co») United States c2) Patent Application Publication ‘Thosar et al. US 201000874121 (10) Pub. No.: US 2010/0087412 AL os) 0s) om a MICRONIZED EPLERENONE ‘COMPOSITIONS laventors: (US): Rajeey D. Gokhale, ‘Waukegan, iL (US): Dwal Talbert, Wadsworth, IL (US) Correspondence Adres: PFIZER INC PATENT DEPARTMENT Bld 114 Mi GROTON, Assignee: Pfizer Tne Appl.Noz 12/634,262 Shilpa S, Thosar, Des Plaines IL (43) Pub, Date: Apr. 8, 2010 (22) Fite Dec. 9, 2009 Related US. Application Data (63) Continuation of epplication No. 11/612,395, filed on Dee. 18, 2006, now abandoned, which is continua tion of application No. 101817,577, fled on Apr. 2, 2004, now Pat. No, 7,157,101 Publication Classification G1) Inc AGIK 31585 (2006.01) (2) USL S173 on ABSTRACT The invention relates to oral pharmaceutical compesitions useful as aldosterone receptor blockers comprising the active ‘agent mieronizedeplerenane in an emtount of about 10 mg to about 1000 mg and one or more carrer materialsPatent Application Publication Apr. 8, 2010 Sheet 1 of 2 US 2010/0087412 Al FIG. 1A EXCIPIENTS EXCEPT TALC, MAGNESIUM STEARATE AND EXTRAGRANULAR. MICROCRYSTALLNE CELLULOSE} WATER AS GRANULATING FLUID WET GRANULATION (HIGH SHEAR MIXER GRANULATOR)Patent Application Publication Apr. 8, 2010 Sheet 2 of 2 US 2010/0087412 Al FIG. 1B DRYING (FLUID BED DRYER) TALC AND AVICEL PH101 GR) OR TALC ONLY (CR) BLENDING (V-BLENDER) LUBRICATION (V-BLENDI ER) COMPRESSION (INSTRUMENTED TABLET PRESS) AQUEOUS FILM COATING (COATING PAN)US 2010/0087412 Al ‘MICRONIZED EPLERENONE, ‘COMPOSITIONS ‘TECHNICAL FIELD [0001] The present invention relates to pharmaceutical ‘compositions comprising the compound eplerenone as an active ingredient, and more particularly w pharmaceutical ‘compositions containing micronized eplerenone, methods of treatment comprising. administering. such pharmaceutical ‘compositions 1 subject in need thereof, andthe use of such ‘composition in the manufacture of medicaments. BACKGROUND OF THE INVENTION [0002] The compound mist hydrogen 9.11ecepoxy- Tachyiony-opreunl-ene- 7.2 -earboxylte, lat. tone (lo refered to heen eplernoae) as fest eported in Grab etal, US. Pat No. 4389332 that dserbes and ‘thins elas of 9.1 pony iid compounds sa hie Sal ogetier wih proces forth preparation faichcone pound: Thee 91 epoxy steroid compounds are described Saldsieone austin canadien her cally effete aaa o at paolo conditions cine with byprldsteroisat sich & ypartesion, ‘aria inslicieaey and eines ofthe ver. US, Pat No '1550'32conaias gnc references to omations forthe Dtnnsttion of hese 8 -eoxy steroid compounds sich Sublets and cps, [0003] Ng et al., WO 98/25948 later disclosed additional Syme process for th preparation of sini els of STTeepoxy sero compound and ies, loclaing perenne. Bath US. Pat No 459,332 and WO 9825938 se incorporated by eerace tin. [oo0s)Epleenone coresponds in stare wo Formula belo o o pu b 0005] Spironolactone, another 20-piroxane-steroid hav ing activity as an aldosterone antagonist is commercially ‘available forthe treatment of hypertension. Spironolactone ‘corresponds in structure to Formula I, below o ° Apr. 8, 2010 [0006] Spironolactone, however, exhibits antiandrogenic activity that can result in gynecomastia and impotence in ‘men, and weak progestational activity that produces men- sinual regularities in women. Commercial formulations of spironolactone (sold under the name Aldaetone™) contain 25, $0 or 10 mg doses of spironolactone ina matrix compris- ing, among other carrer materials, caleium sulfate dihydrate asa diluent, maize starch asa disintegrant povidone K-30 as binding agent, magnesium stearate asa lubricant, and flavor, colorant, and coating ingredients that include hydroxypropyl ethylcellulose and polyethylene glyco! 400. [0007] Gasparo et al. J. Steroid Res,, 22(18):223-227 (1989) report the se of spironolactone and epoxymexrenone in receptorbinding studies. Those material, with spiroaolae ‘one in @ commercial formulation with a particle size of $ ricrons and the epoxymexerenone at s partiele sizeof 20 microns in a non-formulated composition, were also used in vivo to tudy excretion of sodium in urine, [0008] Thece is a need for the development of addtional active aldosterone antagonists suchas eplerenone that inter- ‘act minimally with other steroid roceptor systems such 2 tlucocorticoid, progestin and androgen steroid receptor sys- ‘ems and/or that provide for a broader range of weatment ‘Theres also a. nood for eplerenone compositions that provide 1 realy soluble form of eplerenone, The discussion that {allows discloses eplerenone compositions that help to fulfil that need BRIEF SUMMARY OF THE INVENTION [0009] The effective administration of eplerenone to asub- ject has been complicated bythe compounds low solubility nl ow compressibility as well ashy is eter physical and chemical properties. Phamnaceuical compositions comprs- jing micronized eplerenone and a phamaceucally accep ale cari material, however, have been discovered that can elective deliver a therapeutically preferred amount ofthe compound tothe subject. Inaditon, unique combinations of carver material wih the micronized eplerenane have been fou! that provide stl beter solubilization characteristics ‘These combinations of active compound and carrer materiel have boen found to possess improve bioavailability, chemi cal stably, physical stably, dissolution profiles, disinte- aration times, safety, as wel a other improved pharmacoki- netic, chemical andor physical properties. The present invention comprises these pharmaceutical composition, uit cosage forms based thereon, and methods forthe preparation and use of both. BRIEF DESCRIPTION OF THE DRAWINGS [0010] Inthe drawing forming portion ofthis disclosure, FIG. 1, shown in two portions as FIGS. 1A and IB, is @ schematic diagram of a manufacturing process fora compo- Sitio ofthis invention, DETAILED DESCRIPTION OF THE INVENTION [0011] 1ehas been discovered that pharmaceutical eompo- sitions comprising micronized eplerenone as the active ingre- dient in adaity dosage amount about 10 mgto about 1000 mg along with pharmaceutically acceptable carrier material are ‘unique compositions exhibiting superior performance as aldosterone receptor blockers, Such pharmaceutical compo- sitions exhibit superior activity, poteney, safety and therapeu tie effectiveness at this dosage range. These compositionsUS 2010/0087412 Al provide eplerenone oa patent ata dosage thats suiicient 10 provide prolonged blocking of akosterone receplorsand thus ‘confer the desired therpeutic benefit, while maintaining a safe clearance time. Undesirable side elects such as, but not Fiited 10, gastrointestinal inittion, antiandeogenic and progesational setivty are also minimized withthe pharma- ‘ceutical compositions ofthe present invention. 0012] These pharmaceutical compositions are advanta- aeously usedto block aldosterone ecepins and, amongother pharmacological actions, can increase sodium and water ‘excretion with a concomitant potssium-sparing eect, Such ‘compositions ean be specifically employed for the prophy- Taxis and treatment of cardiovascular diseases such as heart failure: hypertension (espevally the management of mild 10 moderate hypertension; edema associated with iver insufl- iency; post-myceartialinfartion; eirbosis of the liver, stroke prevention; and redvetion of heart rate for subjects ‘exhibiting an accelerated heart rte. These pharmaceutical ‘compositions exhibit, among other features, (i) improved selectivity for aldosterone receptors, (i) reduced binding ality to the progesterone and androgen receptor, and (i) reduced interference from plasma proteins. [0013] Besides being useful for human’testment, these ‘compositions ae also usefil for veterinary teatment of com panion animals, exotic animals and farm animals, inehuding mammal, rodents and the lke, Mor prefered non-human ‘animals inelnde horses, dogs, ad cats. 10014] Unformulated eplerenone adninistered in capsule formisnotwell absorbed inthe gastrointestinal tract. Accord- ingly, aneed exists fr suitable eplerenone dosage forms. The pharmaceatical compositions ofthe preset invention pro- Vide these dosage forms and exhibit one oF more superior properties relative to unformalated eplerenone andor ether ‘compositions comprising eplerenone. These superior proper- tis include, but ae not limited to, one or moe ofthe fllow- ing: 0015] _(1)improved bioavailability; [0016] (2) improved soli ofthe pharmaceutical com- postion, [0017] (3) decreased disintegration times for immediate release orl dosage forms; 10018] (4) decreased dissolution times for immediate release orl dosage forms; 10019] (5) improved dissolution profiles for controlled release orl dosage forms; 0020] (6) decreased tablet ability; 021] (7) increased tablet hardness; 0022] (8) improved safety for oral dosage forms 0023] _()reiuced moisture content andr hyproscopcity for ral dosage forms 0024] (10) improved composition wettability: [0025] (11) improved panicle size distibution of ‘plerenane; 10026] (12) improved composition compressibility; [0027] (13) improved composition fow properties: 10028] (14) improved chemical stability of the final oral ‘dosage form; [0029] (15) improved physical stability of the final oral ‘dosage form; [0030] (16) decreased tablet size; 0031] (17) improved blend uniformity; 0032] (18) improved dose uniform 0033] (19) increased granule deasi ‘compositions for wet granulated Apr. 8, 2010 [034] (20) reduced water requirements for wet granula- ‘ion: [0035] (21) reduced wet granulation ime andor [0036] (22) reduced drying time for wet granulated mix- tures MicronizedFplerenone [0037] Although the pharmaceutical compositions are clfective for broad range of particle sizes for the initial eplerenone starting material used in the compositions, i has been discovered that reduction ofthe particle size 0 & Day particle size of about 25 to about 400 microns can improve eplerenone bioavailability: Bplerenone particles having a Day particle sizeof about 25 to shout 400 microns ae refered to herein as micronized eplerenone or micronized eplerenone particles. [0038] Accordingly, the Duy particle size (that is, the par- ticle size of at east 90 percent of the particles) of the eplerenone used as a starting material inthe composition is [ess than about 400 mierons, preferably Tess than about 200 nictons, more preferably less than about 130 microns, stil more preferably fess than about 100 microns, and still more preferably less than 99 microns. A particularly prefered Day particle size is about 30 to about 110 microns, and more particularly still about 30 to about SO micron. In other pre {erred embodiments, 2 particularly prefered Dy» particle size is about $0 to about 150 microns, and more preferably about 75 about 125 mierons. Mieronized eplerenoneso sized also ‘ypically exhibits a D,. particle size of less than 10 microns For example, as illustrated in Example 30, relocing the Day particle size ofthe stating material eplerenone from about 220 mierons to about 99 mierons can materially improve the bioavailability ofthe pharmaceutical composition Eplerenone Dosage of Pharmaceutical Composition [0039] The pharmaceutical compositions of the present invention comprise micronized eplerenone in an amount of ‘bout 10 mg w about 1000 mg. Preferably the phamoceuri- cal compositions comprise micronized eplerenone in an ‘amount of about 20 mg to about 400 mg, more preferably from about 25 mg to about 200 mg, and still more peefeably from about 25 mg to about 150 mg. “Treatment of Specific Conditions and Disorders [0040] The phamacetical compositions of the present invention are Useful where administration ofan aldosterone receptor blocker is indicated It has boon foun that these compositions are pariculaely effective ia the teatment of caiovascular diseases such os beat failure: hypertension (especially the management of mild t9 moderate hyper: sion); edema associated wit iver insuceney postmyo- carcal infarction; cintosis ofthe liver, stoke prevention; sn eduction of heat ae for subjects exhibiting an acceler stod hea rte {0041} Forthe treatment of hear fire, he pharmaceuti- cal composition preferably provides a daily dosage of eplernone in the amount oF about 25 mg to about 200 mg, nor preleraby about 25 mg to about 75 mg, and till more preferably about SO mg. A daly dose of about 0:3 10 2.67 rglhy body weight (based upoa an average body weight of about 75 ka), preferably between about 0.33 and about 1.00 rnglkg body weight and mos preferably 0.67 mg/kg body