US 20120128733A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0128733 A1 PERRIN et al. (43) Pub. Date: May 24, 2012

(54) PHARMACEUTICAL COMPOSITIONS Publication Classi?cation COMPRISING ACTIVE DRUGS, (51) Int Cl CONTRACEPTIVE KITS COMPRISING 1462K é1/585 (200601) ACTIVE DRUGS, AND METHODS OF A61K 31/56 (200601) ADMINISTERING THE SAME B29B 9/00 (200601) B28B 1 7/00 (2006.01) (76) Inventors: Philippe PERRIN, Paris (FR); Jose 3283 1/08 (2006.01) Luis VELADA, Amersfoort (N L); A61K 9/00 (2006.01) Dominique DROUNIN, Verrieres C07] 53/00 (2006.01) (FR) (52) US. Cl...... 424/400; 514/170; 514/171; 514/175; 540/15; 264/162; 264/69; 264/5; 264/9

(22) Filed: Jun_ 28 2011 The present invention relates to pharmaceutical compositions ’ and kits comprising pharmaceutical compositions, and meth . . ods for administering pharmaceutical compositions compris Related U's' Apphcatlon Data ing active contraceptive drugs in a patient. Speci?cally, the (60) Provisional application No. 61/368,396, ?led on Jul. Pharmaceutical Compositions may COmpriSe 28, 2010. only contraceptives (“POC”), such as .

Patent Application Publication May 24, 2012 Sheet 2 0f 8 US 2012/0128733 A1

‘i“i 33.6@933

3331}

Tim {it}

?gwa 2

P a t e n t A w 2 0 3 3 A 1

M‘

27.... M Xb m@ um...5.. 522{I 3.U S mw2

a2i Wméwwwwuammzn?wuwgammaawwmMEN?”?m?$33?wgm?gu“mggw? .N,.:4 32 f,1 c3 ,.f k1nu.)a v7.8a. .. QMa,‘l.,201» i313?) ai Ks.”MU2l. a”8,Q,6*Q”.n 0‘.. 0n0‘.

Q5&a 54

a4i. Q\v9“W. Y.2, n“WQ,. ‘$55 5 ‘5wnMN &mw,a 1 nu0 aw1 .nwnwmz mNM4Sa”

WU...,,.....

av, 3Q

%d

WM Patent Application Publication May 24, 2012 Sheet 5 0f 8 US 2012/0128733 A1

Figure {is Patent Application Publication May 24, 2012 Sheet 6 0f 8 US 2012/0128733 A1

mm

am ->

aim ~

jiw .

?fL-Q “

5% w "A?a?$83?ziissaiiztimw-ma?wga 136,-6 - 395:; ‘~

_

me ~ '

£232 ' {m

iF'igwa 5a Patent Application Publication May 24, 2012 Sheet 7 0f 8 US 2012/0128733 A1

Figu re 63 Patent Application Publication May 24, 2012 Sheet 8 0f 8 US 2012/0128733 A1 US 2012/0128733 A1 May 24, 2012

PHARMACEUTICAL COMPOSITIONS [0008] Drospirenone as a contraceptive ingredient is avail COMPRISING ACTIVE DRUGS, able only in oral combined pills such as those marketed under CONTRACEPTIVE KITS COMPRISING the name ofYasmin® (3 mg DRSP/30 ug ), ACTIVE DRUGS, AND METHODS OF YaZ® (3 mg DRSP/20 ug ethinylestradiol) and Yasminelle® ADMINISTERING THE SAME (3 mg DRSP/20 ug ethinylestradiol). These pills comprise ethinylestradiol Which acts to increase the inhibi tory effect of drospirenone and to ensure contraception and [0001] This application claims priority under 35 U.S.C. cycle stability. The patent application WO2008031631 §1 19 to US. Provisional PatentApplication 61/368,396, ?led describes combined oral contraceptives in Which dro Jul. 28, 2010. spirenone is used as a progestative agent and ethinylestradiol is replaced by the phytoestrogen 8-prenylnaringenin. These FIELD OF THE INVENTION contraceptives may be included in modi?ed release formula tions of 8-prenylnaringenin and drospirenone Which may [0002] The present invention relates to the ?eld of contra continuously distribute the active ingredients for the gastro ceptive kits, pharmaceutical compositions and methods of intestinal transit time of generally 12 h-16 h. administering and uses for the kits and pharmaceutical com positions. [0009] The commercially available contraceptives Yas min®, YaZ® and Yasminelle® comprise drospirenone in a microniZed form Which promotes its rapid dissolution BACKGROUND OF THE INVENTION and ensures its good oral . It is also the case for [0003] Several contraceptives Which comprise synthetic Angeliq® Which is a replacement medicament com and no oestrogen are commercially available. bining drospirenone and . HoWever, such formula These contraceptives called “progestogen-only contracep tions are characterized by a high plasma concentration peak tives” encompass implants, uterine delivery systems and for drospirenone after oral intake. High plasma concentra pills. tions are not preferred in patients treated With drospirenone [0004] Progestogen only contraceptives (“POC”) have the because of a correlation betWeen high Cmax and certain unde advantage of avoiding the combined administration of estro sirable side effects as Well as poor general tolerance When gens as compared to traditional contraceptive combined pills. hormonal levels ?uctuate too much each and every day. POCs, hoWever, display several major drawbacks. Because of [0010] Accordingly, there is still a need in the art for novel their loW contraceptive reliability, POCs have to be taken each contraceptive kits and for novel pharmaceutical compositions day at the same time Without a pill-free or placebo interval. comprising drospirenone. [0005] The bleeding patterns for Women Who take POCs may be also be altered deeply as compared to the natural SUMMARY OF THE INVENTION menstrual cycle, since or unscheduled bleeding or spotting may occur. Accordingly, POCs are poorly used [0011] The present invention provides pharmaceutical and are usually indicated for Women Who cannot tolerate compositions and kits comprising pharmaceutical composi , for Women in post-partum period and for Women tions, and methods for administering pharmaceutical compo Who are breast-feeding (Amy, Tripathi, 2009, BMJ, 339, 563 sitions for preventing in a patient. The pharmaceu 568; Mandisk, 2008, OBsTETRIC MEDICINE, 1, 78-87). tical compositions may comprise active drugs such as active [0006] Drospirenone (CAS: 67392-87-4; 6b,7b:15b,16b contraceptive drugs. Speci?cally, the active drugs may com Dimethylen-3 -oXo-17a-pregn-4-ene-21,17-carbolactone) is prise progestogen-only contraceptives (“POC”) for inhibiting a synthetic progestogen With a pharmacological pro?le very ovulation. In speci?c embodiments, the pharmaceutical com closely related to that of natural . Drospirenone positions and kits and methods of administering the pharma (“DRSP”) is devoid of androgenic, glucocorticoid and anti ceutical compositions alloW for novel dosing regimens of glucocorticoid activity but does possess potent antimineralo POCs and provide pharrnacokinetic pro?les that re?ect these corticoid and antiandrogenic properties. It Was shoWn that novel dosing regimens. oral daily doses of at least 3 mg of drospirenone are able to [0012] In one embodiment, the pharmaceutical composi inhibit ovulation over a single treatment cycle of 21 days. The tion of the present invention may comprise an active contra combination of 3 mg drospirenone/30 ug ethinylestradiol ceptive drug, Wherein the pharmaceutical composition alloWs provides a reasonable contraceptive safety margin by inhib for a 28 day daily dosing regimen, and Wherein after initial iting ovulation With a loW frequency of follicular maturation administration of the active contraceptive drug has estab (Rosenbaum et a1., 2000, THE EUROPEAN JOURNAL OF CON lished its contraceptive effect in a patient, the patient may skip TRACEPTION AND REPRODUCTIVE HEALTH CARE, 5, 16-24). up to 4 doses Within any 28 day daily dosing regimen period. [0007] Drospirenone (DRSP) is thus an appropriate In a speci?c embodiment, the skipped up to 4 doses may be on progestin ingredient Which may avoid the side-effects occur non-consecutive days. In another speci?c embodiment, the ring With conventional synthetic progestogens such as Weight skipped up to 4 doses may be on consecutive days. In another gain and breast tension When combined With an estrogen for embodiment of the present invention, the pharmaceutical use as a contraceptive. DRSP is also likely to minimiZe ?uid composition may further alloW during the 28 day daily dosing retention and to have neutral effects on metabolic and vascu regimen for the patient to skip up to tWo non-consecutive days lar risks (Blode et a1., 2000, THE EUROPEAN JOURNAL OF of the active contraceptive drug, provided the active contra CONTRACEPTION AND REPRODUCTIVE HEALTH CARE, 5, 256 ceptive drug skipped dose is taken Within about 24 hrs after 264; Sitruk-Ware, 2006, HUMAN REPRODUCTION UPDATE, 12, the up to tWo skipped non-consecutive days. In another 169-178). It has been also reported that drospirenone may embodiment, the active contraceptive drug may inhibit ovu treat moderate because of its Well-established anti-an lation. In another embodiment, the contraceptive effect may drogenic properties. comprise inhibiting ovulation. US 2012/0128733 A1 May 24, 2012

[0013] In another speci?c embodiment, the active contra tion may comprise administering a composition comprising ceptive drug may be a progestogen-only contraceptive an active contraceptive drug, Wherein the pharmaceutical (POC). In another speci?c embodiment, the POCs may be composition alloWs for a 28 day daily dosing regimen, and selected from one or more of the group consisting of dro Wherein after initial administration of the active contraceptive spirenone, 17-hydroxy progesterone esters, 19-nor-17-hy drug has established its contraceptive effect in a patient, the droxy progesterone esters, 170t-ethinyltestosterone and patient may skip up to 4 doses Within any 28 day daily dosing derivatives thereof, 170t-ethinyl-19-nor- and regimen period. In a speci?c embodiment, the skipped up to derivatives thereof, norethindrone, norethindrone acetate, 4 doses may be on non-consecutive days. In another speci?c ethynodiol diacetate, , medroXy-progesterone embodiment, the skipped up to 4 doses may be on consecutive acetate, norethynodrel, , lynoestrenol, days. In another embodiment of the present invention, the fuingestanol acetate, , , dimethi methods may comprise administering pharmaceutical com derome, ethisterone, acetate, , positions Which further alloWs during the 28 day daily dosing , d-170t-acetoXy-13[3-ethyl-170t-a-ethinyl-gon-4 regimen for the patient to skip up to tWo non-consecutive days en-3-one oxime, , , , of the active contraceptive drug, provided the active contra etonorgestrel, , , chlormadione ceptive drug skipped dose is taken Within about 24 hrs after and . In a speci?c embodiment, the POC may be the up to tWo skipped non-consecutive days. In another spe drospirenone. In another speci?c embodiment, each daily ci?c embodiment, the kits may comprise pharmaceutical dose of drospirenone may comprise a dosage amount of at compositions comprising an active contraceptive drug With least about 2 mg. the above-described pharmacokinetic parameters. In another [0014] In another speci?c embodiment, the pharmaceutical speci?c embodiment, the active contraceptive drug may be a compositions may also have a particular pharmacokinetic progestogen-only contraceptive (POC). In another speci?c pro?le. In one embodiment, the present invention may be a embodiment, the POC may be drospirenone. In another pharmaceutical composition Wherein each daily dose of the embodiment, drospirenone may be the only administered active contraceptive drug, When orally administered to a active contraceptive drug. patient in fasting conditions, provides a pharmacokinetic pro [0020] In another embodiment of the present invention, the ?le for the active contraceptive drug having: patient may have a higher risk for developing a complication [0015] i) a Tmax ranging from about 2.2 hrs to 6 hrs; and from the administration of an estrogen than the general popu [0016] ii) a mean Cmax Which is less than about 30 ng/ml. lation. In a speci?c embodiment, the complication from the [0017] In a speci?c embodiment, the pharmacokinetic pro administration of an estrogen may be due to the patient having ?le for the active contraceptive drug may additionally com one or more conditions or characteristics selected from the prise an AUCOh_?aSt Which is at least 300 ng.h/ml. In another group consisting of a higher risk for developing thromboem speci?c embodiment, the AUCOh_?aSt may be at least 350 bolism than the general population, acquired or genetic ng.h/ml. In another speci?c embodiment, the mean Cmax may thrombophilia or hypercoagulability, an age of 35 years or range from about 15 ng/ml to about 30 ng/ml. In another over Who smoke cigarettes, a higher risk for stroke than the speci?c embodiment, the active contraceptive drug With the general population, sickle-cell disease or sickle-cell anemia, above pharmacokinetic parameters may be a POC. In another a higher risk than the general population for myocardial inf speci?c embodiment, the POC may be drospirenone. In arction, and Women currently lactating. another embodiment, drospirenone may be the only admin [0021] In another embodiment of the present invention, the istered active contraceptive drug. patient may be a Woman and have one or more conditions or [0018] In another speci?c embodiment, a kit may comprise characteristics selected from the group consisting of being the pharmaceutical compositions described above. In a spe predisposed to hyperkalemia, suffering from kidney, liver or ci?c embodiment, the kit may comprise one or more packag adrenal diseases, and being on daily, long-term treatment for ing units Wherein each packaging unit comprises up to 28 a chronic condition With medications predisposed to hyper daily active dosage units comprising an active contraceptive kalemia. In a speci?c embodiment, the medications predis drug in a pharmaceutical composition, Wherein the pharma posed to hyperkalemia may be selected from one or more of ceutical composition alloWs for a 28 day daily dosing regi the group consisting of a non steroidal anti-in?ammatory, men, and Wherein after initial administration of the active potassium-sparing diuretics, potassium supplementation drug has established its contraceptive effect in a patient, the medication, angiotensin-converting (ACE) inhibi patient may skip up to 4 doses Within any 28 day daily dosing tors, angiotensin-II receptor antagonists and heparin. In regimen period. In a speci?c embodiment, the skipped up to another speci?c embodiment, the patient may be in need to 4 doses may be on non-consecutive days. In another speci?c improve tolerance for s drospirenone. In another speci?c embodiment, the skipped up to 4 doses may be on consecutive embodiment, the patient may be preparing for Hormone days. In another embodiment of the present invention, the kits Replacement Therapy medicaments. may provide pharmaceutical compositions that further alloW [0022] In another embodiment, the methods of the present during the 28 day daily dosing regimen for the patient to skip invention may comprise producing a pharmacokinetic pro?le up to tWo non-consecutive days of the active contraceptive of an active drug in a patient, Wherein the pharmacokinetic drug, provided the active contraceptive drug skipped dose is pro?le comprises a mean Tmax ranging from about 2.2 hrs to taken Within about 24 hrs after the up to tWo skipped non about 6 hrs, and a mean Cmax Which is less than about 30 consecutive days. In another embodiment, the active contra ng/ml, Wherein the pharmacokinetic pro?le is measured in ceptive drug may inhibit ovulation. In another embodiment, said patient after orally administering a single daily dosage the contraceptive effect may comprise inhibiting ovulation. unit of said active drug to said patient in fasting conditions. In [0019] The present invention also includes methods of another speci?c embodiment, the pharmacokinetic pro?le administering the pharmaceutical compositions described may additionally comprise an AUCOh_?aSt Which is at least above. In one embodiment, the methods of the present inven about 300 ng.h/ml. In another speci?c embodiment, the US 2012/0128733 A1 May 24, 2012

AUCOh_?aSt may be at least about 350 ng.h/ml. In another lynoestrenol, fuingestanol acetate, medrogestone, norg speci?c embodiment, the active drug may be an active con estrienone, dimethiderome, ethisterone, cyproterone acetate, traceptive drug. In another embodiment, the active contracep levonorgestrel, norgestrel, d- l 70t-acetoxy- l 3 [3-ethyl- l 70t-a tive drug may inhibit ovulation. In another speci?c embodi ethinyl-gon-4-en-3 -one oxime, cyproterone acetate, ment, the active contraceptive drug may be a POC. In another gestodene, desogestrel, etonorgestrel, norgestimate, norel speci?c embodiment, the POC may be selected from one or gestromin, chlormadione and dienogest. In another embodi more of the group consisting of drospirenone, l7-hydroxy ment, the POC may be drospirenone. In another speci?c progesterone esters, l9-nor-l7-hydroxy progesterone esters, embodiment of the present invention, each daily dosage unit l 70t-ethinyltesto sterone and derivatives thereof, 1 70t-ethinyl may comprise a dosage amount of at least about 2 mg. l9-nor-testosterone and derivatives thereof, norethindrone, [0028] In another embodiment, the patient may be a Woman norethindrone acetate, ethynodiol diacetate, dydrogesterone, and have one or more conditions or characteristics selected medroXy-progesterone acetate, norethynodrel, allylestrenol, from the group consisting of being predisposed to hyperkale lynoestrenol, fuingestanol acetate, medrogestone, norg mia, suffering from kidney, liver or adrenal diseases, and estrienone, dimethiderome, ethisterone, cyproterone acetate, being on daily, long-term treatment for a chronic condition levonorgestrel, norgestrel, d- l 70t-acetoxy- l 3 [3-ethyl- l 70t-a With medications predisposed to hyperkalemia. In a speci?c ethinyl-gon-4-en-3-one oxime, cyproterone acetate, embodiment, the medications predisposed to hyperkalemia gestodene, desogestrel, etonorgestrel, norgestimate, norel may be selected from one or more of the group consisting of gestromin, chlormadione and dienogest. In another speci?c a non steroidal anti-in?ammatory, potassium-sparing diuret embodiment, the POC may be drospirenone. In another spe ics, potassium supplementation medication, angiotensin ci?c embodiment, drospirenone may be the only adminis converting enZyme (ACE) inhibitors, angiotensin-II receptor tered active drug that inhibits ovulation. antagonists and heparin. In another speci?c embodiment, the [0023] In another embodiment of the present invention, the patient may be in need to improve tolerance for s dro methods may include administering to a patient the compo spirenone. In another speci?c embodiment, the patient may sitions provided above. In another embodiment, the patient be preparing for Hormone Replacement Therapy medica may be a Woman and have one or more conditions or charac ments. teristics selected from the group consisting of being predis [0029] In another embodiment of the present invention, the posed to hyperkalemia, suffering from kidney, liver or adrenal pharmaceutical compositions may comprise active drugs diseases, and being on daily, long-term treatment for a chronic condition With medications predisposed to hyper characterized by dissolution tests. In a speci?c embodiment, a pharmaceutical composition may comprise an active drug, kalemia. In a speci?c embodiment, the medications predis Wherein: posed to hyperkalemia may be selected from one or more of the group consisting of a non steroidal anti-in?ammatory, [0030] (a) a daily active oral dosage unit of the compo potassium-sparing diuretics, potassium supplementation sition comprises an amount of said active drug of at least medication, angiotensin-converting enZyme (ACE) inhibi 2 mg, and tors, angiotensin-II receptor antagonists and heparin. In [0031] (b) the daily active oral dosage unit comprises the another speci?c embodiment, the patient may be in need to active drug in a form such that When subjected to an in improve tolerance for s drospirenone. In another speci?c vitro dissolution test according to the USP XXIII Paddle embodiment, the patient may be preparing for Hormone Method: Replacement Therapy medicaments. [0032] (i) no more than 50% of the active drug initially [0024] In another embodiment of the present invention, the present in the daily active dosage unit is dissolved pharmaceutical compositions may include active drugs that Within 30 minutes, and produce certain pharmacokinetic pro?les. In a speci?c [0033] (ii) at least 50% of the active drug is dissolved embodiment, the pharmaceutical composition may comprise in a time range from 3 hours to 4 hours. an active drug, Wherein a single daily dosage unit of the [0034] In another speci?c embodiment, the active drug may composition, When orally administered to a patient in fasting be an active contraceptive drug. In another embodiment, the conditions provides a pharmacokinetic pro?le for the active active contraceptive drug may inhibit ovulation. In another drug having: speci?c embodiment, the active contraceptive drug may be a [0025] i) a Tmax ranging from about 2.2 hrs to 6 hrs; and POC. In another embodiment, the POC may be selected from [0026] ii) a mean Cmax Which is less than about 30 ng/m. one or more of the group consisting of drospirenone, l7-hy [0027] In another speci?c embodiment, the pharmacoki droxy progesterone esters, l9-nor-l7-hydroxy progesterone netic pro?le may also include an AUCOh_?aSt Which is at least esters, l70t-ethinyltestosterone and derivatives thereof, 170. 300 ng.h/ml. In another speci?c embodiment, the AUCOh_?aSt ethinyl- l 9-nor-testo sterone and derivatives thereof, norethin may be at least 350 ng.h/ml. In another speci?c embodiment, drone, norethindrone acetate, ethynodiol diacetate, dydroges the active drug may be an active contraceptive drug. In terone, medroXy-progesterone acetate, norethynodrel, another embodiment, the active contraceptive drug may allylestrenol, lynoestrenol, fuingestanol acetate, medroge inhibit ovulation. In another speci?c embodiment, the active stone, norgestrienone, dimethiderome, ethisterone, cyproter contraceptive drug may be a POC. In another embodiment, one acetate, levonorgestrel, norgestrel, d-l70t-acetoxy-l3[3 the POC may be selected from one or more of the group ethyl-l70t-a-ethinyl-gon-4-en-3 -one oxime, cyproterone consisting of drospirenone, l7-hydroxy progesterone esters, acetate, gestodene, desogestrel, etonorgestrel, norgestimate, l9-nor-l7-hydroxy progesterone esters, l70t-ethinyltest norelgestromin, chlormadione and dienogest. In another osterone and derivatives thereof, l70t-ethinyl-l9-nor-test embodiment, the POC may be drospirenone. In another osterone and derivatives thereof, norethindrone, norethin embodiment, each daily dosage unit of drospirenone may drone acetate, ethynodiol diacetate, dydrogesterone, comprise a dosage amount of at least about 2.0 mg to about medroXy-progesterone acetate, norethynodrel, allylestrenol, 6.0 mg. In a speci?c embodiment, the each daily dosage unit US 2012/0128733 A1 May 24, 2012

of drospirenone may comprise a dosage amount of at least dro spirenone. In a speci?c embodiment, the contraceptive kit about 3.0 mg to about 4.5 mg. may comprise one or more packaging units Wherein each [0035] The present invention may also include kits that packaging unit comprises 21 to 28 daily active dosage units comprise one or more packaging units Wherein each packag and Wherein ing unit comprises dosage units With an active drug that [0041] (a) the amount of drospirenone in each daily provides certain pharmacokinetic parameters. In a speci?c active dosage unit is at least 2 mg Without estrogen, and embodiment, the kit may comprise one or more packaging [0042] (b) each daily active dosage unit comprises dro units Wherein each packaging unit comprises 21 to 28 daily spirenone in a form such that When subjected to an in active dosage units comprising an active drug and Wherein a vitro dissolution test according to the USP XXIII Paddle single active dosage unit, When orally administered under Method: fasting conditions, is adapted to provide a pharmacokinetic [0043] (i) no more than 50% of the drospirenone ini pro?le for the active drug consisting of one or more of the tially present in the said daily active dosage unit is pharmacokinetic parameters selected from the group consist dissolved Within 30 minutes and (ii) at least 50% of ing of: the said drospirenone is dissolved in a time range from [0036] i) a Tmax ranging from about 2.2 hrs to 6 hrs; and 3 hours to 4 hours. [0037] ii) a mean Cmax Which is less than about 30 ng/ml. [0044] In a speci?c embodiment, drospirenone may be the [0038] In another speci?c embodiment, the pharmacoki sole contraceptive ingredient. In another speci?c embodi netic pro?le may also comprise anAUCOh_?aStWhich is at least ment, the amount of drospirenone in each daily active unit 300 ng.h/ml. In another speci?c embodiment, the AUCOh_?aSt dosage may range from about 2.0 mg to about 6.0 mg. In may be at least 350 ng.h/ml. In another embodiment, the another speci?c embodiment, the amount of drospirenone in mean Cmax may range from about 15 ng/ml to about 30 ng/ml. each daily active unit dosage may range from about 3 .0 mg to In another speci?c embodiment, the active drug may be an about 4.5 mg. active contraceptive drug. In another embodiment, the active [0045] One embodiment of the present invention may contraceptive drug may inhibit ovulation. In another speci?c include pharmaceutical compositions comprising progesto embodiment, the active contraceptive drug may be a POC In gen-only contraceptive (POC) de?ned by a d50 particle siZe. another embodiment, the POC may be selected from one or In a speci?c embodiment, the POC may have a d50 particle more of the group consisting of drospirenone, l7-hydroxy siZe Which ranges from about 10 pm to about 60 pm. In a progesterone esters, l9-nor-l7-hydroxy progesterone esters, speci?c embodiment, the d50 particle siZe may range from l 70t-ethinyltesto sterone and derivatives thereof, 1 70t-ethinyl about 10 pm to about 30 um. In another speci?c embodiment, l9-nor-testosterone and derivatives thereof, norethindrone, the surface area of the particles may be from about 2000 norethindrone acetate, ethynodiol diacetate, dydrogesterone, cm2/ g to about 8500 cm2/ g. In another speci?c embodiment, medroXy-progesterone acetate, norethynodrel, allylestrenol, the surface area of the particles may be from one or more lynoestrenol, fuingestanol acetate, medrogestone, norg selected from the group consisting of about 2000 cm2/g, estrienone, dimethiderome, ethisterone, cyproterone acetate, about 2500 cm2/g, about 3000 cm2/g, about 3500 cm2/g, levonorgestrel, norgestrel, d- l 70t-acetoxy- l 3 [3-ethyl- l 70t-a about 4000 cm2/g, about 4500 cm2/g, about 5000 cm2/g, ethinyl-gon-4-en-3-one oxime, cyproterone acetate, about 5500 cm2/g, about 6000 cm2/g, about 6100 cm2/g, gestodene, desogestrel, etonorgestrel, norgestimate, norel about 6200 cm2/g, about 6300 cm2/g, about 6400 cm2/g, gestromin, chlormadione and dienogest. In another embodi about 6500 cm2/g, about 6600 cm2/g, about 6700 cm2/g, ment, the POC may be drospirenone. about 6800 cm2/g, about 6900 cm2/g, about 7000 cm2/g, [0039] In another embodiment, the patient may be a Woman about 7500 cm2/g, about 8000 cm2/ g and about 8500 cm2/g. and have one or more conditions or characteristics selected [0046] In another embodiment, the POC may be selected from the group consisting of being predisposed to hyperkale from one or more of the group consisting of drospirenone, mia, suffering from kidney, liver or adrenal diseases, and l7-hydroxy progesterone esters, l9-nor-l7-hydroxy proges being on daily, long-term treatment for a chronic condition terone esters, l70t-ethinyltestosterone and derivatives With medications predisposed to hyperkalemia. In a speci?c thereof, l70t-ethinyl-l9-nor-testosterone and derivatives embodiment, the medications predisposed to hyperkalemia thereof, norethindrone, norethindrone acetate, ethynodiol may be selected from one or more of the group consisting of diacetate, dydrogesterone, medroXy-progesterone acetate, a non steroidal anti-in?ammatory, potassium-sparing diuret norethynodrel, allylestrenol, lynoestrenol, fuingestanol ics, potassium supplementation medication, angiotensin acetate, medrogestone, norgestrienone, dimethiderome, converting enZyme (ACE) inhibitors, angiotensin-II receptor ethisterone, cyproterone acetate, levonorgestrel, norgestrel, antagonists and heparin. In another speci?c embodiment, the d-l70t-acetoXy-l3[3-ethyl-l70t-a-ethinyl-gon-4-en-3-one patient may be in need to improve tolerance for s dro oxime, cyproterone acetate, gestodene, desogestrel, etonorg spirenone. In another speci?c embodiment, the patient may estrel, norgestimate, norelgestromin, chlormadione and be preparing for Hormone Replacement Therapy medica dienogest. In another embodiment, the POC may be dro ments. In another speci?c embodiment, each daily dosage spirenone. In another embodiment, the particles may have the unit of drospirenone may comprise a dosage amount of at pharmacokinetic pro?les as characteriZed above. least about 2 mg. In another speci?c embodiment, the amount [0047] One embodiment of the present invention may also of drospirenone in each daily active unit dosage may range include methods comprising siZing drsopirenone to a particu from about 2.0 mg to about 6.0 mg. In another speci?c lar d50 particle siZe. In a speci?c embodiment, the methods embodiment, the amount of drospirenone in each daily active may comprise siZing drospirenone to a d50 particle siZe unit dosage may range from about 3.0 mg to about 4.5 mg. Which ranges from about 10 pm to about 60 um by subjecting [0040] The kits of the present invention may also include drospirenone to one or mills selected from the group consist contraceptive kits comprising one or more packaging units ing of a ball mill, a hammer mill, a ?uid energy mill, a rod that comprise dissolution tests of an active drug, such as mill, a cutting mill and an oscillating granulator. In a speci?c US 2012/0128733 A1 May 24, 2012

embodiment, the methods may further comprise the step of non-consecutive days. In another speci?c embodiment, the subjecting drospirenone to a vibrating sieve. In another skipped up to 4 doses may be on consecutive days. In another embodiment, the methods may comprise sizing dro spirenone embodiment, the POC may inhibit ovulation. to a d50 particle siZe Which ranges from about 10 pm to about [0054] In another embodiment of the present invention, the 60 pm by: methods of the present invention may include administering [0048] (i) dissolving drospirenone in a Water-miscible compositions that comprise drospirenone, Wherein the phar solvent; and maceutical composition alloWs for a 28 day daily dosing [0049] (ii) dispersing the resulting solution in cold Water regimen, and Wherein after initial administration of dro under stirring so that to induce the precipitation of dro spirenone has inhibited ovulation in a patient, the patient may spirenone. skip up to 4 doses Within any 28 day daily dosing regimen [0050] In another speci?c embodiment, the methods may period. In another embodiment, the pharmaceutical compo further comprise the step of subjecting drospirenone to a sition may further alloW during the 28 day daily dosing regi vibrating sieve. In a speci?c embodiment of the present inven men for the patient to skip up to tWo non-consecutive days of tion, the Water-miscible solvent may be selected from one or the drospirenone, provided the drospirenone skipped dose is more of the group consisting of methanol, ethanol, isopro taken Within about 24 hrs after the up to tWo skipped non panol, dimethylformamide, tetrahydrofuran, dioxane or dim consecutive days. In a speci?c embodiment, the skipped up to ethyl sulfoxide, dimethylacetamide and acetone. In another 4 doses may be on non-consecutive days. In another speci?c speci?c embodiment, the Water-miscible solvent may be dim embodiment, the skipped up to 4 doses may be on consecutive ethylacetamide. days. In another embodiment, the drospirenone may inhibit [0051] In another embodiment of the present invention, the ovulation. pharmaceutical compositions may comprise a progestogen [0055] In another embodiment of the present invention, the only contraceptive (POC), Wherein the pharmaceutical com kits may comprise one or more packaging units Wherein each position alloWs for a 28 day daily dosing regimen, and packaging unit comprises up to 28 daily active dosage units Wherein after initial administration of POC has inhibited ovu comprising a progestogen-only contraceptive (POC) in a lation in a patient, the patient may skip up to 4 doses Within pharmaceutical composition, Wherein the pharmaceutical any 28 day daily dosing regimen period. In another embodi composition alloWs for a 28 day daily dosing regimen, and ment, the pharmaceutical composition may further alloW dur Wherein after initial administration of POC has inhibited ovu ing the 28 day daily dosing regimen for the patient to skip up lation in a patient, the patient may skip up to 4 doses Within to tWo non-consecutive days of the POC, provided the POC any 28 day daily dosing regimen period. In another embodi skipped dose is taken Within about 24 hrs after the up to tWo ment, the pharmaceutical composition may further alloW dur skipped non-consecutive days. In a speci?c embodiment, the ing the 28 day daily dosing regimen for the patient to skip up skipped up to 4 doses may be on non-consecutive days. In to tWo non-consecutive days of the POC, provided the POC another speci?c embodiment, the skipped up to 4 doses may skipped dose is taken Within about 24 hrs after the up to tWo be on consecutive days. In another embodiment, the POC skipped non-consecutive days. In a speci?c embodiment, the may inhibit ovulation. skipped up to 4 doses may be on non-consecutive days. In another speci?c embodiment, the skipped up to 4 doses may [0052] In another embodiment of the present invention, the pharmaceutical compositions may comprise drospirenone, be on consecutive days. In another embodiment, the POC may inhibit ovulation. Wherein the pharmaceutical composition alloWs for a 28 day daily do sing regimen, and Wherein after initial administration [0056] In another embodiment of the present invention, the kits may comprise one or more packaging units Wherein each of drospirenone has inhibited ovulation in a patient, the packaging unit comprises up to 28 daily active dosage units patient may skip up to 4 doses Within any 28 day daily dosing comprising drospirenone in a pharmaceutical composition, regimen period. In another embodiment, the pharmaceutical Wherein the pharmaceutical composition alloWs for a 28 day composition may further alloW during the 28 day daily dosing daily dosing regimen, and Wherein after initial administration regimen for the patient to skip up to tWo non-consecutive days of drospirenone has inhibited ovulation in a patient, the of the drospirenone, provided the drospirenone skipped dose patient may skip up to 4 doses Within any 28 day daily dosing is taken Within about 24 hrs after the up to tWo skipped regimen period. In another embodiment, the pharmaceutical non-consecutive days. In a speci?c embodiment, the skipped composition may further alloW during the 28 day daily dosing up to 4 doses may be on non-consecutive days. In another regimen for the patient to skip up to tWo non-consecutive days speci?c embodiment, the skipped up to 4 doses may be on of the drospirenone, provided the dro spirenone skipped dose consecutive days. In another embodiment, the drospirenone is taken Within about 24 hrs after the up to tWo skipped may inhibit ovulation. non-consecutive days. In a speci?c embodiment, the skipped [0053] In another embodiment of the present invention, the up to 4 doses may be on non-consecutive days. In another methods of the present invention may include administering speci?c embodiment, the skipped up to 4 doses may be on compositions that comprise a progestogen-only contracep consecutive days. In another embodiment, the drospirenone tive (POC), Wherein the pharmaceutical composition alloWs may inhibit ovulation. for a 28 day daily dosing regimen, and Wherein after initial administration of POC has inhibited ovulation in a patient, the BRIEF DESCRIPTION OF THE FIGURES patient may skip up to 4 doses Within any 28 day daily dosing regimen period. In another embodiment, the pharmaceutical [0057] FIG. 1: Particle SiZe Distribution composition may further alloW during the 28 day daily dosing [0058] FIG. 1 shoWs the cumulative distribution curve (cdf, regimen for the patient to skip up to tWo non-consecutive days ?lled diamonds) and the probability density function curve of the POC, provided the POC skipped dose is taken Within (pdf, ?lled squares) for drospirenone (DRSP) batch 080053. about 24 hrs after the up to tWo skipped non-consecutive days. The distribution experimental data Were obtained by laser In a speci?c embodiment, the skipped up to 4 doses may be on diffraction method. X-coordinate: particle siZe (pm) in log US 2012/0128733 A1 May 24, 2012

scale. Left Y-coordinate: cumulative distribution in percent [0066] FIG. 4c shows the mean plasma DRSP concentra age. Right Y-coordinate: probability density function. tion versus time curves resulting from the repeated adminis [0059] FIG. 2: In Vitro Dissolution Pro?les tration of one of Yasminelle® (curve n01), that of one [0060] FIG. 2 shoWs the in vitro dissolution pro?les for tablet A-3 mg (curve n03), and that of one tablet A-4 mg tablet (A-3 mg) obtained from DRSP batch 080053 as (curve n02), every 24 hours. These curves Were obtained by described in Example 1 (inventive, curve n02) and compara extrapolation of experimental pharmacokinetic data obtained tive tablets, namely Yasminelle® (curve n04), tablets CO1-3 in the described in Example 3. The X-coordinate: mg (curve n03) and tablets CO2-3 mg (curve n01). Each tablet time after the oral administration of the ?rst tablet (in hours); comprises 3 mg of DRSP. The in vitro dissolution pro?les the Y-coordinate: mean plasma concentration of DRSP in Were determined by the USP XXIII Paddle Method as ng/ml. described in Example 2. X-coordinate: time in hours, Y-co [0067] FIG. 5a and FIG. 5b: In Vitro Dissolution Pro?le ordinate: mean dissolution percentage of DRSP relating to and Mean Drospirenone Serum Concentration Versus Time the initial amount of DRSP contained in the tested tablet. Curve for Tablet Comprising 4 mg of DRSP (B-4 mg). [0061] FIG. 3a and FIG. 3b: Mean Drospirenone Serum [0068] FIG. 5a shoWs the mean in vitro dissolution pro?le Concentration Versus Time Curves for tablets obtained from DRSP batch N0 PR100003 as [0062] FIG. 3a shoWs DRSP plasma mean concentration described in Example 5 (see part 1). The tablet comprises 4 versus time curves obtained after the oral administration of a mg of DRSP. The X-coordinate: time in hours; the Y-coordi single tablet of reference product, i.e. Yasminelle® (empty nate: mean dissolution percentage of DRSP relating to the squares) or after the oral administration of a single tablet initial amount of DRSP contained in the tested tablet. obtained from DRSP batch 080053 as described in Example [0069] FIG. 5b shoWs DRSP plasma mean concentration 1 (test product, ?lled squares). In both cases, the DRSP dos versus time curves obtained after the oral administration of a age Was 3 mg. These clinical data Were obtained during a single tablet of reference product, i.e. Yasminelle® (empty monocentric, open, randomized, single-dose, tWo period squares) or after the oral administration of a single tablet B-4 crossover clinical trial conducted on 14 healthy female vol mg (?lled squares) under fasting conditions (see Example 5, unteers as described in Example 3 part 1. Each volunteer part 2). The X-coordinate: time after the oral administration received randomly, an oral single dose of 1 tablet of the test of the tablet (in hours); the Y-coordinate: mean plasma con product or one tablet ofYasminelle® on tWo single occasions, centration of DRSP in ng/ml. alWays under fasting conditions. Study periods Were sepa [0070] FIGS. 6a and 6b: Individual Plasma Levels of rated by a real Wash-out phase of 7 days. In each study, blood Progesterone and Estradiol in Patients During Treatment samples Were collected before the administration of the tablet Period and FolloW Up Period. (pre-dose, time 0) and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, [0071] FIGS. 6a and 6b shoW the results of a clinical trial 5:00, 6:00, 8:00, 12:00, 24:00, 48:00 and 72:00 hours post aiming to illustrate the contraceptive ef?ciency of the contra dosing for assaying the DRSP plasma concentration. The ceptive compositions according to the invention. The meth X-coordinate: time after the oral administration of the tablet odology of the clinical trial is described in Example 4. Brie?y, (in hours); and Y-coordinate: mean plasma concentration of the treatment period comprises tWo treatment cycles in Which DRSP in ng/ml (arithmetic mean). the subjects took one pill of 4 mg DRSP (tablet B-4 mg) from [0063] FIG. 3b shoWs DRSP plasma mean concentration day 1 to day 24 and one placebo tablet from day 25 to day 28 versus time curves obtained after the oral administration of a of each treatment cycle at a ?xed hour. On day 5 and day 13 single tablet of reference product i.e. Yasminelle® (empty of the second cycle, the pill intake Was delayed for 24 hours squares) or after the oral administration of a single tablet (i.e. no pill Was taken on day 5 and day 13 and that 2 pills Were CO1-3 mg (?lled diamonds) or after the oral administration taken on day 6 and day 14, respectively). The complete study of a single tablet CO2-3 mg (?lled squares) under fasting consisted of a 56-day treatment period and a 28-day post conditions (see Example 3, part 2). The X-coordinate: time treatment folloW-up period. The pill corresponds to tablet B-4 after the oral administration of the tablet (in hours); the Y-co mg. ordinate: mean plasma concentration of DRSP in ng/ml [0072] FIG. 6a shoWs the variation of the individual plasma levels of progesterone during the treatment period and the (arithmetic mean). folloW-up period. The X-coordinate: time in days after the [0064] FIGS. 4a, 4b and 4c: Simulation Based on Pharma cokinetic Results from Clinical Trial Described in Example 3 ?rst pill intake; theY-coordinate: progesterone level in ng/ml. [0073] FIG. 6b shoWs the variation of the individual plasma [0065] FIG. 4a and FIG. 4b shoW the experimental DRSP levels of estradiol during the treatment period and the folloW plasma mean concentration versus time curves: (i) for the oral up period. The X-coordinate: time in days after the ?rst pill administration of a single tablet of Yasminelle® (compara intake; The Y-coordinate: estradiol level in pg/ml. tive, ?lled squares); and (ii) for the oral administration of a single tablet as described in Example 1 (A-3 mg, invention, DETAILED DESCRIPTION OF THE INVENTION empty triangles). BothYasminelle® tablet and tablet A-3 mg contains 3 mg of DRSP. FIGS. 4a and 4b also shoW the [0074] The present invention relates to pharmaceutical predicted mean DRSP plasma concentration versus time compositions and contraceptive kits comprising a plurality of curve (invention, empty diamonds) obtained for the oral active daily dosage units. Each active daily dosage unit may administration of a tablet similar to that described in Example include a pharmaceutical composition comprising an active 1, but containing 4 mg of DRSP (tablet A-4 mg). Such a curve drug. In a speci?c embodiment, each daily dosage unit may Was extrapolated from the experimental pharmacokinetic include a pharmaceutical composition comprising an active data obtained in the clinical trial described in Example 3, part drug such as a progestogen-only contraceptive (POC). In 1. The X-coordinate: time after the oral administration of the another speci?c embodiment, each daily dosage unit may tablet (in hours); the Y-coordinate: mean plasma concentra include a pharmaceutical composition comprising dro tion of DRSP in ng/ml. spirenone. In preferred embodiments, the said pharmaceuti US 2012/0128733 A1 May 24, 2012

cal composition may include drospirenone, Without estrogen. also, to an increase of potassium plasma level. It has been In other Words, the contraceptive kit comprises a progesto suggested that the Cmax of drospirenone correlates to the Cmax gen-only contraceptive kit. Drospirenone may be the sole of potassium released after drospirenone administration. contraceptive agent present Within the pharmaceutical com Such an increase of potassium plasma concentration after position. The active daily dosage unit enables to prevent dro spirenone administration may lead to hyperkalemia Which pregnancy When daily administered to a Woman of child is knoWn to induce various disorders such as diZZiness, pal bearing age over a period of 21 to 28 consecutive days. The pitations, muscle Weakness and even cardiac arrhythmia. number of active daily dosage units in the contraceptive kit may vary depending on the contraceptive method in Which the [0082] When orally administered, the DRSP-containing contraceptive kit is intended to be used. compositions according to the invention, induces a reduced [0075] In order to disclose the contraceptive kit of the plasmatic Cmax for drospirenone. A reduced Cmax for DRSP is invention in a manner suf?ciently clear and complete, the expected to reduce the release of potassium in plasma. Con pharmaceutical composition of the active daily dosage units sequently, in the case of the compositions according to the of the kit and the contraceptive method for Which the kit is invention, the tolerance for drospirenone may be improved dedicated are fully-described in Sections 1 and 2, respec especially for Women Who are predisposed to hyperkalemia, tively, hereunder. In Section 3, speci?c embodiments of the to Women Who suffer from kidney, liver or adrenal diseases, contraceptive kit of the invention are also described. and for Women Who are on daily, long-term treatment for a chronic condition With medications predisposed to hyper 1. Pharmaceutical Compositions kalemia. Medications predisposed to hyperkalemia include, Without being limited to, non steroidal anti-in?ammatory [0076] The commercially available drospirenone-contain drugs, potassium-sparing diuretics, potassium supplementa ing contraceptive pills comprise both ethinyl-estradiol and tion, angiotensin-converting enZyme (ACE) inhibitors, microniZed drospirenone. According to European patent angiotensin-II receptor antagonists and heparin. EPl2l4076Bl, the microniZed form of drospirenone pro motes its rapid dissolution in vitro. This rapid dissolution in [0083] Consequently, the DRSP-containing compositions vitro is claimed to be a necessary condition for obtaining a according to the invention may be particularly appropriate to good bioavailability via the oral route. The rapid dissolution prepare any oral medicament in Which the mean Cmax value rate of drospirenone in vitro is assessed to be correlated to a for DRSP should be controlled in order to improve the toler rapid absorption in vivo of DRSP Which avoids its degrada ance for drospirenone. For example, the compositions tion by gastric or intestine environments. Several other pat according to the invention may be used for preparing Hor ents and patent applications, such as WO2006128907, or mone Replacement Therapy medicaments (HRT). WO2009138224, describe drospirenone compositions Which [0084] Since the DRSP-containing composition of the exhibit a rapid dissolution of drospirenone in vitro. invention combined a reduced Cmax With a delayed tmax and an [0077] Accordingly, the international application AUCOh_?aSt su?icient to provide a contraceptive effect, the WO2006128907 shoWs that surfactants may enhance the dis said compositions are appropriate for use in progestogen solution rate of non-microniZed drospirenone having a spe only pills. As illustrated in Example 5, part 3, the composi ci?c surface area loWer than 10 000 cm2/ g. The international tions according to the present invention provide an ef?cient application WO2009138224 provides that the dissolution and stable contraceptive drospirenone blood level When daily rate of drospirenone may be signi?cantly improved by co administered to a female patient. Thus, the co-administration milling drospirenone With an appropriate carrier so as to of an oestrogen to ensure contraception and cycle stability is obtain drospirenone in an amorphous state. not required. Since the mean Cmax value is signi?cantly [0078] As mentioned in EPl2l4076Bl, a rapid dissolution reduced, the contraceptive compositions of the invention pro of drospirenone in vitro generally means that at least 70% of vides a more stable plasma concentration of drospirenone, i.e. the drospirenone is dissolved Within 30 minutes When the a DRSP plasma concentration With loW ?uctuations betWeen composition is subjected to an in vitro dissolution assay such tWo consecutive administrations. Such a feature further as USP XXIII Paddle Method II. reduces the incidence of unscheduled spotting and bleeding [0079] Surprisingly, in vieW of these data, the present and, thus, signi?cantly improves the bleeding pro?le as com invention shoWed, through in vivo pharmacokinetic assays, pared to conventional POCs. that a rapid dissolution of drospirenone in vitro is not required [0085] As described in Example 5, the compositions of the for obtaining a good oral bioavailability. In this respect, the present invention remains a contraceptive even When a pla present invention provides a drospirenone-containing com cebo period is introduced in the contraceptive regimen and position With a sloW dissolution rate of drospirenone in vitro some daily pills are missed. Accordingly, the compositions and Which exhibits a similar mean AUC value (Area Under Will exhibit a higher contraceptive reliability than other the Curve) as compared to Yasminelle® When orally admin progestogen only pills, Which Will alloW the patients to be less istered to female patients. compliant With treatment Without risking unWanted preg [0080] Moreover, the present invention relates to DRSP nancy. containing compositions Which also display a signi?cantly [0086] Also the contraceptive compositions of the inven mean reduced Cmax value (Maximum Plasma Concentration) tioniWhich do not contain estrogeniWill be as e?icient as associated With a delayed mean tmax value for drospirenone as a combined oral pill Without inducing the side effects related compared to Yasminelle®. The decrease of DRSP Cmax to estrogen, in particular, Without increasing the risk of car improves the tolerance of the DRSP-containing composition diovascular events. Thus, in some embodiments of the inven by reducing or avoiding side-effects, in particular those tion, the pharmaceutical compositions may be appropriate to related to the plasma level of potassium. be used as an oral contraceptive. In some other speci?c [0081] Drospirenone has an anti-mineralocorticoid prop embodiments, the pharmaceutical composition of the inven erty Which leads to an increase of potassium and tion may be used as a progestogen-only pill. US 2012/0128733 A1 May 24, 2012

[0087] As used herein “progestogen-only contraceptive”, centration over a period of about 72 h after a single oral intake or “progestogen-only pill” means a pill or a contraceptive of one daily dosage unit of the said drospirenone-containing Which comprises progestogens as sole contraceptive agents composition. and does not comprise any estrogen. [0095] The single oral administration of the said dro [0088] By “composition having an improved pharmacoki spirenone-containing composition, in one embodiment, may netic pro?le for drospirenone” as used herein, is thus meant be preferably performed in fasting conditions ie Without that the oral administration of a single daily dosage unit of food and not close to mealtime (in general, approximately 6 said drospirenone-containing composition provides a phar h-10 h after meal) since food ingestion may modify the macokinetic pro?le for drospirenone characterized by a absorption rate of drospirenone in the gastrointestinal tractus. delayed mean tmax and a reduced mean Cmax as compared to [0096] The tmax and Cmax values refer to the maximum the administration of a single daily dosage unit of Yas DRSP plasma concentration and the time to reach it, respec minelle®. The pharmacokinetic pro?le of Yasminelle® is tively, after the oral administration of a single daily dosage described in Example 3 unit of the DRSP-containing composition of interest. In other Words, tmax and Cmax refer to the characteristics of dro [0089] In some embodiments, the invention may provide a spirenone plasma concentration peak observed after the oral pharmaceutical DRSP-containing composition that When intake of a single daily dosage unit of the composition of orally administered as a single daily dosage unit of said com position, is adapted to provide a pharmacokinetic pro?le for interest. DRSP having a mean Cmax Which is less than 85% of the mean [0097] The AUCOh_?aSt corresponds to the area obtained by Cmax obtained after the oral administration of a single dosage integration of the drospirenone plasma concentration versus unit of Yasminelle®. The pharmaceutical DSRP-containing time over the interval [0h-tlast], the point “0h” referring to the composition according to the present invention may further oral intake of a single daily dosage unit of the composition of be characteriZed by, When orally administered, a single daily interest and the point “tlast” refers to the last time for Which dosage unit of the composition is adapted to provide a phar plasma concentration of DRSP can be quanti?able. macokinetic pro?le for DRSP having a mean tmax Which is at [0098] DRSP plasma concentration may be determined by least 150% of the mean tmax obtained after the oral adminis Well-knoWn methods. For example, an appropriate method of tration of a single dosage unit of Yasminelle® quanti?cation comprises the extraction of DRSP from human plasma and then its quanti?cation using liquid chromatogra [0090] Thus, the administration of a single dosage unit of phy coupled With tandem mass spectrometry. the composition may provide a mean AUCOh_?aSt Which is [0099] In a preferred embodiment, one skilled in the art suf?cient to produce the pharmaceutical or the biological may adapt the analytical method described by Kirk et al effect Which is sought by the administration of drospirenone. (Rapid Communication in Mass Spectrometry, 2006; In the present invention, the pharmaceutical or biological 20: 1247-1252). Such a method comprises a step of derivati effect generally refers to a contraceptive effect. Zation of drospirenone With Girard P hydraZine solution in [0091] When the compositions of the invention are used as order to increase the response of DRSP during the subsequent a contraceptive, it may be further required that the mean MS analysis. This method is generally appropriate to quantify AUCOh_?aSt obtained upon the administration of a single daily DRSP in human EDTA plasma over a concentration range dosage unit of said composition is at least 70% of the mean from about 0.25 to about 100 ng/ml. AUCOh_?aSt obtained in the case of Yasminelle®. In other [0100] As used herein, the meanAUCOh_?aSt, the mean Cmax Words, in some embodiments of the invention, the daily dos and the mean tmax refer to arithmetic mean values determined age unit of the pharmaceutical composition according to the from individual pharmacokinetic data obtained for a group of invention may posses a combination of physical and/or healthy female volunteers of child-age bearing subjected to a chemical features such that, When orally administered, the single oral administration of one daily dosage unit of a dro daily dosage unit is adapted to provide a pharmacokinetic spirenone-containing composition. The group of healthy pro?le having the folloWing characteristics: female volunteers may comprise enough Women to provide [0092] (i) a mean Cmax Which is no more than 85% ofthe statistically con?dent pharmacokinetic results. Preferably, mean Cmax obtained after the oral administration of a the said group comprises at least ten healthy Women of child single dosage unit of Yasminelle® and bearing age. [0093] (ii) a mean tmax Which is at least 150% of the mean [0101] As used herein, a healthy Woman of child-bearing tmax obtained after the oral administration of a single age refers to a pre- Caucasian female betWeen 18 dosage unit of Yasminelle®, and, optionally, a mean and 40 years, With normal body Weight and With no health AUCOh_?aStWhich is at least 70% of the meanAUCOh_?aSt problem, in particular, With no , renal, liver or obtained after the oral administration of a single dosage gynaecologic disorders. A “normal body Weight” refers to a unit of Yasminelle®. body mass index (BMI) ranging from 18 to 29 kg/m2. [0094] In some embodiments, the mean AUCWHZM may be [0102] Preferably, such volunteers have not taken any hor at least 85% of the mean AUCOh_?aSt obtained after the oral mone-containing compositions Within 3 months prior to the administration of a single dosage unit of Yasminelle®. In trial to determine the pharmacokinetic parameters of interest. some embodiments, the pharmaceutical compositions of the [0103] The mean Cmax, tmax and AUCOh_?aSt for Yas invention display one or more of the previous mentioned minelle® and for the drospirenone-containing composition pharmacokinetic characteristics. The AUCOh_?aSt, the Cmax according to the invention are determined for the same group and the tmax are determined based on the dro spirenone plasma of female patients. BetWeen the administration of the single concentration versus time curve. According to the present daily dosage unit of Yasminelle® and that of the DRSP invention, for a given drospirenone-containing composition, containing composition according to the invention, the the drospirenone plasma concentration versus time curve female volunteers may be subjected to a Washout period of at may be determined by folloWing plasma drospirenone con least 7 days. The mean C max: the mean tmax and the mean US 2012/0128733 A1 May 24, 2012

AUCOh_?aSt for DRSP may be determined from raW individual progestogen-only contraceptive (POC). In another speci?c pharmacokinetic data by Well-known statistical methods of embodiment, the POC may be selected from one or more of the prior art. the group consisting of drospirenone, l7-hydroxy progester [0104] For example, all endpoints listed above may be one esters, l9-nor-l7-hydroxy progesterone esters, l70t-ethi determined in a model-independent Way. The highest concen nyltestosterone and derivatives thereof, l70t-ethinyl-l9-nor tration really measured and the time at Which it Was registered testosterone and derivatives thereof, norethindrone, after each dose in any given volunteer may be regarded as norethindrone acetate, ethynodiol diacetate, dydrogesterone, Cmax and tmax respectively according to the algorithm of the medroxy-progesterone acetate, norethynodrel, allylestrenol, program NC_PKP.sas. lynoestrenol, fuingestanol acetate, medrogestone, norg [0105] The daily dosage unit of the DRSP containing-com estrienone, dimethiderome, ethisterone, cyproterone acetate, position of the invention may comprise at least 2 mg of levonorgestrel, norgestrel, d- l 70t-acetoxy- l 3 [3-ethyl- l 70t-a drospirenone. A daily amount of DRSP from 3 mg to 4.5 mg ethinyl-gon-4-en-3 -one oxime, cyproterone acetate, may be preferred When the composition of the invention is gestodene, desogestrel, etonorgestrel, norgestimate, norel used as contraceptive. gestromin, chlormadione and dienogest. In a speci?c embodi [0106] As used herein, Yasminelle® is a combined oral pill ment, the POC may be drospirenone. commercialized by Bayer/Schering. The daily dosage unit of [0116] In a speci?c embodiment, the present invention may Yasminelle® is a coated tablet Which comprises 3 mg of provide a pharmaceutical DRSP-containing composition, micronized drospirenone and ethinylestradiol betadex clath When orally administered as a single daily dosage unit of said rate in an amount corresponding to 20 pg of ethinylestradiol. composition, is adapted to provide a pharmacokinetic pro?le The tablet further comprises lactose monohydrate, maize for DRSP having a mean Cmax Which is less than about 30 starch and stearate as main excipients. The coat ng/ml. The said pharmaceutical DRSP-containing composi ing of the tablet comprises hypromellose, talc, titane oxide tions may be further characterized in that, When orally admin and iron oxide red. istered, a single daily dosage unit of said composition is [0107] As used herein, Yasminelle® (marketed under the adapted to provide a pharmacokinetic pro?le for DRSP hav name of Jasminelle® in ) refers to the pharmaceutical ing a mean tmax Which is at least about 2.2 h. product covered by the French Marketing Authorization [0117] The administration of a single dosage unit of the related to CIS number (Code d’Identi?cation de Spécialité) said composition including DRSP may provide a mean 65052799 and revised on Sep. 17, 2009. AUCOh_?aSt Which is su?icient to produce the pharmaceutical [0108] In a preferred embodiment, the pharmacokinetic or the biological effect Which is sought by the administration parameters (namely Cmax, tmax and AUCOh_?aSt) are deter of drospirenone. Accordingly, When the compositions of the mined after the ?rst oral administration of a single unit do sage invention are used as a contraceptive, it may be further of the DRSP-containing composition of interest, said ?rst oral required that the mean AUCOh_?aSt obtained upon the admin administration occurring in fasting conditions. istration of a single daily dosage unit of said composition is at [0109] In a more general aspect, the present invention may least about 300 ng*ml/h. In other Words, in some embodi provide a pharmaceutical composition comprising an active ments, the daily dosage unit of the pharmaceutical composi drug, When orally administered as a single daily dosage unit tion according to the invention may possess a combination of of said composition, is adapted to provide a pharmacokinetic physical and/or chemical features such that, When orally pro?le for said active drug having a mean Cmax Which is less administered, the daily dosage unit is adapted to provide a than about 30 ng/ml. The pharmaceutical composition com pharmacokinetic pro?le having the folloWing characteristics: prising an active drug may be further characterized in that, [0118] (i) a mean Cmax Which is less than about 30 ng/ml When orally administered, a single daily dosage unit of said [0119] (ii) a mean tmax of at least about 2.2 h composition is adapted to provide a pharmacokinetic pro?le and, optionally, a meanAUCOh_?aSt of at least about 300 ng*h/ for said active drug having a mean tmax Which is at least about ml. 2.2 h. [0120] In some embodiments, the pharmaceutical compo [0110] In another embodiment, the mean AUCOh_?aSt sition of the invention may display all the previous mentioned obtained upon the administration of a single daily dosage unit pharmacokinetic characteristics. of said composition may be at least about 300 ng*ml/h. The [0121] As used herein, the term “about” before a “speci?c daily dosage unit of the pharmaceutical composition accord value” de?nes a range from “the speci?c value minus at least ing to the invention may possesses a combination of physical 10% of the speci?c value” to “the speci?c value plus at least and/ or chemical features such that, When orally administered, 10% of the speci?c value”. For example, “about 50” de?nes a the daily dosage unit is adapted to provide a pharmacokinetic range from 45 or less to 55 or more. In addition, it may de?ne pro?le having the folloWing characteristics: a range Where “the speci?c value minus at least 20% of the [0111] (i) a mean Cmax Which is less than about 30 ng/ml speci?c value” to “the speci?c value plus at least 20% of the [0112] (ii) a mean tmax of at least about 2.2 h; and, option speci?c value” Further, it may de?ne a range Where “the ally, speci?c value minus at least 30% of the speci?c value” to “the [0113] (iii) a mean AUCOh_?aSt of at least about 300 ng*h/ speci?c value plus at least 30% of the speci?c value” and so ml. on. [0114] In another speci?c embodiment, the Tmax may range [0122] A mean AUCOh_?aSt of at least about 300 ng*h/mL from about 2.2 hrs to 6 hrs. In another speci?c embodiment, includes a mean AUCOh_?aSt of at least about 310 ng*h/mL, at said AUCOh_?aSt may be at least 350 ng.h/ml. least about 320 ng*h/mL, at least about 330 ng*h/mL, at least [0115] In another embodiment of the present invention, the about 340 ng*h/mL, at least about 350 ng*h/mL, at least active drug, When orally administered and provides such a about 360 ng*h/mL, at least about 370 ng*h/mL, at least pharmacokinetic pro?le, may be a drug that inhibits ovula about 380 ng*h/mL, at least about 390 ng*h/mL, at least tion. In a speci?c embodiment, the active drug may be a about 400 ng*h/mL, at least about 410 ng*h/mL at least about US 2012/0128733 A1 May 24, 2012

420 ng*h/mL, at least about 430 ng*h/mL. In some embodi [0135] The pharmaceutical composition of the invention is ments, the mean AUCOh_?aSt is at least about 350 ng*h/ml. particularly appropriate to be used as a contraceptive, in par [0123] A mean tmax of at least about 2.2 h includes a mean ticular, as a POC. The pharmaceutical compositions of the tmax of at least about 2.5 h, of at least about 3.0 h, of at least invention may also be used for preparing any other medica about 3 .5 h, of at least about 4 h. In a speci?c embodiment, the ments for Which the improvement of the DRSP tolerance may mean tmax does not exceed 6 hours in order to not signi?cantly be sought. Such medicaments include, Without being limiting impair the bioavailability of DRSP. Thus, the mean tmax pref to, HRT medicament. erably may range from about 2.2 h to about 6 h. In some [0136] Without Wishing to be bound by any theory, the embodiments, a t max ranges from about 3.0 h to about 4.0 h. present invention shoWs that the in vitro dissolution rate of [0124] A mean Cmax Which is less than about 30 ng/ml drospirenone is correlated to its pharmacokinetic pro?le in includes a Cmax less than about 28 ng/ml, less than about 26 vivo. A composition displaying a pharmacokinetic pro?le for ng/ml, less than about 24 ng/ml, less than about 22 ng/ml, less drospirenone as fully-described above may exhibit a sloW in than about 20 ng/ml, less than about 19 ng/ml, less than about vitro dissolution rate of drospirenone such that no more than 18 ng/ml, less than about 17 ng/ml, less than about 16 ng/ml, 50% of drospirenone initially present in the said composition less than about 15 ng/ml, less than about 14 ng/ml. In some is dissolved Within 30 minutes. embodiments, the mean Cmax ranges from about 15 ng/ml to [0137] In one aspect, the present invention provides phar about 30 ng/ml. In other embodiments, the mean Cmax ranges maceutical compositions comprising drospirenone that is from about 15 ng/ml to about 26 ng/ml. characterized by a sloW dissolution rate of drospirenone in [0125] In certain embodiments, the daily dosage unit of the vitro. As used herein, by “a sloW dissolution rate of dro pharmaceutical composition according to the invention may spirenone in vitro” is meant that the release of drospirenone is be adapted to provide a pharmacokinetic pro?le having the such that no more than about 50% of drospirenone initially folloWing characteristics: present in the said composition is dissolved Within 30 minutes [0126] (i) a mean Cmax ranges from 15 ng/ml to 30 ng/ml, When the said composition is subjected to a dissolution test. [0127] (ii) a mean tmax ranges from 2.2 h to 6 h, and [0138] As intended herein, no more than about 50% of the [0128] (iii) optionally, a mean AUCOh_?aSt of at least about drospirenone encompasses no more than 45%, 40%, 35%, 300 ng*h/ml, 30%, 25%, 20%, 15%, 10% of the drospirenone initially When the said daily dosage unit is administered under fasting present in the contraceptive composition. In some embodi condition. ments, no more than about 40% of the drospirenone initially [0129] In a speci?c embodiment, the pharmacokinetic present in the composition is dissolved Within 30 min. parameters (namely Cm“, tmax and AUCOh_?aSt) may be deter [0139] As used herein, the percentage of drospirenone is mined after the ?rst oral administration of a single unit do sage related to the amount of drospirenone initially present in the of the active drug, said ?rst oral administration occurring in said contraceptive composition. fasting conditions. [0140] The in vitro dissolution rate of any active drug of the [0130] In one embodiment, pharmaceutical compositions present invention, including drospirenone, may be assessed may comprise an active drug, Wherein a single daily dosage by anyone of Well-known methods described in the prior art. unit of the composition, When orally administered to a patient The in vitro dissolution rate of drospirenone is preferably in fasting conditions provides a pharmacokinetic pro?le for assessed by the USP XXIII Paddle Method. Brie?y, a tablet the active drug having: consisting of the contraceptive composition comprising dro [0131] i) a Tmax ranging from about 2.2 hrs to 6 hrs; and spirenone to be tested is placed in 900 mL of Water at 370 C. [0132] ii) a mean Cmax Which is less than about 30 ng/ml; (105° C.). The dissolution test is performed using a USP [0133] In some embodiments, the oral administration of the dissolution test apparatus 2 at a stirring rate of 50 rpm. active drug provides a pharmacokinetic pro?le that may fur [0141] In the context of the present invention, the term ther be characterized by a mean AUCOh_?aSt of at least 300 “active drug” includes any compound intended to furnish ng*ml/h, more preferably of at least 350 ng*ml/h. In another pharmacological activity or other direct effect in the diagno speci?c embodiment, the mean tmax may range from about 2 .2 sis, cure, mitigation, treatment and/or prevention of a condi hs to about 6 hrs. In another embodiment, the Cmax may range tion. See 21 C.F.R. 210.3(b)(7). Further, “active drugs” from about 15 ng/ml to about 30 ng/ml. include those compounds of the composition that may [0134] In another speci?c embodiment, the active drug may undergo chemical change during the manufacture of the com be an active contraceptive drug. In another speci?c embodi position and be present in the ?nal composition in a modi?ed ment, the active contraceptive drug may be a POC. In another form intended to furnish an activity or effect. Id. As used speci?c embodiment, the POC may be selected from one or herein, an “active contraceptive drug” thus means an active more of the group consisting of drospirenone, 17-hydroxy drug that may prevent pregnancy When administered in an progesterone esters, 19-nor-17-hydroxy progesterone esters, effective amount to a female patient through its contraceptive 1 70t-ethinyltesto sterone and derivatives thereof, 1 70t-ethinyl effect. The active contraceptive drug may prevent pregnancy 19-nor-testosterone and derivatives thereof, norethindrone, to occur by various contraceptive effects. For example, the norethindrone acetate, ethynodiol diacetate, dydrogesterone, contraceptive effect may include, but is not limited to, one or medroxy-progesterone acetate, norethynodrel, allylestrenol, more of the inhibition of ovulation, thickening of cervical lynoestrenol, fuingestanol acetate, medrogestone, norg mucus (Which reduces the sperm viability and penetration) estrienone, dimethiderome, ethisterone, cyproterone acetate, and/or preventing or otherWise impeding embryo implanta levonorgestrel, norgestrel, d-170t-acetoxy-13[3-ethyl-170t-a tion. ethinyl-gon-4-en-3-one oxime, cyproterone acetate, [0142] The term “drospirenone” includes drospirenone gestodene, desogestrel, etonorgestrel, norgestimate, norel itself, i.e. the chemical entity identi?ed by the CAS registry gestromin, chlormadione and dienogest. In one speci?c Number 67392-87-4, solvates of drospirenone, and deriva embodiment, the POC may be drospirenone. tives or prodrugs of drospirenone. US 2012/0128733 A1 May 24, 2012

[0143] Drospirenone may be prepared by Well-known 2000 cm2/g to about 8500 cm2/g. Such a speci?c area range methods described in the prior art, for example, described in Which includes values of about 2000 cm2/ g, 2500 cm2/ g, 3000 Us. Pat. No. 4,129,564, WO9806738, EP11746101 or cm2/g, 3500 cm2/g, 4000 cm2/g, 4500 cm2/g, 5000 cm2/g, WO2006061309. The method described in WO2006061309 5500 cm2/ g, 6000 cm2/g, 6100 cm2/g, 6200 cm2/g, 6300 may be particularly suitable for preparing drospirenone. It cm2/g, 6400 cm2/g, 6500 cm2/g, 6600 cm2/g, 6700 cm2/g, goes Without saying that the method for preparing dro 6800 cm2/ g, 6900 cm2/ g, 7000 cm2/ g, 7500 cm2/ g, 8000 spirenone may be performed so as to meet the Good Manu cm2/ g and 8500 cm2/g. facturing Practice (GMP) requirements. [0152] In a speci?c embodiment, concerning the size par [0144] To ensure a good bioavailability of the active drug, a ticle distribution, active drugs particles having a diameter signi?cant amount of the active drug initially comprised in greater than 200 um are preferably avoided. In a speci?c the contraceptive composition has to be released in a reason embodiment, drospirenone particles having a diameter able time range. An in vitro dissolution rate of said active drug greater than 200 um are preferably avoided in order to not may be such that at least 50% of the active drug initially drastically impair the in vitro dissolution rate and, thus, the in present in the said compositions Was dissolved in a time range vivo bioavailability since such particles are poorly soluble. In from about 3 hours to about 4 hours. In a speci?c embodi a speci?c embodiment, drospirenone may preferably have a ment, the active drug may be a POC. In another embodiment, d50 of less than about 70 pm. In a preferred embodiment, the the POC may be drospirenone. Indeed, the Applicant shoWed d50 of the drospirenone particles may range from about 10 that a good bioavailability of drospirenone Was achieved in pm to about 60 um. A d50 ranges from about 10 pm to about the case of compositions comprising drospirenone Which had 60 um encompasses a d50 ofabout 10 um, ofabout 15 pm, of an in vitro dissolution rate of drospirenone such that at least about 20 pm, of about 25 um, of about 30 pm, of about 35 pm, about 50% of the drospirenone initially present in the said of about 40 pm, of about 45 pm, of about 50 um, of about 55 compositions Was dissolved in a time range from about 3 um and of about 60 pm. hours to about 4 hours. [0153] In some embodiments, the particle size distribution [0145] Accordingly, an object of the present invention is a of the active drug present in the composition according to the contraceptive composition comprising drospirenone Wherein invention may be characterized by: the in vitro dissolution rate of the said drospirenone is such [0154] (i) a d90 particle size less than about 100 um, and/or that no more than about 50% of the said drospirenone is [0155] (ii) a d50 particle size ranging from about 10 pm to dissolved Within 30 minutes and such that at least about 50% about 60 um and/or of the drospirenone is dissolved in a time range from 3 hours [0156] (iii) a d10 particle size more than about 3 um. to 4 hours. [0157] In some other embodiments, the d50 of the active [0146] A time range from about 3 hours to about 4 hours drug particles may range from about 10 um to about 30 pm. In may include, in speci?c non-limiting embodiments, a time a speci?c embodiment, the active drug may be a POC. In such range from 3.25 hours, to 3.5 hours, and from 3.75 hours, to embodiments, the particle size distribution of the POC 4 hours. present in the composition according to the invention is char [0147] At least about 50% of the active drug such as dro acterized by at least one of the folloWing characteristics: spirenone encompasses at least 50%, 55%, 60%, 65%, 70%, [0158] (i) a d90 particle size less than about 100 um, 75%, 80%, 85%, at least 88%, at least 90%, at least 91%, at [0159] (ii) a d50 particle size ranging from about 10 pm to least 92%, at least 93%, at least 94%, at least 95%, at least about 30 um and 96%, at least 97%, at least 98%, at least 99%, and at least [0160] (iii) a d10 particle size more than about 3 um. 99.5%. [0161] In a speci?c embodiment, the particle size distribu [0148] In some embodiments, at least about 60% of the tion of, drospirenone present in the composition according to active drug, such as DRSP, initially present is dissolved in a the invention may be characterized by: time range from about 3 hours to about 4 hours. In some other [0162] (iv) a d90 particle size less than about 100 um, embodiments, the said contraceptive composition is further and/or characterized in that at least about 70% of the active drug, [0163] (v) a d50 particle size ranging from about 10 pm to such as drospirenone is dissolved Within about 6 hours. about 60 um and/or [0149] The applicant has shoWn that speci?c surface area of [0164] (vi) a d10 particle size more than about 3 um. DRSP has a direct impact on the in vitro dissolution rate of [0165] In other speci?c embodiments, the d50 of dro drospirenone and its in vivo pharmacokinetic pro?le. spirenone particles may range from about 10 pm to about 30 [0150] One Way to obtain the active drug-containing com pm. In such embodiments, the particle size distribution of the positions of the invention is to use the active drug in a particle drospirenone present in the composition according to the form having an appropriate speci?c surface area. Active drugs invention is characterized by at least one of the folloWing may be present in the pharmaceutical compositions of the characteristics: invention in a non-micronized particle form. In a speci?c [0166] (iv) a d90 particle size less than about 100 pm, embodiment, the active drug may be a POC. For example, it [0167] (v) a d50 particle size ranging from about 10 pm to has been also shoWn that the active drug drospirenone in a about 30 um and particle form having a speci?c surface area from about 2000 [0168] (vi) a d10 particle size more than about 3 um. cm2/ g to about 8500 cm2/ g may be suitable for obtaining the [0169] As used herein, the term “about” before a “speci?c contraceptive compositions of the invention. The speci?c sur value” de?nes a range from “the speci?c value minus 10% of face area may be experimentally determined using the BET the speci?c value” to “the speci?c value plus 10% of the method (gas adsorption method). speci?c value”. For example, “about 50” de?nes a range from [0151] In some embodiments, the contraceptive composi 45 to 55. In addition, it may de?ne a range Where “the speci?c tions of the invention comprises active drugs such as dro value minus at least 20% of the speci?c value” to “the speci?c spirenone in a particle form having a speci?c area from about value plus at least 20% of the speci?c value.” Further, it may