Drospirenone-based contraceptives for overweight female patients

Abstract

Use of drospirenone in an amount of at least 3 mg contained in a daily active dosage unit as the sole contraceptive ingredient as a contraceptive for obese female patients.

Description

[0001] The present application is a divisional application of an invention patent application filed on June 23, 2016, with application number 201680045547.0 and invention name “Drospirenone-based contraceptive for overweight female patients”. Technical Field

[0002] The present invention relates to the field of contraceptive compositions and methods, particularly for overweight female patients including overweight or obese female patients. Background Art

[0003] In the general population, excess weight (ie, overweight and obesity) in adults has increased dramatically over time.

[0004] The World Health Organization (WHO) has established a standard weight status classification based on body mass index (BMI), with the following ranges for adults:

[0005] – Characterized by a BMI less than 18.5 kg / m 2 underweight status;

[0006] – Characterized by a BMI of 18.5 kg / m 2 -24.9kg / m 2 normal weight status;

[0007] – Characterized by a BMI of 25.0 kg / m 2 -29.9kg / m 2 overweight status; and

[0008] – Characterized by a BMI of 30.0 kg / m 2 or higher obesity status.

[0009] Based on the latest OECD health statistics report, the majority of adults (53%) in the European Union are overweight or obese, with obese adults accounting for approximately 17% of the adult population (OECD / European Union (2014), "Overweight and obesity among adults", in Health at a Glance: Europe 2014, OECD Publishing). In the United States, 64% of women are overweight or obese, of whom 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 high blood pressure, high cholesterol, diabetes, cardiovascular disease, and some forms of cancer.

[0010] The incidence of unintended pregnancy is comparable to that of being overweight or obese. Approximately 40% of all pregnancies worldwide are unintended, including 43% in Europe and 51% in North America (Sedgh G. et al. Studies in Family Planning 2014; 45(3): 301-314). Obese women, especially those with comorbidities, are at higher risk for pregnancy-related complications. Therefore, avoiding unintended pregnancy is particularly important in these women (Cedergren MI. Obstet. Gynecol. 2004; 103: 219-24).

[0011] The best way to prevent unintended pregnancy is to provide appropriate contraception with safe and well-tolerated options.

[0012] Hormonal contraceptives are one of the most widely used contraceptive methods in the world and have the widest geographical distribution of any method. They are also the most common form of reversible female contraception in the developed world (United Nations Department of Economic and Social Affairs-Population Division World Conceptive Patterns 2013). Hormonal contraceptives include combined contraceptives (pills, vaginal rings, or transdermal patches) and progestogen-only contraceptives (progestogen-only pills, injections, or implants).

[0013] Combined hormonal contraceptives contain a combination of progestin and estrogen components.

[0014] A number of pharmacological actions contribute to the contraceptive effects of progestins. These include inhibiting ovulation by suppressing the function of the hypothalamic-pituitary-ovarian axis; altering the subsequent pituitary surge of luteinizing hormone and follicle-stimulating hormone. They also include slowing the transport of the egg through the fallopian tube, which limits the time available for fertilization; thickening cervical mucus, which impedes sperm transport; and inhibiting the activation of sperm enzymes required for egg penetration. The primary purpose of estrogen is to provide adequate circulatory (bleeding) control; it also inhibits the release of follicle-stimulating hormone and, therefore, follicle development.

[0015] One of the side effects of combined oral contraceptives is an increased risk of venous thromboembolism (VTE) with two clinical features: deep vein thrombosis or pulmonary embolism. Each year, 10,000 women of childbearing age develop venous thromboembolic disease, and the incidence increases threefold to fivefold in women using combined hormonal contraceptives. In women of childbearing age, combined hormonal contraception remains the most important factor in the development of VTE and remains the sole cause of disease in most cases (Blanco-Molina MA et al., Progestin-only contraception and venous thromboembolism. Thrombosis Research. 2012; 129: e257-e262).

[0016] Obesity is an independent risk factor for venous thromboembolism (VTE) (Abdollahi M. et al. Thromb. Haemost. 2003;89(3):493-498). The use of combined oral contraceptives is associated with an increased risk of VTE in obese patients. A population-based case-control study conducted in the Netherlands has demonstrated this increased risk. Among women who did not use oral contraceptives, the risk was 2.5 times higher in overweight women and 3.0 times higher in obese women compared with normal-weight women who did not use oral contraceptives. Compared with non-users with a normal BMI, the risk of VTE in overweight oral contraceptive users was 11.6 times higher, and the risk of VTE in obese oral contraceptive users was 23.8 times higher (Murthy AS. Semin Reprod Med. 2010 Mar;28(2):156-63; Pomp ER et al. Br J Haematol 2007;139:289-296.).

[0017] The estrogen component of contraceptive formulations is believed to be the primary cause of the prothrombotic effects of combined hormonal contraception.

[0018] According to the guidelines of the World Health Organization and the U.S. Centers for Disease Control and Prevention ("Medical eligibility criteria for contraceptive use"), women aged 35 years and older who are obese, hyperosmolar, smoke, or have diabetes are discouraged from using combined oral contraceptives. Progestogen-only contraception is recommended for all forms, even for women at high risk of VTE, such as those with hereditary thrombophilias, a history of estrogen-induced venous thromboembolism, or a history of recurrent venous thromboembolism (Centers for Disease Control and Prevention. 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).

[0019] Recall that progestin-only contraception (POC) relies on maintaining high levels of progesterone in the female body, thereby suppressing the secretion of follicle-stimulating hormone and luteinizing hormone. POC treatment results in the absence of any new follicle development.

[0020] Among POC contraceptive preparations, one can cite numerous progestogen molecules that have been proven to be effective as active ingredients in contraceptives, such as norethindrone, norethindrone diacetate, levonorgestrel, desogestrel, ethinylestradiol, drospirenone or depot medroxyprogesterone acetate (DMPA).

[0021] Regarding progestogen-only contraception, a systematic review and meta-analysis from Mantha evaluated the risk of VTE in users of progestogen-only contraceptives and did not identify a significant risk of venous thromboembolism associated with the use of progestogen-only contraception (Mantha S et al. BMJ 2012;345:e4944). In a more recent study, Lidegaard analyzed over 29,000 women using a third-generation progestogen-only pill (desogestrel) and did not show any increased risk of VTE associated with its use (adjusted venous thromboembolic event rate 0.64 (95% confidence interval 0.29-1.42)) (Lidegaard O. et al., 2001-9. BMJ 2011;343:d6423).

[0022] Therefore, progestogen-only contraceptives should be the best choice for women at risk for VTE and should therefore be a safe option for overweight or obese women.

[0023] However, the major known disadvantage of progestin-only contraceptives is an alteration in bleeding profile, leading to breakthrough bleeding or spotting during hormonal therapy.

[0024] It is well known that irregular bleeding is one of the main reasons for stopping contraception, which increases the risk of unintended pregnancy. Women who stop taking oral contraceptives often fail to switch to another contraceptive or use a less effective method. In fact, one study showed that among the 6% of users who stopped taking oral contraceptives due to irregular bleeding, 23% had an unintended pregnancy (Rosenberg MJ et al. J Reprod. Med. 1995; 40(5); 355-360).

[0025] The incidence of breakthrough bleeding in overweight or obese women using hormonal contraception is unknown. A retrospective analysis of data from a study evaluating two different formulations of low-dose oral contraceptives in 2893 women (613 overweight or obese) found that the rate of breakthrough bleeding did not differ between weight categories (Hampton RM et al., Contraception 2008; 77(6): 415-419). Another study showed that during the use of the contraceptive vaginal ring Nuvaring (etonogestrel / ethinyl estradiol), there was no overall difference in the total number of days of bleeding or spotting reported between the normal BMI group and the obese group (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).

[0026] Irregular menstrual flow and frequency and weight gain are well-documented side effects of POC therapies such as DMPA, a long-acting, reversible, progestogen-only contraceptive that is injected every 3 months (Harel Z et al. Adolescents' reasons for and experience 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 US clinicians. Int J Fertil Womens Med 1998;43(2):73-83; Keder LM et al. Compliance with depot medroxyprogesterone acetate: a randomized, controlled trial of intensive reminders. Am J Obstet Gynecol 1998;179(3 Pt 1):583-5; Fraser J et al. Compliance with depot medroxyprogesterone acetate: a randomized, controlled trial of intensive reminders. Am J Obstet Gynecol 1998;179(3 Pt 1):583-5; Fraser J et al. IS et al. Depo-Provera use in an Australian metropolitan practice. MedJ Australia1994; 160(9):553-6; Nutley T et al. contraceptive.Medscape Womens Health 1998;3(1):4).

[0027] The only experimental study related to DMPA-based POC contraception seems to indicate 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 who appeared overweight or obese had a lower risk of increased or excessive bleeding when treated with DMPA for POC than their height-weight counterparts. Connor et al. (2002) focused on physiological effects including excessive flow, excessive bleeding, persistent bleeding, and persistent flow (collectively referred to as "excessive bleeding") and effects including increased spotting, increased flow, heavier menses, and increased menstrual duration (collectively referred to as "increased bleeding"). The comparative results published by Connor et al. (2002) only involved unique, overall bleeding parameters including "excessive bleeding" and "increased bleeding."

[0028] However, Connor et al. did not address the possible effect of DMPA on the duration of bleeding episodes, particularly the number of days with bleeding or spotting.

[0029] However, as shown in the study by Connor et al., women who appear to be overweight or obese still experience unwanted spotting and bleeding.

[0030] Still further, reference may also be made to a study published by Casey et al. (2013, Contraception, Vol. 87:370-374), which relates to an etonogestrel-based POC contraceptive in the form of a subcutaneous implant (ESI). Casey et al. (2013) showed that obese women were less likely to have their ESI implant removed due to irregular bleeding than non-obese women.

[0031] From the prior art knowledge discussed above, it is known that each of the known progestogen candidate molecules intended for formulating a POC contraceptive formulation suitable for a specific administration regimen may behave differently, including in terms of their effects on various bleeding events.

[0032] Finally, it is generally known in the art that POC treatment is also often associated with weight gain, which may become a challenge for overweight women, particularly overweight women, and especially obese women. This weight gain effect may increase the incidence of diseases related to overweight and / or obesity, such as, for example, coronary heart disease, hypertension, stroke, type 2 diabetes, dyslipidemia, metabolic syndrome, cancer, osteoarthritis, sleep apnea, obesity hypoventilation syndrome, infertility, gallstones, and gout.

[0033] In particular, a systematic review by Curtis evaluating the use of progestogen-only contraceptives in obese women showed that obese or overweight adolescent DMPA users gained 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 blame contraception for weight gain. Many women stop their contraception because of this perceived side effect. In fact, a study of oral contraceptive users found that perceived weight gain was one of the most important reasons for women in the United States to stop using contraception (Rosenberg M. Weight change with oral contraceptive use and during the menstrual cycle: results of daily measurements. Contraception 1998;58:345-9).

[0034] Therefore, due to the above-mentioned disadvantages, overweight women, particularly overweight women and especially obese women who experience unwanted bleeding or spotting, weight gain, are likely to discontinue POC treatment, thereby increasing their chances of unintended pregnancy.

[0035] Therefore, there is a need to provide safe and effective contraceptive formulations for overweight women (including overweight and obese women), in particular to provide well-tolerated contraceptive formulations that show improved patient compliance. Summary of the Invention

[0036] The present invention relates to the use of drospirenone (DRSP) in an amount of at least 3 mg in a daily active dosage unit as the sole contraceptive ingredient for use as a contraceptive for overweight female patients, including overweight female patients and obese female patients.

[0037] The present invention also relates to the use of drospirenone as the sole contraceptive ingredient in the preparation of a contraceptive composition for overweight female patients, including overweight female patients and obese female patients.

[0038] The present invention also relates to the use of drospirenone in the preparation of a contraceptive formulation that results in a reduction in the number of days with bleeding episodes in overweight female patients, including overweight and obese female patients. A general and substantial reduction in the number of days with bleeding episodes compared to female patients who are not overweight is described throughout this specification. Contraceptive formulations containing drospirenone as the sole contraceptive ingredient are described in detail in the embodiments throughout this specification.

[0039] In another aspect, the present invention also relates to a method comprising administering a pharmaceutical composition comprising drospirenone in an amount of at least 3 mg to an overweight female patient, including an overweight female patient and an obese female patient.

[0040] The present invention relates to a method comprising administering to an overweight female patient, including overweight female patients as well as obese female patients, a pharmaceutical composition comprising drospirenone in an amount of at least 3 mg, wherein the pharmaceutical composition allows for a 28-day daily dosing regimen, and wherein after the initial administration of drospirenone has established its contraceptive effect in the patient, the patient can skip up to 4 doses within the 28-day daily dosing regimen cycle.

[0041] The present invention also relates to the use of drospirenone in the preparation of a contraceptive formulation that results in a generally substantial reduction in the number of days with bleeding episodes in female patients, particularly overweight female patients, including obese female patients. The general and substantial reduction in the number of days with bleeding episodes compared to female patients who are not overweight is described throughout this specification. Contraceptive formulations containing drospirenone as the sole contraceptive ingredient are described in detail in the embodiments throughout this specification.

[0042] The present invention also relates to the use of drospirenone for the preparation of a contraceptive kit resulting in a generally substantial reduction in the number of days with bleeding episodes in female patients, wherein the contraceptive kit comprises one or more packaging units, wherein each packaging unit comprises 21 to 28 daily active dosage units, wherein:

[0043] a) each daily active dosage unit contains drospirenone in an amount of at least 3 mg, without estrogen, and

[0044] b) when administered orally in the fasting state, the single daily active dosage unit is suitable for providing a pharmacokinetic profile of drospirenone having the following:

[0045] (i) Average t max 2.2h-6h and

[0046] (ii) Average C max less than about 30 ng / ml, and

[0047] (iii) Optional mean AUC 0h-t最后 is at least about 300 ng*h / ml.

[0048] C max and t max The values refer to the maximum DRSP plasma concentration and the time to reach it, respectively, after oral administration of a single daily dosage unit of the composition of interest comprising DRSP. In other words, C max and t maxIt refers to the characteristic of the peak drospirenone plasma concentration observed after oral ingestion of a single daily dosage unit of the composition of interest.

[0049] AUC 0h-t最后 The area obtained by integrating the drospirenone plasma concentration over time corresponds to the interval [0h-tlast], the point "0h" refers to a single daily dosage unit of the oral ingestion of the composition of interest, and the point "tlast" refers to the last time that the DRSP plasma concentration can be quantified.

[0050] DRSP plasma concentration can be determined by well-known methods. For example, a suitable quantitative method includes extracting DRSP from human plasma and then quantifying it using liquid chromatography coupled with tandem mass spectrometry.

[0051] In one embodiment, one skilled in the art can employ the analytical method described by Kirk et al. (Rapid Communication in Mass Spectrometry, 2006; 20: 1247-1252). This method includes a step of derivatizing drospirenone with Girard P hydrazine solution to increase the reaction of DRSP during subsequent MS analysis. This method is generally suitable for quantifying DRSP in human EDTA plasma at concentrations ranging from about 0.25 to about 100 ng / ml.

[0052] As used herein, the mean AUC 0h-t最后 , average C max and average t max The term "drosarone" refers to the arithmetic mean of individual pharmacokinetic data obtained from a group of healthy female volunteers of childbearing age who were orally administered a single daily dosage unit of a composition comprising drospirenone. The group of healthy female volunteers may include sufficient women to provide statistically confident pharmacokinetic results. Preferably, the group includes at least ten healthy women of childbearing age.

[0053] As used herein, a healthy female of reproductive age is defined as a premenopausal Caucasian female aged 18-40 years, of normal weight and free of health problems, particularly metabolic, renal, hepatic or gynecological diseases.

[0054] The present invention also relates to the use of drospirenone for the preparation of a contraceptive kit for reducing the number of days with bleeding episodes in female patients, wherein the contraceptive kit comprises one or more packaging units, wherein each packaging unit comprises 21 to 28 daily active dosage units, wherein:

[0055] (a) each daily active dosage unit contains at least 3 mg of drospirenone and is estrogen-free, and

[0056] (b) each daily active dosage unit comprises drospirenone in a form such that:

[0057] (i) not more than 50% of the drospirenone initially present in the daily active dosage unit dissolves within 30 minutes, and

[0058] (ii) at least 50% of said drospirenone dissolves within a period of 3 hours to 4 hours when the daily active dose is subjected to an in vitro dissolution test according to the USP XXIII paddle method, the percentage of drospirenone being relative to the amount of drospirenone initially present in said daily active dose unit. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 Figure 3: Graph showing the correlation between body mass index (BMI) and weight change (kg) for women undergoing DRSP-based contraceptive therapy. Weight change was measured by subtracting the weight at visit 6 (24 ± 2 days of cycle 13) from the weight at screening. Any negative result indicates weight loss. BMI below 30 kg / m 2 (Left) Women do not show any average weight change and have a BMI of 30 kg / m 2 Women with a mean weight of 18 or higher (right) showed slight but significant weight changes during contraceptive treatment.

[0060] Figure 2 Figure 3: A graph showing the correlation between body mass index (BMI) and heart rate change in women undergoing DRSP-based contraceptive treatment. Heart rate change was measured by subtracting the heart rate at visit 6 (24 ± 2 days of cycle 13) from the heart rate at screening. Any negative result indicates a higher heart rate during contraceptive treatment. BMI below 30 kg / m 2 (Left) A woman with a BMI of 30 kg / m2 shows a slight but significant increase in heart rate during contraceptive treatment. 2 Women with a heart rate of 10 or higher (right) did not show any changes in heart rate during contraceptive treatment. Detailed Description of the Invention

[0062] The inventors have recently developed a novel contraceptive kit and a novel contraceptive pharmaceutical composition based on crystalline and non-micronized drospirenone (WO 2012 / 000981). DRSP is a fourth-generation progestogen derived from spironolactone and has pharmacological properties that mimic natural progesterone.

[0063] DRSP does not have androgen origin, glucocorticoid and anti-glucocorticoid activity, but does have powerful anti-mineralocorticoid and anti-androgen origin properties. It has been shown that oral daily dosage is that DRSP of at least 3 mg can suppress ovulation in a single treatment cycle of 21 days. The combination of 3mg DRSP / 30 μg ethinylestradiol provides reasonable contraceptive safety limit (Rosenbaum etc., 2000, The European Journal of Contraception and Reproductive Health Care, 5,16-24) by suppressing ovulation and low-frequency follicle maturation.

[0064] In contrast to other DRSP-based contraceptive formulations on the market, the DRSP-based contraceptive formulation according to WO 2012 / 000981 relies on the slow dissolution rate of DRSP in vitro.

[0065] In addition, the DRSP-based contraceptive formulations according to WO 2012 / 000981 exhibit unique pharmacokinetic characteristics. In particular, when administered orally in the fasting state, a single daily active dosage unit comprising at least 3 mg of DRSP is suitable for providing a DRSP pharmacokinetic profile having the following:

[0066] -Average t max 2.2h-6h and

[0067] -Average C max Less than about 30 ng / ml.

[0068] It has been shown that contraceptive pharmaceutical compositions based on crystalline and non-micronized form of drospirenone (DRSP) disclosed in WO 2012 / 000981 are suitable for the treatment of women with a BMI below 30 kg / m 2 Administered to female patients.

[0069] In the following context, the term is used to standardize the description of bleeding and / or spotting in female patients on contraceptive therapy (Mishell et al., 2007, Contraception, 75(1): 11).

[0070] The term "hemorrhage" or the expression "bleeding episode" is intended to mean blood loss requiring the use of a tampon, pad or panty liner.

[0071] The term "petting" or the expression "petting episode" is intended to refer to minimal blood loss that does not require the use of any type of protective measures.

[0072] The expression "episodes of bleeding and / or spotting" is intended to mean days of bleeding and / or spotting delimited on either side by two days without bleeding or spotting.

[0073] In some embodiments, the term "hemorrhage" may also encompass "spotting."

[0074] As shown in the Examples herein, overweight women (i.e., with a BMI of 25 kg / m2) treated with the DRSP-based POC formulations described herein 2 The number of days of bleeding events per treatment cycle (i) in women with a BMI of 24.9 kg / m2 or more was similar to that in non-overweight women taking the same contraceptive treatment. 2 22.5% reduction during treatment cycles 2-4 compared to women with a BMI of 24.9 kg / m2 or less, and (ii) a 22.5% reduction during treatment cycles 2-4 compared to non-overweight women taking the same contraceptive treatment (i.e., women with a BMI of 24.9 kg / m2). 2 27.7% reduction during treatment cycles 2-6 compared to women with a BMI of 24.9 kg / m2 or less, and (iii) a 27.7% reduction during treatment cycles 2-6 compared to non-overweight women taking the same contraceptive treatment (i.e., women with a BMI of 24.9 kg / m2). 2 30.8% reduction during treatment cycles 2-9 compared to women with a BMI of 24.9 kg / m2 or less (iv) and 30.8% reduction during treatment cycles 2-9 compared to non-overweight women (i.e., women with a BMI of 24.9 kg / m2) taking the same contraceptive treatment. 2 1% reduction during treatment cycles 5-7 compared to women with a BMI of 24.9 kg / m2 or less, and (v) a 23.1% reduction during treatment cycles 5-7 compared to non-overweight women (i.e., women with a BMI of 24.9 kg / m2) taking the same contraceptive treatment. 2 Compared to women with ≥15 years of age (≥2 years), the reduction was approximately 22.5% during treatment cycles 7 to 9. The observed difference was statistically significant (p<0.01) using the Wilcoxon-rank sum test.

[0075] As further shown in the Examples herein, overweight women (i.e., BMI 25 kg / m 2 The mean number of days with bleeding events in women with ≥6 years of age (i) during treatment cycles 2-4 did not exceed 13% per treatment cycle; (ii) during treatment cycles 2-6 did not exceed 11% per treatment cycle; and (iii) during treatment cycles 2-9, during treatment cycles 5-7, or during treatment cycles 7-9 did not exceed 10% per treatment cycle.

[0076] As used herein, a "treatment cycle" encompasses a 28-day course of treatment in which the treatment comprises the administration of 21-28 consecutive daily doses of active test product tablets and may comprise the administration of up to 7 daily doses of placebo tablets.

[0077] In a preferred embodiment, the treatment cycle comprises the administration of 24 consecutive daily doses of active test product tablets followed by 4 consecutive days of administration of placebo tablets.

[0078] As used herein, "bleeding event days per treatment cycle" encompasses days with one or more bleeding episodes within a treatment cycle, regardless of the time period of the cycle, ie, active test product or placebo.

[0079] As shown in the Examples herein, overweight women (i.e., with a BMI of 25 kg / m2) treated with the DRSP-based POC formulations described herein 2 The number of days of bleeding events per treatment cycle in women with a BMI of 24.9 kg / m2 or above was similar to that in non-overweight women taking the same contraceptive treatment (i.e., women with a BMI of 24.9 kg / m2). 2 There was always a reduction of at least 5.0% during any of the treatment cycles studied, compared to women with ≥5 years of age (≥1 year).

[0080] As used herein, a reduction of "at least 5%" in the number of days with bleeding events per treatment cycle encompasses a reduction of 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%.

[0081] For example, the mean percentage reduction in the number of days with bleeding events per treatment cycle in overweight women treated with a DRSP-based POC formulation compared to non-overweight women taking the same contraceptive treatment over three consecutive treatment cycles can be assessed and can range from 15% to 30%, preferably from 20% to 25%, and more preferably from 22% to 24%.

[0082] It will be appreciated that the percentage reduction in the number of days with bleeding events per treatment cycle in overweight women may vary depending on parameters such as, for example, initial body weight, age, time elapsed before treatment initiation.

[0083] As further shown in the Examples herein, obese women (i.e., with a BMI of 30 kg / m2) treated with the DRSP-based POC formulations described herein 2 The number of days of bleeding events per treatment cycle (i) in women with a BMI of 29.9 kg / m2 or above was similar to that in non-obese women taking the same contraceptive treatment (i.e., women with a BMI of 29.9 kg / m2). 2 60.1% reduction during treatment cycles 2-4 compared to women with a BMI of 29.9 kg / m2 or less, and (ii) a 60.1% reduction during treatment cycles 2-4 compared to non-obese women (i.e., women with a BMI of 29.9 kg / m2) taking the same contraceptive treatment. 2 9% reduction during treatment cycles 2-6 compared to women with a BMI of 29.9 kg / m2 or less, and (iii) a reduction of approximately 67.9% during treatment cycles 2-6 compared to non-obese women (i.e., women with a BMI of 29.9 kg / m2) taking the same contraceptive treatment. 2 9 kg / m2 or less) during treatment cycles 2-9, and (iv) compared to non-obese women (i.e., women with a BMI of 29.9 kg / m2) taking the same contraceptive treatment.2 48.1% reduction during treatment cycles 5-7 compared to women with a BMI of 29.9 kg / m2 or less) and (v) a 48.1% reduction during treatment cycles 5-7 compared to non-obese women (i.e., women with a BMI of 29.9 kg / m2) taking the same contraceptive treatment. 2 There was a decrease of approximately 62.0% during treatment cycles 7-9 compared to women with ≥5 years of age (≥18 years).

[0084] The observed differences were statistically significant (p<0.01) using the Wilcoxon-rank sum test.

[0085] As further shown in the Examples herein, obese women (i.e., BMI 30 kg / m 2 The average number of days with bleeding events in women with ≥6 years of age (i) during treatment cycles 2-4 and during treatment cycles 5-7 did not exceed about 7%; and (ii) during treatment cycles 2-6, during treatment cycles 2-9, and during treatment cycles 7-9 did not exceed about 5%.

[0086] Furthermore, as further shown in the Examples herein, drospirenone-based compositions may benefit obese women as compared to other POC-based contraceptive compositions, as a significant reduction in the number of days with bleeding or spotting events within the cycle is observed.

[0087] Thus, as shown in the Examples herein, obese women (i.e., with a BMI of 30 kg / m 2 The number of days of bleeding events per treatment cycle in women with a BMI of 29.9 kg / m2 or above was similar to that in non-obese women taking the same contraceptive treatment (i.e., women with a BMI of 29.9 kg / m2). 2 There was always a reduction of at least 10.0% or more during any of the treatment cycles studied, compared to women with ≥5 years of age (≥18 years).

[0088] As used herein, a “at least 10%” reduction in the number of days with bleeding events per treatment cycle encompasses a reduction of 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%, 44%, 45%, 46%, 47%, 48%, 49%, and 50%.

[0089] The mean percentage reduction in the number of days with bleeding events per treatment cycle in obese women treated with the DRSP-based POC formulation compared to non-obese women taking the same contraceptive treatment over three consecutive treatment cycles can be further evaluated and can range from 30% to 75%, preferably from 40% to 75%, and more preferably from 45% to 65%.

[0090] The inventors have shown that a reduction in the number of days of bleeding or spotting can benefit overweight women, including overweight and obese women, and considerably improve their comfort of life, while providing compliance with contraceptive treatment and increased efficacy of contraceptive treatment.

[0091] In addition to a reduction in the number of days of bleeding or spotting, oral administration of a DRSP-based POC treatment according to WO 2012 / 000981 to overweight women, particularly overweight women, particularly obese women, may also provide benefits in weight change and benefits in resting heart rate change, as shown in the Examples herein.

[0092] These unexpected observations could not be expected from the previous clinical evaluation disclosed in WO 2012 / 000981.

[0093] In fact, when administered to overweight women, especially overweight women, especially obese women, this DRSP-based contraceptive composition resulted in a significant average weight loss and no change in resting heart rate compared to women from the general population, where no effect on weight change and a slightly significant increase in resting heart rate were observed during treatment.

[0094] Therefore, the DRSP-based contraceptive treatment according to the present invention allows the inclusion of obese women (which encompasses a body mass index (BMI) of 30 kg / m 2 Overweight women (women with 100g or more) are better able to adhere to prescribed contraceptive treatment, thereby reducing the risk of discontinuing said contraceptive treatment and thus reducing the risk of increasing unintended pregnancy.

[0095] Thus, in some embodiments, the present invention relates to the use of drospirenone as the sole active ingredient contained in a daily active dosage unit in an amount of 3 mg or more, in particular in an amount of 3-6 mg, as a contraceptive for reducing the number of days with bleeding events in overweight women by 5% or more, preferably by 10% or more, compared to non-overweight women taking the same contraceptive treatment.

[0096] Furthermore, the experimental data disclosed herein show that the effect of reducing the number of days of bleeding episodes per treatment cycle tends to increase with the duration of contraceptive treatment with the DRSP-POC formulation, reaching a reduction of 15% or more. As disclosed in the Examples herein, the number of days of bleeding episodes per treatment cycle was reduced by greater than 30% in overweight women over a period of treatment cycles 2-9.

[0097] Still further, the present invention relates to the use of drospirenone as the sole active ingredient in a daily active dosage unit in an amount of 3 mg or more, in particular 3-6 mg, as a contraceptive to reduce the number of days with bleeding episodes in obese women by 10% or more compared to non-obese women taking the same contraceptive treatment. As disclosed in the Examples herein, the number of days with bleeding episodes in obese women was reduced by more than 45% over a period of treatment cycles 2-9.

[0098] As further shown in the Examples herein, the number of days with bleeding events in overweight or obese patients does not exceed about 20%, 15%, 10%, 8%, or 5% of any treatment cycle after the initial treatment cycle.

[0099] 1- Daily active dose of drospirenone

[0100] In one aspect, the present invention relates to the use of DRSP in an amount of at least 3 mg in a daily active dosage unit as the sole contraceptive ingredient for use as a contraceptive for overweight female patients, including overweight female patients and obese female patients.

[0101] In a specific embodiment, the present invention relates to the use of DRSP in an amount of at least 3 mg contained in a daily active dosage unit as the sole contraceptive ingredient for use as a contraceptive for obese female patients.

[0102] In certain embodiments, the present invention relates to a method of administering DRSP in an amount of at least 3 mg per daily active dosage unit as the sole contraceptive ingredient for use in a patient with a BMI of 30 kg / m 2 or above for female patients using contraceptive pills.

[0103] As used herein, a "contraceptive ingredient" refers to an ingredient that can prevent pregnancy when administered daily to a female patient in an effective amount for a period of 21-28 consecutive days. A contraceptive ingredient can prevent pregnancy from occurring through various biological actions. For example, pregnancy can be prevented by inhibiting ovulation, by thickening cervical mucus (which reduces sperm motility and penetration), and / or by preventing embryo implantation.

[0104] As used herein, the expression "the only contraceptive ingredient" is intended to mean that the DRSP is the only ingredient that promotes contraception. In other words, the contraceptive ingredient does not contain estrogen.

[0105] Drospirenone or DRSP, 6β,7β,15β,16β-dimethylene-3-oxo-17a-pregnan-4-ene-21,17-carboxylactone and further identified as CAS registry number 67392-87-4, is a synthetic progestogen with pharmacological characteristics very close to those of natural progesterone.

[0106] As used herein, the term "drospirenone" refers to drospirenone itself, drospirenone solvates, and drospirenone derivatives or prodrugs.

[0107] DRSP can be prepared by well-known methods described in the prior art, such as the methods described in US4129564, WO9806738, EP11746101 or WO2006061309. The method described in WO2006061309 may be particularly suitable for preparing DRSP.

[0108] It goes without saying that the method of preparing DRSP can be implemented to meet the requirements of Good Manufacturing Practice (GMP).

[0109] To ensure good bioavailability of DRSP, a significant amount of DRSP initially contained in the contraceptive composition must be released within a reasonable time frame.

[0110] Good bioavailability of DRSP can be achieved when the in vitro dissolution rate of the DRSP of a composition comprising DRSP is such that at least 50% of the DRSP initially present in the composition is dissolved within a period of 3 to 4 hours.

[0111] As used herein, an "active daily dosage unit" refers to a dosage unit that is capable of preventing pregnancy when administered daily to a female patient. In a preferred embodiment, the active daily dosage unit is capable of inhibiting ovulation.

[0112] As used herein, "female patient" refers to a female individual of childbearing age (ie, from puberty to menopause). Female individuals of childbearing age also include perimenopausal women.

[0113] Body mass index (BMI) is a simple weight-to-height index commonly used to classify overweight and obesity in adults. It is defined as a person's weight in kilograms divided by the square of their height in meters (kg / m 2 ).

[0114] The World Health Organization (WHO) accepts the following weight status categories related to BMI ranges for adults:

[0115] – Less than 18.5kg / m 2 A BMI of 1% indicates underweight;

[0116] –18.5kg / m 2 -24.9kg / m 2 A BMI of indicates normal weight status;

[0117] –25.0kg / m 2 -29.9kg / m 2 A BMI indicating overweight status; and

[0118] –30.0kg / m 2 A BMI of 10 or higher indicates obesity.

[0119] As used herein, an overweight female patient is defined as having a BMI of 25.0 kg / m 2 or above female patients, including overweight female patients and obese female patients.

[0120] As used herein, overweight female patients include those with a BMI of 25.0 kg / m 2 -29.9kg / m 2 female patients.

[0121] As used herein, an obese female patient or a female patient suffering from obesity encompasses a BMI of 30.0 kg / m 2 Female patients with or above.

[0122] In certain embodiments, a female patient has a BMI of 25.0 kg / m 2 or above.

[0123] In certain preferred embodiments, the BMI of female patients is 30.0 kg / m 2 or above.

[0124] In certain embodiments, the daily active dosage unit is contained in a contraceptive kit, wherein the kit comprises one or more packaging units, wherein each packaging unit comprises 21-28 daily active dosage units, wherein:

[0125] a) each daily active dosage unit contains at least 3 mg of DRSP and is estrogen-free, and

[0126] b) Each daily active dosage unit comprises a DRSP in a form such that:

[0127] (i) not more than 50% of the DRSP initially present in the daily active dosage unit dissolves within 30 minutes, and

[0128] (ii) at least 50% of the DRSP is dissolved within a period of 3 hours to 4 hours,

[0129] The percentage of DRSP is relative to the amount of DRSP initially present in the daily active dose unit when the daily active dose is subjected to in vitro dissolution testing according to the USP XXIII paddle method.

[0130] The daily active dosage unit comprising DRSP is characterized by a slow in vitro dissolution rate of DRSP.

[0131] As used herein, "slow in vitro dissolution rate of DRSP" means that when the daily active dosage unit is subjected to a dissolution test, the release of DRSP is such that no more than 50% of the DRSP initially present in the daily active dosage unit dissolves within 30 minutes.

[0132] As intended herein, no more than 50% of DRSP encompasses no more than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% of the DRSP initially present in the daily active dosage unit.

[0133] In some embodiments, no more than 40% of the DRSP initially present in the daily active dosage unit is dissolved within 30 minutes.

[0134] As used herein, percentages of DRSP are relative to the amount of DRSP initially present in the daily active dosage unit.

[0135] The in vitro dissolution rate of DRSP can be assessed by any of the well-known methods described in the art.

[0136] The in vitro dissolution rate of DRSP is preferably assessed by the USP XXIII paddle method. Briefly, a tablet consisting of a 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 speed of 50 rpm.

[0137] In a preferred embodiment, the content of DRSP in each daily active unit dose 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.

[0138] In some embodiments, the active daily dosage unit consisting of the contraceptive composition described above can contain a DRSP content of about 3 mg to about 6 mg. A daily dosage of about 3 mg to about 6 mg encompasses daily dosages of 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, and 6 mg.

[0139] In certain embodiments, the DRSP content in each daily active unit dose is about 3.5 mg to 4.5 mg.

[0140] As used herein, the term "about" preceding "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 of 45-55.

[0141] In certain embodiments, one or more packaging units further contain 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.

[0142] In the context of the present invention, the term "placebo" is intended to mean a pharmacologically inert or harmless substance.

[0143] In certain embodiments, each packaging unit contains 24 daily active dosage units.

[0144] In certain embodiments, each packaging unit contains four daily placebo dosage units.

[0145] In certain embodiments, the DRSP is in crystalline form.

[0146] In certain embodiments, the DRSP is in non-micronized form.

[0147] As already mentioned, the crystalline and non-micronized form of DRSP allows for a slow in vitro dissolution rate of DRSP.

[0148] One way to obtain the DRSP-containing compositions of the present invention is to use DRSP in the form of particles having an appropriate specific surface area, such as non-micronized particles. It has also been shown that the specific surface area is about 2000 cm 2 / g-about 8500cm 2 DRSP in the form of particles of 1000 μg / g can be suitably used to obtain the contraceptive composition of the present invention. The specific surface area can be measured experimentally using the BET method (gas adsorption method).

[0149] In certain embodiments, the DRSP in particulate form has a specific surface area of about 2000 cm 2 / g-about 8500cm 2 / g.

[0150] This specific surface area range includes the following values: approximately 2000 cm 2 / g、2500cm 2 / g、3000cm 2 / g、3500cm 2 / g、4000cm 2 / g、4500cm 2 / g、5000cm 2 / g、5500cm 2 / g、6000cm 2 / g、6100cm 2 / g、6200cm 2 / g、6300cm 2 / g、6400cm 2 / g、6500cm 2 / g、6600cm2 / g、6700cm 2 / g、6800cm 2 / g、6900cm 2 / g、7000cm 2 / g、7500cm 2 / g, 8000cm2 / g and 8500cm2 / g.

[0151] Regarding the particle size distribution, DRSP particles with a diameter greater than 200 μm should be avoided in order not to too drastically impair the in vitro dissolution rate and hence the in vivo bioavailability, since such particles are poorly soluble.

[0152] In certain embodiments, the d 50 Less than 70μm.

[0153] In certain preferred embodiments, the d 50 10μm-60μm. d of about 10μm-about 60μm 50 The range covers 10μm, 15μm, 20μm, 25μm, 30μm, 35μm, 40μm, 45μm, 50μm, 55μm and 60μm d 50 .

[0154] In some embodiments, the particle size distribution of the DRSP present in the composition according to the present invention is characterized by:

[0155] (i)d 90 A particle size of less than about 100 μm, and / or

[0156] (ii)d 50 A particle size of about 10 μm to about 60 μm, and / or

[0157] (iii)d 10 The particle size is greater than about 3 μm.

[0158] In some other embodiments, the d 50 In this embodiment, the particle size distribution of the DRSP present in the composition according to the present invention is characterized by at least one of the following characteristics:

[0159] (i)d 90 Particle size is less than about 100 μm,

[0160] (ii)d 50 A particle size of about 10 μm to about 30 μm, and

[0161] (iii)d 10 The particle size is greater than about 3 μm.

[0162] As used herein, “d 90 The term "particle size" refers to a particle size distribution such that at least 90% of the particles have a particle size diameter smaller than a specified value.

[0163] As used herein, “d 50 The term "particle size" refers to a particle size distribution such that at least 50% of the particles have a particle diameter smaller than a specified value.

[0164] As used herein, “d 10 The term "particle size" refers to a particle size distribution such that at least 10% of the particles have a particle diameter smaller than a specified value.

[0165] d 90 Particle size less than about 100 μm including d 90 The particle size is less than about 90μm, 80μm, 70μm, 60μm, 55μm, 50μm, 45μm, 40μm, 38μm, 36μm, 34μm, 32μm, 30μm, 28μm, 26μm, 24μm, 22μm, 20μm.

[0166] d 50 Particle size values of about 10 μm to about 30 μm include values of about 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, and 30 μm.

[0167] d 10 Particle size values greater than about 3 μm include d 10 The particle size values are greater than about 3 μm, 3.5 μm, 4.5 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, and 12 μm.

[0168] Needless to say, d 10 Particle size value is less than d 50 Particle size value, d 50 Particle size value is less than d 90 Particle size value.

[0169] DRSP particle size distribution, especially d 90 d 10 and d 50 The particle size distribution can be determined by methods well known in the art, such as sieve analysis, laser diffraction, optical analysis or optical counting. Laser diffraction is particularly preferred. The particle size distribution can be determined by laser diffraction in a wet dispersion. The dispersant is preferably water.

[0170] In some embodiments, the pharmaceutical composition of the present invention comprises DRSP in particulate form having a particle size distribution having a combination of two characteristics selected from the group consisting of:

[0171] (i)d 90 Particle size is less than about 100 μm,

[0172] (ii)d 50 A particle size of about 10 μm to about 30 μm, and

[0173] (iii)d 10 The particle size is greater than about 3 μm.

[0174] 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 feature (iii).

[0175] In some embodiments, the pharmaceutical composition of the present invention comprises a non-micronized form of DRSP having a particle size distribution characterized by:

[0176] (i)d 90 Particle size is less than about 100 μm,

[0177] (ii)d 50 A particle size of about 10 μm to about 30 μm, and

[0178] (iii)d 10 The particle size is greater than about 3 μm.

[0179] In a preferred embodiment, the DRSP particle size distribution is further characterized by d 90 The particle size values are less than 50 μm, and no particles have a particle size greater than 80 μm.

[0180] In some embodiments, the contraceptive composition of the present invention comprises DRSP in the form of particles, wherein 90 The particle size is about 20 μm to about 40 μm, d 50 The particle size is from about 10 μm to about 30 μm and the d10 is from about 3 μm to about 9 μm, wherein no particle has a particle size greater than 80 μm, more preferably no particle has a particle size greater than 60 μm.

[0181] In some other embodiments, the contraceptive composition of the present invention comprises drospirenone in the form of particles, which:

[0182] (i)d 90 The particle size is about 30 μm to about 40 μm,

[0183] (ii)d 50 A particle size of about 15 μm to about 25 μm, and

[0184] (iii)d 10 The particle size of the particles is from about 5 μm to about 9 μm, and no particle has a particle size greater than 80 μm, more preferably no particle has a particle size greater than 60 μm.

[0185] In some other embodiments, the contraceptive composition of the present invention has a surface area of about 2000 cm 2 / g-about 8000cm 2 / g and d 50 DRSP is expressed in the form of particles with a particle size of 10 μm to 60 μm.

[0186] To obtain DRSP in the form of particles having the above-mentioned specific surface area and / or particle size distribution, a person skilled in the art can use well-known methods in the art, such as a grinding process, optionally combined with a screening process.

[0187] For example, DRSP obtained by any of the synthesis methods described in the prior art can be subjected to a ball mill or hammer mill step, optionally followed by a vibratory sieving step. The subsequent vibratory sieving step can remove the smallest and largest DRSP particles that would impair the pharmacokinetic and in vitro dissolution characteristics of the DRSP.

[0188] Those skilled in the art can adjust the parameters of the grinding and sieving steps by routine experimentation to obtain DRSP in the appropriate granular form. Suitable mills that can be used include hydraulic mills, ball or rod mills, hammer mills, cutters, and oscillating granulators.

[0189] Suitable DRSP in granular form can also be prepared by crystallization or precipitation methods, optionally combined with a sieving step, to fully control the DRSP particle size. The precipitation method may comprise the steps of: (i) dissolving the DRSP in a water-miscible solvent, and then (ii) dispersing the resulting solution in cold water with stirring to induce precipitation of the DRSP. The DRSP particles can then be recovered by filtration.

[0190] The water-miscible solvent may be a solvent commonly used in crystallization or precipitation processes, such as methanol, ethanol, isopropanol, dimethylformamide, tetrahydrofuran, dioxane or dimethyl sulfoxide, dimethylacetamide or acetone.

[0191] This method enables DRSP to be obtained in a substantially crystalline form.

[0192] By routine experimentation, one skilled in the art can determine the parameters of the precipitation method to be used in order to obtain the appropriate DRSP form.

[0193] The parameters of the precipitation method (such as the amount of solvent, the amount of water and the amount of optional surfactant to be used) can be adjusted by a person skilled in the art by routine experiments.

[0194] 2- Contraceptive methods

[0195] The present invention also relates to a method comprising administering to an overweight female patient a pharmaceutical composition comprising DRSP in an amount of at least 3 mg, wherein the pharmaceutical composition allows for a 28-day daily dosing regimen, and wherein after the initial administration of the DRSP establishes its contraceptive effect in the patient, the patient can skip up to 4 doses within the 28-day daily dosing regimen cycle.

[0196] In some embodiments, the present invention is also directed to a method comprising administering to an obese female patient a pharmaceutical composition comprising DRSP in an amount of at least 3 mg, wherein the pharmaceutical composition allows for a 28-day daily dosing regimen, and wherein after the initial administration of the DRSP establishes its contraceptive effect in the patient, the patient can skip up to 4 doses within the 28-day daily dosing regimen cycle.

[0197] In some embodiments, the present invention further relates to a method comprising providing a BMI of 30 kg / m 2 A method of administering a pharmaceutical composition comprising DRSP in an amount of at least 3 mg to a female patient of 100 mg or greater, wherein the pharmaceutical composition allows for a 28-day daily dosing regimen, and wherein after the initial administration of the DRSP establishes its contraceptive effect in the patient, the patient can skip up to 4 doses within the 28-day daily dosing regimen cycle.

[0198] In some embodiments of the above method, the female patient has a BMI of 25 kg / m 2 or higher.

[0199] In some embodiments of the above methods, the female patient suffers from obesity.

[0200] In certain embodiments, the female patient has a BMI of 30 kg / m 2 or higher.

[0201] As used herein, "daily dosing regimen" refers to a method of contraception for obese female patients comprising the step of administering to said female patient an active daily dosage unit consisting of a pharmaceutical composition as fully described herein on consecutive days within a 28-day period (i.e., a period corresponding to the average length of a menstrual cycle).

[0202] As used herein, an "active daily dosage unit" refers to a dosage unit that is capable of preventing pregnancy when administered daily to a female patient over a period of 28 consecutive days.

[0203] After DRSP establishes its contraceptive effect, method can comprise the second phase of no contraceptive period (i.e., the phase in which contraceptive component is not applied to female patient). During said second phase, daily placebo dosage unit can be applied to female patient. In some other cases, pill is not applied to female patient.

[0204] A "daily placebo dosage unit" is understood to mean a dosage unit comprising ingredients that are pharmaceutically inert or harmless. In other words, a daily placebo dosage unit does not contain any contraceptive ingredients as defined herein.

[0205] This second phase allows regular menstrual bleeding to occur, thus mimicking a natural menstrual cycle.

[0206] Furthermore, it is believed that this second phase results in the secretion of endogenous estradiol, which may have some benefits on bone metabolism in female patients.

[0207] In certain embodiments, the pharmaceutical composition further allows the patient to skip up to two non-consecutive days of the DRSP during the 28-day daily dosing regimen, provided that the skipped dose of the DRSP is taken within about 24 hours of the skipped up to two non-consecutive days.

[0208] In certain embodiments, the skipped up to 4 doses are on non-consecutive days.

[0209] In certain embodiments, the skipped up to 4 doses are on consecutive days.

[0210] In general, it is preferred to use DRSP in non-micronized and crystalline form for the preparation of the pharmaceutical compositions of the present invention.

[0211] The daily dosage regimen of the DRSP to be used to obese female patients can also be regulated according to individual factors such as age, body weight, overall health and diet of the female patients. Said daily dosage regimen can also change based on possible drug interactions. Said daily dosage regimen can also change based on other biological effects expected by using DRSP except preventing pregnancy.

[0212] The daily dosage regimen of DRSP to be administered daily to female patients may be lower or higher than the doses mentioned above. For example, perimenopausal female patients may require a higher or lower daily dose of DRSP to improve their overall condition, for example, to improve the regularity of their menstrual cycles.

[0213] Adjustments to the daily dosing regimen can be made routinely by a physician.

[0214] In a preferred embodiment, the pharmaceutical composition of the present invention further comprises one or more pharmaceutically acceptable excipients.

[0215] The pharmaceutical compositions of the present invention can be formulated according to standard methods such as those described in Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins; Twenty first Edition, 2005).

[0216] Pharmaceutically acceptable excipients that can be used to formulate the contraceptive compositions of the present invention are described inter alia in Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association (Pharmaceutical Press; 6 th Revised edition, 2009).

[0217] Examples of suitable excipients include, but are not limited to, fillers, carriers, diluents, binders, anti-caking agents, plasticizers, disintegrants, lubricants, flavorings, buffers, stabilizers, colorants, dyes, antioxidants, anti-adherents, softeners, preservatives, and glidants.

[0218] In some embodiments, the contraceptive compositions of the present invention comprise one or more excipients selected from the group consisting of binders, fillers, glidants, and lubricants.

[0219] 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, dextran, sucrose, mannitol, and sorbitol, and combinations thereof.

[0220] Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, talc, propylene glycol, PEG, stearic acid, vegetable oils, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, mineral oil, polyoxyethylene monostearate, and combinations thereof.

[0221] Examples of binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; gums such as gum tragacanth, gum arabic, and gelatin; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropylmethyl cellulose; polyvinyl pyrrolidone, and combinations thereof.

[0222] Examples of glidants include silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0223] In a preferred embodiment, pharmaceutical compositions according to the present invention do not comprise significant amounts of surfactant. Significant amounts of surfactant may impair the in vitro dissolution characteristics of DRSP by increasing its initial dissolution rate. Surfactants include nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters and ionic surfactants such as sodium lauryl sulfate.

[0224] It goes without saying that the DRSP to be used may be one having a specific surface area and / or d 90 d 10 and d 50 Particle size and particle form.

[0225] The contraceptive composition may optionally contain additional excipients which may comprise from about 0.1% to 10% by weight.

[0226] The contraceptive composition according to the present invention can be formulated into galenic forms suitable for oral administration. Such forms include, but are not limited to, tablets, lozenges, granules, pills, capsules, powders and suspensions.

[0227] In a preferred embodiment, the contraceptive composition is formulated in solid forms for oral administration, such as tablets, capsules, granules, lozenges and pills.

[0228] Such solid forms are particularly suitable for use as daily active dosage units in the contraceptive kit according to the invention.

[0229] When the pharmaceutical composition is formulated into a solid form such as a tablet or pill, the solid form may be conveniently coated with a suitable film-forming agent such as hydroxypropylmethylcellulose, hydroxypropylcellulose or ethylcellulose, to which may optionally be added a suitable excipient, for example a softener such as glycerol, propylene glycol, diethyl phthalate or glyceryl triacetate; a filler such as sucrose, sorbitol, xylitol, glucose or lactose; or a coloring agent such as titanium hydroxide or the like.

[0230] Pharmaceutical compositions in the form of tablets, pills or granules can be prepared by conventional methods such as direct compression, dry granulation and wet granulation.

[0231] In some embodiments, the solid form is obtained by direct compression.

[0232] It is a further object of the present invention to provide a method for preparing the contraceptive composition described herein, comprising the steps of:

[0233] (i) providing the DRSP in granular form as fully described hereinbefore;

[0234] (ii) providing one or more pharmaceutically acceptable excipients; and

[0235] (iii) mixing the DRSP provided in step (i) with the one or more excipients provided in step (ii).

[0236] As fully described above, applicants provide technical guidance to obtain compositions comprising a form of DRSP such that:

[0237] (i) no more than 50% of the DRSP initially present in the composition dissolves within 30 minutes, and

[0238] (ii) at least 50% of the DRSP is dissolved within a period of 3 hours to 4 hours,

[0239] When the composition is subjected to an in vitro dissolution test, the percentage of DRSP is relative to the amount of DRSP initially present in the composition.

[0240] Compositions comprising DRSP having such in vitro dissolution characteristics or in vivo pharmacokinetic characteristics as fully described above can be achieved in various other ways.

[0241] By routine experimentation and based on their general knowledge, those skilled in the art can vary (i) the particle size distribution of the DRSP and (ii) the content and nature of the excipients to obtain other alternative compositions that exhibit the in vitro dissolution characteristics or in vivo pharmacokinetic characteristics described herein.

[0242] For example, one skilled in the art can contemplate a composition comprising (i) micronized DRSP and (ii) a sustained-release agent to reduce the dissolution rate of the DRSP.

[0243] One skilled in the art may also contemplate combining (i) large particles of DRSP and (ii) a surfactant and / or wetting agent to ensure dissolution of the DRSP.

[0244] In certain embodiments, the pharmaceutical composition comprises a contraceptive kit comprising one or more packaging units, wherein each packaging unit comprises 21-28 daily active dosage units, wherein:

[0245] a) each daily active dosage unit contains at least 3 mg of drospirenone, without estrogen, and

[0246] b) Each daily active dosage unit comprises drospirenone in a form such that:

[0247] (i) not more than 50% of the drospirenone initially present in the daily active dosage unit dissolves within 30 minutes, and

[0248] (ii) at least 50% of the drospirenone is dissolved within a period of 3 hours to 4 hours.

[0249] The percentage of drospirenone is relative to the amount of drospirenone initially present in the daily active dosage unit when the daily active dosage unit is subjected to an in vitro dissolution test according to the USP XXIII paddle method.

[0250] The contraceptive kit comprises one or more packaging units.

[0251] The one or more packaging units include, but are not limited to, 1 packaging unit, 2 packaging units, 3 packaging units, 4 packaging units, 5 packaging units, and 6 packaging units.

[0252] Each packaging unit contains 21-28 daily active dosage units. As fully described above, each daily active dosage unit consists of the contraceptive composition of the present invention.

[0253] As fully described above, the daily active dosage unit preferably does not contain any estrogen or estrogen derivative such as ethinyl estradiol, ethinyl estradiol methyl ether or 8-isopentenylnaringenin. In other words, the DRSP is preferably present in a daily active dosage unit that does not contain an estrogen.

[0254] In a more preferred embodiment, DRSP is the only contraceptive ingredient contained in the daily active dosage unit.

[0255] Each packaging unit optionally contains 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.

[0256] In some embodiments, the contraceptive kit is characterized in that each packaging unit contains 28 daily dosage units and does not contain daily dosage units of a pharmaceutically acceptable placebo. Such a contraceptive kit is particularly suitable for carrying out the contraceptive method of the present invention, which consists in "continuous" administration of DRSP without a contraceptive-free period.

[0257] In other embodiments, each packaging unit comprises

[0258] - 21 to 27 daily dosage units consisting of the contraceptive composition fully described herein, and

[0259] - Optionally, 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.

[0260] This contraceptive kit is particularly suitable for carrying out the contraceptive method of the present invention, and comprises:

[0261] - a first phase, in which obese female patients are administered an active daily dosage unit according to the invention which does not contain estrogen over a period of 21 to 27 consecutive days, followed by;

[0262] - A second phase, in which no contraceptive composition is administered to the female patient for a period of 1 to 7 consecutive days.

[0263] In some other embodiments, each packaging unit of the kit contains 24 daily dosage units containing an effective amount of a contraceptive composition described herein and, optionally, 4 daily dosage units of a pharmaceutically acceptable placebo.

[0264] The packaging unit may have a conventional form commonly used for oral contraceptives.

[0265] For example, the packaging unit can be a conventional blister pack, which contains an appropriate number of dosage units in a blister pack sealed with a cardboard, paperboard, foil or plastic backing and enclosed in a suitable cover. Each blister container can be conveniently numbered or labeled to promote compliance.

[0266] The packaging unit may contain the daily dosage units in the order in which they are to be ingested, i.e. starting with a first of at least 21 dosage units comprising the DRSP composition, optionally followed by 7 or fewer empty blisters, or 7 or fewer dosage units comprising a pharmaceutically acceptable placebo.

[0267] The kit of the present invention may include other appropriate components, such as instructions for use.

[0268] The following examples are illustrative and are not intended to limit the scope of the invention as claimed. DETAILED DESCRIPTION

[0269] Example 1 - LF111 (DRSP) treatment reduces the number of days of bleeding and / or spotting

[0270] 1 / Target

[0271] The following study, CF111 / 302, represents a pivotal, multicenter, double-blind, double-dummy, randomized trial of the contraceptive efficacy, tolerability, and safety of LF111 (DRSP) over 9 cycles of 28-day treatment (24 active test product tablets followed by 4 days of placebo tablets).

[0272] The first goal is to confirm the contraceptive efficacy of LF111, and the second goal is to confirm the safety and tolerability of LF111, especially in terms of bleeding patterns.

[0273] 2 / Materials and Methods

[0274] a) Test products, dosages and administration methods

[0275] LF111 film-coated tablets (test product: 24 tablets containing 4 mg of DRSP followed by 4 placebo tablets: León Farma) were administered orally during the trial. LF111 tablets have the following formula:

[0276]

[0277] 1 Crystalline and non-micronized drospirenone, prepared according to a method similar to that described in WO 2006 / 061309;

[0278] b) Experimental design

[0279] Methods: A prospective, multicenter, randomized, double-blind, double-dummy trial was conducted in 857 women at risk of pregnancy, aged 18-45 years, with systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg, who were not at risk for uncontrolled current disease and were followed in approximately 73 centers in Austria, the Czech Republic, Germany, Hungary, Poland, Romania, Slovakia, and Spain.

[0280] After providing informed consent at Visit 1a (Screening; V1a) and receiving study medication at Visit 1b, subjects will attend Visits 2-4 on Days 24±2 of Cycles 1, 3, and 6, and Visit 5 (V5) on Days 29+2 of Cycle 9. Follow-up (Visit 6; V6) will be conducted 7-10 days after the last LF111 intake.

[0281] The planned total duration of the trial was set at 16 months, with a maximum of 6 months for the recruitment process, 9 months for the contraceptive treatment itself, and 10 days for the follow-up step. The duration of contraceptive treatment for a single woman was 9 x 28 days.

[0282] c) Exclusion criteria

[0283] Pregnant subjects; breastfeeding subjects; subjects known or suspected to be unable to follow study procedures and use IMP (investigational medicinal product); abnormal findings on pelvic, breast, or vaginal ultrasound that preclude participation in the trial; unexplained amenorrhea; known polycystic ovary syndrome; subjects with ASC-US or worse findings on Pap smear; subjects with known toxicity to the active ingredient (drospirenone) or excipients (cellulose, lactose, silicon dioxide, magnesium stearate, corn starch, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, aquarius BT16035 cottage green, talc, titanium dioxide; anhydrous colloidal silica, all-rac-α-tocopherol, lactose, monohydrate, corn starch, povidone, stearic acid, hypromellose, polyethylene glycol 400); severe cardiovascular, liver, or kidney disease, diabetes with vascular involvement, uncontrolled thyroid disease, or recent venous thrombosis or embolism; undiagnosed vaginal bleeding; known or suspected sex hormone-sensitive malignancy; history or presence of severe liver disease as long as liver function values have not returned to normal; alcohol, drug, or substance abuse Indications or history of use (within the last 12 months); known bleeding disorders or history of unexplained bleeding or bruising within the last 12 months before V1a; prohibited previous medications / contraceptives (injectable hormonal contraceptive methods within the last 6 months before V1a, progestin-releasing IUDs (intrauterine devices) or contraceptive implants within the last 2 months before V1a, antiretroviral therapy within the last 6 months before V1a, microsomal enzyme-inducing drugs within the last 28 days before starting IMPs); dependence on the following prohibited concomitant medications: estrogen, progestin , activated charcoal, microsomal enzyme-inducing drugs, anticonvulsants [e.g., hydantoins, phenytoin, carbamazepine, oxcarbazepine, topiramate, felbamate, prametin], barbiturates, antibiotics [e.g., rifabutin or rifampin], ritonavir, nelfinavir, atorvastatin, bosentan, griseofulvin, phenylbutazone, St. John's wort [Hypericum perforatum], drugs that increase serum potassium [ACE inhibitors, angiotensin-H receptor antagonists, potassium-sparing diuretics, potassium supplements, heparin, aldosterone antagonists, and NSAIDs]; Planned surgery within the expected timeframe of participation in this trial that requires discontinuation of oral contraceptives; regular concurrent use of barrier methods, spermicides, IUDs, or other contraceptive measures (except for occasional use due to risk of infection); signs or history of neurotic personality, psychosis, or suicide; participation in a trial of another investigational drug or device concurrent with this trial or less than 90 days prior to entry into the trial, or prior participation in such a trial; employee of the investigator or trial site, or family member of an employee or investigator; any condition that, in the opinion of the investigator, could jeopardize the conduct of the trial according to this protocol.

[0284] d) Evaluation criteria

[0285] d.1) Efficacy

[0286] - Main: Overall Pell Index (Overall PI);

[0287] - Secondary: PI for method failure; adjusted PI for backup contraception; pregnancy rate.

[0288] d.2) Safety / tolerability

[0289] Proportion of subjects with unscheduled bleeding / spotting during Cycles 2-6; proportion of subjects with unscheduled bleeding / spotting for each cycle in Cycles 2-9 and cumulatively for Cycles 2-6 and Cycles 2-9; number of days with bleeding / spotting during Cycles 2-4; number of days with bleeding / spotting during Cycles 7-9; number of days with bleeding / spotting during Cycles 2-9; number of episodes of bleeding / spotting during Cycles 2-4; number of episodes of bleeding / spotting during Cycles 7-9; number of episodes of bleeding / spotting during Cycles 2-9; proportion of subjects with amenorrhea; change in weight from baseline (V1a); change in systolic and diastolic blood pressure from baseline (V1a); adverse events (AEs); pulse rate; electrocardiogram (ECG) for subgroups of subjects; clinical laboratory parameters; specific clinical laboratory parameters (hemostatic variables, carbohydrate metabolism, and bone metabolism) for subgroups of subjects.

[0290] d.3) Statistical methods

[0291] d.3.1) Efficacy parameters

[0292] The primary efficacy variable, defined as the overall PI, will be analyzed in the full analysis set (FAS) and per-protocol set (PPS). The primary efficacy assessment will be based on the FAS. A two-sided 95% confidence interval (CI) for the overall PI will be calculated, assuming a Poisson distribution of pregnancy events. Secondary efficacy analyses will be based on the FAS. A two-sided 95% CI for the PI for method failure will be calculated. A Clopper-Pearson 95% confidence interval for the pregnancy rate will be calculated. The cumulative pregnancy rate will be calculated using the Kaplan-Meier estimator. A two-sided 95% CI will be calculated for the adjusted PI for backup contraception.

[0293] d.3.2) Safety and tolerability parameters

[0294] The analysis of parameter blood pressure, weight and bleeding pattern will be based on FAS. The analysis of safety endpoint will be carried out using only the safety analysis set. All adverse events (AE) and treatment-emergent adverse events (TEAE) will be summarized by calculating the number and percentage of subjects with AE by preference and system organ class. In addition, TEAE will be summarized by severity and relationship with treatment. The number and percentage of TEAEs that cause the study to terminate will be provided. Laboratory parameters, pulse rate and abnormal ECG results (such as QT prolongation) will be summarized by calculating absolute values and summary statistics of the changes from V1a (specific laboratory parameters and ECG: V1b) to V3, V4 and V5. A shift table will be provided to illustrate the changes relative to the laboratory normal range between V1a and V5 (or EDV). The number and percentage of subjects with values outside the clinical significance limit will be summarized.

[0295] 2 / Results

[0296] As shown in Table 1 below, overweight women (BMI 25 kg / m2) treated with DRSP had a significantly higher risk of developing leukemia compared to non-overweight women receiving the same contraceptive treatment. 2 or higher) had significantly fewer days of bleeding and / or spotting.

[0297] Table 1: Number of days with spotting and / or bleeding during the treatment cycle in overweight women compared to non-overweight women treated with DRSP.

[0298]

[0299]

[0300] N: number of subjects in the test group in the specific BMI group

[0301] n: number of subjects with available data

[0302] SD: Standard deviation

[0303] As shown in Table 2 below, the number of days with bleeding and / or spotting was significantly reduced in obese women treated with DRSP compared to non-obese women taking the same contraceptive treatment.

[0304] Table 2: Number of days with spotting and / or bleeding during the treatment cycle in obese women compared to non-obese women treated with DRSP.

[0305]

[0306]

[0307] N: Number of subjects in the test group in a specific BMI group

[0308] n: number of subjects with available data

[0309] SD: Standard deviation

[0310] Example 2 - Correlation between BMI and DRSP-based treatment on the one hand and weight change and heart rate change on the other hand

[0311] 1 / Method

[0312] In Example 2, the LF111 formulation described in Example 1 was used.

[0313] The CF111 / 301 clinical trial protocol included 713 healthy, sexually active women willing to use oral contraceptives recruited at approximately 41 centers in five countries (Hungary, Poland, Czech Republic, Germany, and Romania).

[0314] After signing informed consent at Visit 1a (Screening) and receiving study drug at Visit 1b, eligible subjects will attend Visits 2 through 6 on Days 24 ± 2 of Cycles 1, 3, 6, 9, and 13. Follow-up (Visit 7) will occur 10 to 28 days after Visit 6. At least 515 subjects will complete each of the 13 cycles of the study.

[0315] The dataset has information on demographic and clinical parameters, gynecological and medical history data, laboratory and vital signs evaluations, data related to prior / concomitant medications / contraceptive devices.

[0316] Statistics p values were calculated by using Fisher's exact test and were found to be significant at a threshold of p ≤ 0.05.

[0317] 2 / Results

[0318] For obesity (BMI ≥ 30 kg / m 2 ) women, a trend toward decreases in weight and heart rate from Visit 1 (measured at baseline) to Visit 6 (measured at the end of the study).

[0319] BMI group (BMI < 30 and BMI ≥ 30 kg / m 2 ) The distribution of changes in weight and heart rate for women from visit 1 to visit 6 is shown in Figure 1 and 2 .

[0320] Linear model analysis showed that the effect of BMI group in the changes of weight (F-statistic: 14.49 on 1, DF of 668, p-value: 0.0001541) and heart rate (F-statistic: 4.947 on 1, DF of 666, p-value: 0.02647) from visit 1 to 6 was statistically significant.

[0321] Example 3 - Reduced Side Effects of DRSP-Based Therapy in Obese Women

[0322] 1 / Method

[0323] The CF111 / 1SS clinical trial protocol included 1571 (1500 + 71) healthy, sexually active women willing to use oral contraceptives recruited at approximately 114 centers in Austria, the Czech Republic, Germany, Hungary, Poland, Romania, Slovakia, and Spain. A separate study was conducted in a non-obese group of women (BMI < 30 kg / m 2 ) and obese female group (BMI ≥ 30 kg / m 2 ).

[0324] 2 / Results

[0325] Table 3 describes the quantitative results of TEAEs (treatment emergent adverse events) in the group of women who used the composition comprising drospirenone according to the present invention ("LF111") for contraception. 2 ) and obese women (BMI ≥ 30 kg / m 2 ).

[0326] The results disclosed in Table 3 indicate that the percentage of TEAEs in women using the DRSP-POC formulation was similar regardless of whether the women were obese or non-obese.

[0327] Therefore, the results indicate that obese women should have a high observance rate for the formulation comprising drospirenone according to the present invention.

[0328] Table 3: Incidence of TEAEs by BMI Subgroup in Individuals Treated with LF111

[0329]

[0330]

[0331] N: the number of subjects in a specific treatment group

[0332] n: number of subjects with adverse events

[0333] %: Percentage based on N

[0334] [a] TEAE: Treatment-emergent adverse event. TEAEs are defined as AEs that begin on or after the first IMP administration and include those that begin before the first IMP administration but worsen after the first administration. Adverse events that begin after the last IMP administration but within the follow-up period after the last IMP administration will be considered treatment-emergent.

[0335] Heart rate is understood to be the number of heartbeats per minute of a person at rest (e.g., not exercising). Preferably, heart rate can be measured after the patient has been lying down for at least 5 minutes, preferably at least 10 minutes, and most preferably at least 15 minutes. Alternatively, heart rate can be measured upon waking in the morning and before getting out of bed. Heart rate is an important health indicator.

[0336] Although a normal heart rate for an adult can be about 60 to about 100 beats per minute, a lower heart rate indicates more efficient heart function and cardiovascular health. Although overweight and obese women are often observed to have higher heart rates than women of normal weight, a faster heart rate has also been found to be a warning sign of increased cardiovascular problems and a predictor of obesity in later life. Women with higher heart rates have been found to be more susceptible to obesity and diabetes. 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, diabetes, blood clot formation that can lead to stroke or heart attack, heart failure, fainting, and even sudden death.

[0337] Therefore, heart rate reduction is very desirable, especially for overweight or obese women, because reducing heart rate can lead to a reduced risk of developing various adverse health conditions. It is believed that reducing heart rate by at least 5 beats per minute, at least 10 beats per minute, and at least 15 beats per minute will significantly reduce this risk factor.

[0338] Example 4 - Comparison of Bleeding or Spotting Events Observed in Obese Women Using DRSP-Based Therapy According to the Invention and Desogestrel-Based Therapy

[0339] 1 / Purpose

[0340] The following study, CF111 / 302, represents a pivotal, multicenter, double-blind, double-dummy, randomized trial of the contraceptive efficacy, tolerability, and safety of LF111 (DRSP) compared with desogestrel 0.075 mg (Cerazette) over 9 cycles.

[0341] The first objective was to demonstrate the contraceptive efficacy of LF111, and the second objective was to demonstrate the safety and tolerability of LF111 compared with desogestrel 0.075 mg, particularly with regard to bleeding patterns.

[0342] 2 / Materials and Methods

[0343] a) Test and reference products, dosages and routes of administration

[0344] Two tablets were administered orally during the trial:

[0345] - LF111 film-coated tablets (test product: 24 tablets containing 4 mg DRSP followed by 4 placebo tablets: León Farma). The formulation of LF111 tablets is disclosed in Example 1 (see Section 2, subsection a)).

[0346] - Desogestrel 0.075 mg film-coated tablets (reference product: 28 active tablets, NV Organon).

[0347] b) Experimental design

[0348] Methods: A prospective, multicenter, randomized, double-blind, double-dummy trial was conducted in approximately 1200 women (857 with LF111 and 343 with desogestrel 0.075 mg; randomization ratio 5:2) at approximately 88 centers in Austria, the Czech Republic, Germany, Hungary, Poland, Romania, Slovakia, and Spain who were at risk of pregnancy, aged 18-45 years, and had a systolic blood pressure <140 mmHg or a diastolic blood pressure <90 mmHg.

[0349] After providing informed consent at Visit 1a (Screening; V1a) and receiving study medication at Visit 1b, subjects will attend Visits 2 to 4 on Days 24 ± 2 of Cycles 1, 3, and 6, and Visit 5 (V5) on Days 29 + 2 of Cycle 9. Follow-up (Visit 6; V6) will be conducted 7-10 days after the last LF111 intake.

[0350] The planned total duration of the trial was set at 16 months, with a maximum of 6 months for the recruitment process, 9 months for the contraceptive treatment itself, and 10 days for the follow-up step. The duration of contraceptive treatment for each woman was 9 x 28 days.

[0351] c) Exclusion criteria

[0352] See the relevant sections of Example 1 above.

[0353] d) Evaluation criteria

[0354] See the relevant sections of Example 1 above.

[0355] 3 / Results

[0356] Tables 4 and 5 show the effects of the DRSP-based treatment according to the present invention (LF111) and the desogestrel-based treatment (which can be used as Comparison of bleeding or spotting events observed in obese women treated with dapoxetine (available as a commercially available pill).

[0357] Table 4: Obese female individuals (BMI ≥ 30 kg / m 2 Bleeding or spotting events observed in

[0358]

[0359] Table 5: Normal or overweight female individuals (BMI < 30 kg / m 2 Bleeding or spotting events observed in

[0360]

[0361] It was observed that obese female subjects administered the drospirenone-based contraceptive treatment disclosed herein experienced significantly fewer bleeding or spotting events across all cycle phases analyzed compared to obese female subjects receiving treatment based on a contraceptive composition comprising desogestrel.

[0362] On the contrary, BMI below 30 kg / m 2 female individuals (including individuals of normal weight or individuals with excess weight) experience the same or equivalent bleeding or spotting events regardless of which contraceptive treatment they receive.

Claims

1. Use of drospirenone in an amount of 3.5 mg to 4.5 mg in a daily active dosage unit as the sole contraceptive ingredient in the preparation of a contraceptive kit for obese female patients, wherein the female patient has a BMI of 30 kg / m 2 or higher.

2. The method according to claim 1, wherein the contraceptive kit comprises one or more packaging units, wherein each packaging unit comprises 21 to 28 daily active dosage units, wherein: a) each daily active dosage unit contains 3.5 mg to 4.5 mg of drospirenone and contains no estrogen, and b) Each daily active dosage unit comprises drospirenone in a form such that: (i) not more than 50% of the drospirenone initially present in the daily active dosage unit dissolves within 30 minutes, and (ii) at least 50% of the drospirenone dissolves within a period of 3 hours to 4 hours, The percentage of drospirenone correlates to the amount of drospirenone initially present in the daily active dosage unit when the daily active dosage is subjected to in vitro dissolution testing according to the USP XXIII paddle method.

3. The use according to claim 2, wherein the one or more packaging units further comprise 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.

4. The use according to claim 2, wherein each packaging unit comprises 24 daily active dosage units.

5. The use according to claim 4, wherein each packaging unit comprises 4 daily placebo dosage units.

6. The use according to any one of claims 1 to 5, wherein the drospirenone is in crystalline form.

7. The use according to any one of claims 1 to 5, wherein the drospirenone is in a non-micronized form.

8. The use according to any one of claims 1 to 5, wherein the d of the drospirenone is 50 Less than 70μm.

9. The use according to any one of claims 1 to 5, wherein the drospirenone is in the form of particles.

10. The use according to any one of claims 1 to 5, wherein the content of drospirenone in each daily active dosage unit is 4 mg.

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