 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 packaging unît as described above may hâve one of the conventional forms usually used for oral contraceptives.

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

The packaging unît may contain daily dosage units in the order in which they are to be taken, i.e. starting with the first of the at least 21 dosage units that contain the composition of DRSP optionally followed by 7 or less empty blisters or by 7 or less dosage units that comprise a pharmaceutically acceptable placebo.

The kit of the invention 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

Examnle 1 — LFI II (DRSP) treatment decreases the number of days with bleeding and/or spottine

1/Objectives

The study CFI 11/302 below represents a pivotai, multicentre, double-blind, double-dummy, randomised trial on the contraceptive efficacy, tolerability and safety of LFI 11 (DRSP) over 9 cycles of 28 days of treatment (24 active test product tablets followed by 4 days of placebo tablets).

The first objective is to demonstrate the contraceptive efficacy of LFI 11 and the second objective is to demonstrate the safety and tolerability of LFI 11, especially regarding bleeding pattern.

2/ Ma tenais and methods

a) Test product, doses and mode of administration

LFI 11 film-coated tablets (test product; 24 tablets containing 4 mg DRSP followed by 4 placebo tablets; Leôn Farina) was orally administered during this trial. LFI 11 tablets are of the following formula:

	ingrédient	mg/tablet
Active ingrédient	Drospirenone*	4.00
Excipient	Microcrystalline cellulose	33.02
	Lactose, anhydrous	17.50
	Silica, colloïdal anhydrous	0.29
	Magnésium stéarate	0.29
	White coating system	1.65
Total		56.75

’ crystallized and non-micronized drospirenone, prepared according to the process similar to that described in WO 2006/061309;

b) Trial design

This prospective, multicentre, randomised, double-blind, double-dummy trial was conducted on 857 women without uncontrolled current diseases, at risk of pregnancy, at the âge of 18-45 years, systolic blood pressure < 140 mmHg, diastolic blood pressure < 90 mmHg followed in approximately 73 centres in Austria, Czech Republic, Germany, Hungary, Poland, Romania, Slovakia and Spain.

After providing informed consent at visit la (screening; V la) and receiving study médication at visit lb, subjects will attend visits 2 to 4 at day 24±2 of the Γ*, 3^rt, and 6^λ cycle, and visit 5 (V5) at day 29+2 of the 9^,h cycle. The follow-up (visit 6; V6) will take place 7-10 days after last LFI 11 intake.

The planned total duration of the trial was set to be 16 months, with a maximum of 6 months for the enrolment process, a maximum of 9 months for the contraceptive treatment per se and 10 days for the follow-up step. The duration of contraceptive treatment for the individual women is 9 x 28 days.

c) Exclusion criteria

Prégnant subject; Breast-feeding subject; Subject is known to or suspected of not being able to comply with the study protocol and the use of the lMPs (lnvestigational Médicinal Products); Abnormal finding on pelvic, breast or intravaginal ultrasound examination that precludes participation in the trial; Unexplained amenorrhoea, known polycystic ovary syndrome; Subject having ASC-US or more severe finding on Pap smear; Known contraindication or hypersensitivîty to the active ingrédient (drospirenone) or excipients of IMPs (cellulose, lactose, silicon dioxide, magnésium stéarate, com starch, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, aquarius BT16035 cottage green, talc, titanium dioxide; silica colloïdal anhydrous, all-rac-a-tocopherol, lactose, monohydrate, maize starch, povidone, stearic acid, hypromellose, macrogol 400); Significant cardiovascular, hepatic or rénal disease, diabètes with vascular involvement, uncontrolled thyroid disorder or current venous thrombosis or embolism; Undiagnosed vaginal bleeding; Known or suspected sex-steroid sensitive malignancîes; Presence or history of severe hepatic disease as long as liver function values hâve not retumed to normal; Evidence or history of alcohol, médication or drug abuse (within the last 12 months); Known bleeding disorder or history of unexplained bleeding or bruising within the last 12 months prior to Via; Prohibited previous médication / contraceptives 5 (injectable hormonal methods of contraception within the last 6 months before Via, progcstin-releasing IUD (intra uterine device) or contraceptive implant within the last 2 months before Via, anti-retroviral therapy within the last 6 months before Via, microsomal enzyme-inducing drugs within the last 28 days before the start of IMP intake); Dependence on prohibited co-medication (estrogens, progestogens, activated charcoal, 10 microsomal enzyme-inducing drugs, anticonvulsants [e.g. hydantoins, phenytoin, carbamazepinc, oxcarbazepinc, topiramate, felbamate, primidone], barbiturates, antibiotics [such as rifabutin or rifampicin], ritonavir, nelfinavir, atorvastatin, bosentan, griseoulvin, phenylbutazon, St. John’s wort [hypericum perforatum], médications that may increase sérum potassium [ACE inhibitors, angiotensin - H receptor antagonists, potassium-sparing 15 diuretics, potassium supplémentation, heparin, aldostérone antagonists and NSAIDs]);

Planned surgery during the anticipated time of participation in this trial requiring withdrawal of an oral contraceptive; Regular concomitant use of barrier contraceptive methods, spermicides, IUDs or other contraceptive measures (excepting occasional use due to risk of infection); Evidence or history of neurotic personality, psychiatrie illness or 20 suicide; Participation in another trial of investigational drugs or devices parallel to, or less than 90 days before trial entry, or previous participation in this trial; Employée of the investigator or trial centre, or family member of the employées or the învestigator, Any condition that, in the opinion of the investigator, may jeopardise the trial conduct according to the protocol.

d) Criteria for évaluation

d.B Efficacy

-primary: Overall Pearl Index (overall PI);

-secondary: PI for method failures; PI after correction for back-up contraception; 30 Pregnancy ratio.

d.2) Safety/Tolerability

Proportion of subjects with unscheduled bleeding/spotting in cycles 2 to 6; Proportion of subjects with unscheduled bleeding/spotting in each cycle from cycles 2 to 9 and cumulative in cycles 2 to 6 and cycles 2 to 9; Number of days of bleeding/spotting 5 during cycles 2 to 4; Number of days of bleeding/spotting during cycles 7 to 9; Number of days of bleeding/spotting during cycles 2 to 9; Number of bleeding/spotting épisodes during cycles 2 to 4; Number of bleeding/spotting épisodes during cycles 7 to 9; Number of bleeding/spotting épisodes during cycles 2 to 9; Proportion of subjects with amenorrhoea; Change in body weight from baseline (Via); Change in systolic and 10 diastolic blood pressure from baseline (Via); Adverse events (AEs); Puise rate;

Electrocardiogram (ECG) for a subset of subjects; Clinical laboratory parameters; Spécial clinical laboratory parameters (haemostatic variables, carbohydrate metabolism and bone metabolism) for a subset of subjects.

d.3) Statistical methods

d.3.1) Efficacy parameters:

Analysis of the primary efficacy variable defined as overall PI will be performed for the Fui! Analysis Set (FAS) and the Per Protocol Set (PPS). Primary assessment of efficacy will be based on the FAS. Two-sided 95% confidence interva! (CI) 20 for overall PI will be calculated assuming that events of pregnancy hâve a Poisson distribution. Secondary efficacy analysis will be based on the FAS. Two-sided 95% Cls will be calculated for the method failures PI. The Clopper-Pearson 95% confidence interva! will be calculated for the pregnancy ratio. The cumulative pregnancy rate will be calculated using the Kaplan Meier estimator. Two sided 95% CI will be calculated for the 25 PI after correction for back-up contraception.

d.3.2) Safety and tolerability parameters

Analysis of the parameters blood pressure, body weight, and bleeding pattem will be based on FAS.. Analysis of safety endpoints will be conducted using the Safety Set only. Ail adverse events (AEs) and treatment-emergent adverse events (TEAEs) will be summarised by calculating the number and percent of subjects with AEs by preferred term and system organ class. Also TEAEs will be summarised by severity and relationship to t

treatment. Number and percent of TEAEs leading to study termination will be provided.

Laboratory parameters, puise rate and abnormal ECG results (e.g. QT prolongation) will be summarised by calculating summary statistics on the absolute values and on the change from Via (spécial laboratory parameters and ECG: Vlb) to V3, V4 and V5. Shift tables will be provided to illustrate changes with respect to the laboratory normal ranges between

Via and V5 (or EDV). The number and percent of subjects with values outside the limits of clinical significance will be summarised.

2/ Results

As shown in Table 1 below, there is a significant réduction in the number of days with bleeding and/or spotting for the DRSP treatment in women with excess weight (BMI of 25 kg/m² or greater) as compared with non-overweight women subjected to the same contraceptive treatment.

Table 1; Number of days with spotting and/or bleeding by period of 15 treatment cycles for a cohort of women with excess weight* as compared with a cohort of women with no excess weight for the DRSP treatment.

Cycle		BMI<25 kg/m²(N=660)	% per treatment cycle	BMI>25 kg/m² (N=198)	% per treatment cycle	Total (N=858)	Wilcoxonrank-sumtest p value
Cycles 2 -4	n	401		126		527
	Mean (SD)	13.8 (12.84)	16.4%	10.7 (13.46)	12.7%	13.1 (13.05)	0.0007
	Médian	11.0		6.0		10.0
	Min/ Max	0/60		0/66		0/66

Cycles 2 -6	n	315		107		422
	Mean (SD)	20.6 (18.62)	14.7%	14.9 (18.64)	10.6%	19.1 (18.77)	0.0005

t

Cycle		BMI<25 kg/m²(N=660)	% per treatment cycle	BMI>25 kg/m²(N=198)	%per treatment cycle	Total (N=858)	Wilcoxonrank-sumtest p value
	Médian	17.0		7.0		14.0
Min/ Max	0/100		0/89		0/100

Cycles 2 -9	n	221		84		305
	Mean (SD)	32.1 (27.85)	14.3%	22.2 (26.65)	9.9%	29.4 (27.84)	0.0010
Médian	26.0		13.5		21.0
Min/ Max	0/109		0/106		0/109

Cycles 5 -7	n	315		108		423
	Mean (SD)	10.8 (11.13)	12.8%	8.3(10.98)	9.9%	10.2 (11.13)	0.0053
Médian	7.0		4.0		6.0
Min/ Max	0/67		0/49		0/67

Cycles 7 -9	n	280		94		374
	Mean (SD)	10.2 (10.10)	12.1%	7.9(11.09)	9.4%	9.7(10.39)	0.0040
Médian	8.0		3.5		6.0
Min/ Max	0/60		0/55		0/60

N: Number of subjects in the Test group in the particular BMI group n: Number of subjects with data available

SD: Standard déviation

As shown in Table 2 below, there is a significant réduction in the number of days with bleeding and/or spotting for the DRSP treatment in obese women as compared with non-obese women subjected to the same contraceptive treatment.

Table 2: Number of days with spotting and/or bleeding by period of treatment cycles for a cohort of obese women, as compared with a cohort of non10 obese women for the DRSP treatment.

Cycle		BMl<30 kg/m²(N-828)	% per treatment cycle	BMI230 kg/m²(N=30)	% per treatment cycle	Total (N=858)	Wilcoxonrank-sumtest p value
Cycles 2 -4	n	511		16		527
	Mean (SD)	13.3 (13.13)	15.8%	5.3 (6.66)	6.3%	13.1 (13.05)	0.0097
Médian	10.0		2.0		10.0
Min/ Max	0/66		0/22		0/66

Cycles 2 -6	n	408		14		422
	Mean (SD)	19.6 (18.88)	14.0%	6.3 (7.89)	4.5%	19.1 (18.77)	0.0053
Médian	16.0		2.0		14.0
Min/ Max	0/100		0/24		0/100

Cycles 2 -9	n	291		14		305

Cycle		BMI<30 kg/m²(N=828)	% per treatment cycle	BMI>30 kg/m²(N=30)	% per treatment cycle	Total (N=858)	Wilcoxonrank-sumtest p value
	Mean (SD)	30.4 (28.02)	13.6%	9.2(12.10)	4.1%	29.4 (27.84)	0.0027
Médian	22.0		2.0		21.0
Min/ Max	0/109		0/36		0/109

Cycles 5 -7	n	405		18		423
	Mean (SD)	10.4 (11.18)	12.4%	5.4 (8.76)	6.4%	10.2 (11.13)	0.0217
Médian	7.0		1.5		6.0
Min/ Max	0/67		0/29		0/67

Cycles 7 -9	n	356		18		374
	Mean (SD)	10.0 (10.47)	11.9%	3.8 (6.62)	4.5%	9.7(10.39)	0.0037
Médian	7.0		0.0		6.0
Min/ Max	0/60		0/20		0/60

SD: Standard déviation ·* .

Example 2 - Corrélation between BMI and DRSP-based treatment on one hand and change in weight andchange in heart rate on the other hand

M Methods

In example 2, the LFI 11 formulation described in Example 1 was used.

The CFI 11/301 clinical trial protocol included 713 healthy sexually active women willing to use oral contraceptives enrolled in approximately 41 centres located in 5 countries (Hungary, Poland, the Czech Republic, Germany and Romania).

After sîgning an Informed Consent Form at visit la (screening) and receiving study médication at visit lb, eligible subjects attended vïsits 2 to 6 at day 24±2 ofthe l^sl, 3^rd, 6^λ, 9^λ and I3^ft cycle. The follow-up (visit 7) took place 10 to 28 days after visit 6. At least 515 subjects completed the study with 13 cycles each.

Data set had information on démographie and clinical parameters, gynaecological and medical history data, laboratory and vital signs assessments, prior/concomitant medications/contraceptive devices related data.

Statistical p values were calculated by using a Fisher exact test, and p value was found significant test at the threshold p<0.05.

2/ Results

For women affected with obesity (BMI >30 kg/m²) a trend in decreasing their weight and heart rate from visit 1 (measured at baseline) to visit 6 (measured at the end of the study) was observed.

Distribution of the change in weight and heart rate from visit 1 to 6 for women by BMI group (BMI < 30 and BMI > 30 kg/m²) is shown in Figures 1 and 2 respectively.

The linear model analysis showed that the effect of BMI group was statistically significant in the change of weight (F-statistic: 14.49 on I and 668 DF, pvalue: 0.0001541) and heart rate (F-statistic: 4.947 on 1 and 666 DF, p-value: 0.02647) from visit 1 to 6.

t *· .

Example 3 — Reduced adverse effects ofthe DRSP-based treatment in obese women

1/ Methods

The CF111/1SS clinical trial protocol included 1571 (1500 + 71 ) healthy sexually active women willing to use oral contraceptives enrolled în approximately 114 centres located in in Austria, Czech Republie, Germany, Hungary, Poland, Romania, Slovakia and Spain. A group of non-obese women (BMI< 30 kg/m²) and of obese women (BMI> 30 kg/m²) were studied separately.

2/ Results

Table 3 depicts the results of quantification of TEAEs (Treatment Emergent Adverse Events) in a cohort of women subject to contraception with a drospirenonecontaining composition according to the invention (“LFI II”). Non-obese women (BM1< 30 kg/ m²) and obese women (BMI> 30 kg/m²) were studied, respectively.

The results disclosed in Table 3 show that the percentage of TEAEs was similar în women subjected to the DRSP-POC formulation, irrespective of whether these women are obese women or non-obese women.

Thus, the results show that the drospirenone-containing formulation according to the invention shall be endowed with a high observance rate by obese women.

Table 3î Incidence of TEAEs by BMI subgroup of Individuals treated with LFI 11

	BMl<30kg/m² (N=1500)	BMI>30kg/m² (N=71)
	n (%)	n (%)
Subjects with at least one TEAEs [a]	650(43.3)	30 (42.3)

N: Number of subjects in specified treatment group.

n: Number of subjects with adverse events.

%: Percentage based on N.

[a] TEAE: Treatment Emergent Adverse Event. TEAEs are defined as AEs which started at or after the first administration of an IMP and includes those events started prior to the first administration of an IMP but which worsened after the first intake. Adverse events starting » ^,ι » after the last administration of an IMP but within the follow up period after last 1MP will be regarded as treatment-emergent.

Heart rate is understood as the number of times a person’s heart beats per minute at rest (e.g., not exercising). Preferably, heart rate may be measured after a patient has been lying down for at least 5 minutes, preferably for at least 10 minutes, and most preferably for at least 15 minutes. Altematively, heart rate may be measured upon waking in the moming and before rising from bed. Heart rate is an important indicator of health.

While a normal heart rate for adults may range from about 60 to about 100 beats per minute, a lower heart rate is indicative of a more efficient heart function and of cardiovascular fitness. While overweight and obese women are generally observed to hâve a higher heart rate than women of normal weight, it has also been found that a faster heart rate is a waming sign for increased cardiovascular problems and also as a predictor for obesity later in life. Women with higher heart rates hâve been found to be predisposed to obesity and diabètes mellitus, Shigetoh, et al., Am. J. Hypertension, vol. 22, number 2, pp. 151-155, Feb. 2009. Higher heart rates are believed to be associated with metabolic syndrome, diabètes, formation of blood clots that can cause a stroke or heart attack, heart failure, fainting spells, and even sudden death.

Thus, the réduction in heart rate is extremely désirable, especially for overweight or obese women, as lowering heart rate may resuit in reducing the risk of developing various deleterious health conditions. It is believed that réductions in heart rate of at least 5 beats per minute, of at least 10 beats per minute and at least 15 beats per minute will provide signîficant réductions of such risk factors.

Example 4 — Comparison of the bleeding or spotting events observed in obese women, with a DRSP-based treatment according to the invention and a treatment based on desogestrel

1/ Objectives

The study CFI 11/302 below represents a pivotai, multicentre, double-blind, double-dummy, randomised trial on the contraceptive efficacy, tolerability and safety of LFI 11 (DRSP) over 9 cycles in comparison with desogestrel 0.075 mg (Cerazette).

The first objective is to demonstrate the contraceptive efficacy of LFI 11 and the second objective is to demonstrate the safety and tolerability of LFI 11 in comparison to desogestrel 0.075 mg, especially regarding bleeding pattern.

2/ Materials and methods

a) Test and reference products. doses and mode of administration

Two kinds of tablets were orally administered during this trial:

- LFI 11 film-coated tablets (test product; 24 tablets containing 4 mg DRSP followed by 4 placebo tablets; Leôn Farma) was orally administered during this trial.

The formula of LFI 11 tablets is disclosed in example 1 (see section 2, subsection a)).

- Desogestrel 0.075 mg film-coated tablets (reference product; 28 active tablets; NV Organon).

b) Trial design

This prospective, multicentre, randomîsed, double-blind, double-dummy trial was conducted on 1200 women without uncontrolled current diseases, at risk of pregnancy, at the âge of 18-45 years, systolic blood pressure < 140 mmHg, diastolic blood pressure < 90 mmHg (857 for LFI 11 and 343 for desogestrel 0.075 mg; Randomisation ratio 5:2) followed in approximately 88 centres in Austria, Czech Republic, Germany, 20 Hungary, Poland, Romania, Slovakia and Spain.

After providing informed consent at visit la (screening; V la) and receiving study médicationat visit lb, subjects will attend visits 2 to 4at day 24±2 ofthe l^st,3^rd, and 6^th cycle, and visit 5 (V5) at day 29+2 of the 9⁴¹¹ cycle. The follow-up (visit 6; V6) will take place 7-10 days after last LF! 11 intake.

c) Exclusion criteria

See the corresponding section of example 1 above.

d) Criteria for évaluation

See the corresponding section of example 1 above.

3/ Results

The Tables 4 and 5 show the comparison of the bleeding or spotting events observed in obese women, with a DRSP-based treatment according to the invention (LFI 11) and a treatment based on desogestrel (commercially available as Cerazette® pills).

Table 4: Bleeding or spotting events observed in obese female ïndividuals 10 (BMI > 30 kg/m³), with respect to the treatment undertaken

Bleeding or spotting Mean # days	BMI >30 kg/m²
DRSP-based treatment	desogestrel
Period cycles 2-4	5.3	21.8
Period cycles 2-6	6.3	16.3
Period cycles 2-9	9.2	33.9

Table S: Bleeding or spotting events observed in normal or ovcr-weight female ïndividuals (BMI < 30 kg/m²), with respect to the treatment undertaken

Bleeding or spotting Mean # days	BMI <30 kg/m¹
DRSP-based treatment	desogestrel
Period cycles 2-4	13.3	16.6
Period cycles 2-6	19.6	24.1
Period cycles 2-9	30.4	34.7

It is observed that obese female Ïndividuals that are administered with the drospirenone-based contraceptive treatment, as disclosed herein, suffer significantly less bleeding or spot events during the all the periods cycles that were analysed, as compared to obese female ïndividuals undertaking a treatment based on a desogestrel-containing contraceptive composition.

Contrarily, female ïndividuals having a BMI lower than 30 kg/m², including ïndividuals with a normal weight or ïndividuals with excess weight, suffer from identical • *’« · or équivalent of bleeding or spotting events, irrespective of the contraceptive treatment that is undertaken.

Claims

L Drospirenone as the sole contraceptive ingrédient comprised in a daily active dosage unit in an amount of at least 3 mg for use as a contraceptive for a female patient affected with obesity.
2. Drospirenone for its use according to claim 1, for a female patient having a BMI of 30 kg/m² or greater.
3. Drospirenone for its use according to any one ofclaims 1 or 2, wherein the said daily active dosage unit is comprised within a contraceptive kit comprising one or more packaging units wherein each packaging 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 3 mg without estrogen, and

b. each daily active dosage unît comprises drospirenone in a form such that:

i. no more than 50% of the drospirenone initially présent in the said daily active dosage unit is dissolved within 30 minutes and ii. at least 50% of the said drospirenone is dissolved in a time range from 3 hours to 4 hours, when the daily active dosage unit is subjected to an in vitro dissolution test according to the USP XX11I Paddle Method, the percentages of drospirenone being related to the amount of drospirenone initially présent in the said daily active dosage unit.
4. Drospirenone for its use according to claim 3, wherein the amount of drospirenone in each daily active unit dosage ranges from about 3.5 mg to 4.5 mg.

5. Drospirenone for its use according to any one of claims 3 and 4, wherein the one or more packaging units further comprise from 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.

6. Drospirenone for its use according to claim 3 wherein each packaging unit comprises 24 daily active dosage units.

7. Drospirenone for its use according to claim 3 wherein each packaging unit comprises 4 daily placebo dosage units.

8. Drospirenone for its use according to any one of claims 1 to 7, wherein the said active ingrédient is in a crystalline form.

·’ * *<·

9. Drospirenone for its use according to any one of claims 1 to 8, wherein the said active ingrédient is in a non-micronîzed form.

10. Drospirenone for its use according to any one of claims 1 to 9, wherein the said active ingrédient has a dso of less than 70 gm.
5 11. Drospirenone for its use according to any one of claims claim 1 to 10, wherein the said active ingrédient in a particle form has a spécifie surface area from about 2,000 cm²/g to about 8,500 cm²/g.