US008715735B2

(12) United States Patent (10) Patent No.: US 8,715,735 B2 Funke et al. (45) Date of Patent: May 6, 2014

(54) STABILISED SUPERSATURATED SOLIDS OF OTHER PUBLICATIONS LIPOPHILIC DRUGS V. Buehler, “Kollidon (R). Polyvinylpyrrollidone for the pharmaceu (75) Inventors: Adrian Funke, Berlin (DE); Torsten tical industry.” Mar. 1998, BASF AG Fine Chemicals, Ludwigshafen, Wagner, Berlin (DE); Ralph Lipp, Germany, pp. 88-116, XP002297940. Zionsville, IN (US) K. Khougaz et al., “Crystallization inhibition in solid dispersions of (73) Assignee: Bayer Intellectual Property GmbH, MK-0591 and poly(vinylpyrrollidone)polymers,” Journal of Pharma Monehim (DE) ceutical Sciences, Oct. 2000, vol. 89, No. 10, pp. 1325-1334. XP002297939, the whole document. (*) Notice: Subject to any disclaimer, the term of this T. Watanabe et al., "Stability of amorphous indomethacin com patent is extended or adjusted under 35 pounded with silica.” International Journal of Pharmaceutics, U.S.C. 154(b) by 759 days. 2001, vol. 226, pp. 81-91, XP002310637. (21) Appl. No.: 11/076,022 T. Watanabe et al., “Prediction of apparent equilibrium solubility of indomethacin compounded with silica by 13C solid state NMR.” Int. (22) Filed: Mar 10, 2005 J. Pharmaceutics, 2002, vol. 248, pp. 123-129, XP002310638. (65) Prior Publication Data T. Watanabe et al., “Comparison between polyvinylpyrrollidone and silica nanoparticles as carriers for indomethacin in a solid state dis US 2005/02O7990 A1 Sep. 22, 2005 persion.” Int. J. Pharmaceutics, 2003, vol. 250, pp. 283-286, XPOO23 10639. Related U.S. Application Data H. Takeuchi et al., “Spherical Solid dispersion containing amorphous tolbutamide embedded in enteric coating polymers or colloidal silica (60) Provisional application No. 60/551.330, filed on Mar. prepared by spray-drying technique.” Chemical and Pharmaceutical 10, 2004. Bulletin, Pharmaceutical Society of Japan, Tokyo, 1987, vol. 35. No. (51) Int. Cl. 9, pp. 3800-3806. XP001 183548, ISSN: 0009-2363. A6 IK9/00 (2006.01) K.P.R. Chowdary et al., “Enhancement of dissolution rate of A6 IK 9/14 (2006.01) meloxicam.” Indian Journal of Pharmaceutical Sciences, Mar. 2001, A6 IK9/20 (2006.01) vol. 63, pp. 150-154, XP009037083, ISSN: 0250-474X. A6 IK9/48 (2006.01) H. Nakagami. “Solid dispersions of indomethacin and griseofulvin in non-porous fumed silicon dioxide, prepared by melting.” Chemical (52) U.S. Cl. and Pharmaceutical Bulletin, Pharmaceutical Society of Japan, USPC ...... 424/489: 424/400; 424/451; 424/464 Tokyo, Sep. 1991, vol. 39, No. 9, pp. 2417-2421, XP001 183546, (58) Field of Classification Search ISSN: 0009-2363. USPC ...... 424/464, 400, 451, 489 D.C. Monkhouse et al., “Use of adsorbents in enhancement of drug See application file for complete search history. dissolution I.” Journal of Pharmaceutical Sciences, American Phar maceutical Association, Washington, US, Sep. 1972, vol. 61, No. 9. (56) References Cited pp. 1430-1435, XP001105645, ISSN: 0022-3549. Degussa AG, Duesseldorf, "Aerosil (R)—Internet presentation—En U.S. PATENT DOCUMENTS try No. 5 Dry binder: A new concept of pressed powders,” "Online 4,013,785 A 3, 1977 Weintraub et al. Retrieved from the internet: URL:https://www1.sivento.com/wps3/ 4,254,099 A 3/1981 Asmussen et al. portal/action/ChangePage?.pg/85/..reqid-1?cqurl=/en/aerosil?ebusi 4,639,370 A 1, 1987 Carl ness/news0> retrieved on 12-114-2004 See "Aeroperl (R)'. 5,569,652 A 10, 1996 Beier et al. Cab-O-Sil M5 (C) Product Inforamtion Sheet. Retrieved from http:// 5,656,622 A 8, 1997 Bullet al. talasonlinen.com/photos?inatructions/fumed silica info.pdf Pub 5,789,442 A 8, 1998 Garfield et al. lished 2004. 6,027,747 A 2/2000 Ducloset al. Syloid 244 FPSilica Product Information Sheet. Retrieved from

6,787,531 B1* 9/2004 Hilman et al...... 514,171 2002/0142032 A1* 10, 2002 Sherwood et al...... 424/465 http://www.discoverysciences.com/uploadedFiles/Preparative 2003/OO54037 A1 3/2003 Babcock et al. and Process/B561 SYLOID US ver FINAL.pdf Published 2003/01 19798 A1* 6/2003 Heil et al...... 514f175 2011. 2006,0182691 A1 8, 2006 Besse et al. Limnel, Tarja. Mesoporous silica and silicon based materials as car riers for poorly water soluble drugs. Retrieved from https://helda. FOREIGN PATENT DOCUMENTS helsinki.fi/bitstream/handle/10138/27709/rnesoporo. pdf?sequence=1 published 2011. EP O336014 10, 1989 EP O474098 3, 1992 EP O492007 A1 * T 1992 * cited by examiner EP 1 260 225 11, 2002 EP 1380 301 1, 2004 Primary Examiner — Barbara P Badio GB 1365,661 9, 1974 (74) Attorney, Agent, or Firm — Millen, White, Zelano, JP 2006 505704 2, 2006 Branigan, P.C. JP 200651982O 8, 2006 KR 10 2000 OO16 3, 2000 (57) ABSTRACT WO WO-97 47290 12/1997 WO WO O1, 52857 T 2001 Methods for improving solubility and bioavailability of lipo WO WOO152857 T 2001 philic compounds are described. Particularly, described are WO WOO3O43630 5, 2003 WO WO 2004/O22065 3, 2004 stabilized Supersaturated Solid solutions, particularly in WO WO 2004/041289 5, 2004 power from, of lipophilic drugs, such as Steroidal molecules. WO WO 2004/073689 9, 2004 WO WO 2005/087.194 9, 2005 17 Claims, 2 Drawing Sheets U.S. Patent US 8,715,735 B2

U.S. Patent May 6, 2014 Sheet 2 of 2 US 8,715,735 B2

Figure 2

He et al.

ert Carrier

Solvent layer containing dissolved drospirenone

Renova of solvent

net. Carrier

Solid drospirer one deposited on Surface of inert Carrier US 8,715,735 B2 1. 2 STABLISED SUPERSATURATED SOLIDS OF Solvent together with a hydrophilic polymer and evaporating LIPOPHILIC DRUGS the solvent to dryness to form a co-precipitate of the drug with the hydrophilic polymer. This application claims the benefit of the filing date of U.S. Khougaz Ketal. relates to the formulation of solid disper Provisional Application Ser. No. 60/551.330 filed Mar. 10, 5 sions comprising a hardly soluble drug Substance together 2004. with a carrier (PVP), wherein the drug substance is present in amorphous form or in crystalline form (Khougaz K et al. FIELD OF INVENTION Crystallisation inhibition in solid dispersions of MK-0591 and PVP polymers, J Pharm Sci vol.89, October 2000, pages The present invention relates to the field of pharmaceutical 10 1325-1334). formulation Science, in particular with respect to methods of Watanabe Tet al. relates to the formulation of solid com improving solubility and bioavailability of lipophilic com positions comprising indomethacin and silica. The pounds. The specific formulation technique of the present indomethacin is physically mixed with the silica by co-grind invention relates to stabilised Supersaturated Solid solutions ing or melting resulting in amorphous form of indometacin 15 (Watanabe Tetal. Stability of amorphous indomethacincom oflipophilic drugs, such as steroidal molecules and hormones pounded with silica, IntJ Pharm, 226, 2001, pages 81-91). in general. The Solid solutions are suitable for being pro Watanabe Tet al. also relates to the formulation of solid cessed into tablets or other Solid dosage forms. compositions comprising indomethacin and silica. The indomethacin is physically mixed with the silica by co-grind BACKGROUND ing or melting resulting in amorphous form of indometacin (Watanabe T et al. Prediction of apparent equilibrium solu Poor bioavailability of lipophilic compounds is a well bility of indometacin compounded with silica by 13C solid known problem, in particular in connection with per oral state NMR, IntJ Pharm, 248, 2002, pages 123-129). administration, wherein the compound is to be dissolved in Watanabe Tetal relates to the formulation of solid com the gastric fluid and/or intestinal fluid before being absorbed 25 positions comprising indomethacin and silica or PVP. The from the gastro-intestinal tract into the blood circulation. indomethacin is physically mixed with the silica or PVP by Thus, the rate-limiting step in the absorption of compounds co-grinding or melting resulting in amorphous form of from the gastro-intestinal tract is often the dissolution rate of indometacin (Watanabe Tet al. Comparision between Poly the compound in water and other liquids, which are similar to vinylpyrrolidone and silica nano particles as carriers for the ones found in the gastro-intestinal tract. 30 indomethacin in a solid state dispersion. Int J Pharm, 250, Many attempts at increasing the Solubility of a lipophilic 2003, pages 283-286). compound have been suggested and used in the past years. GB 1365 661 relates to the formulation of solid composi Examples are attempts to increase the Surface area of a com tions comprising a drug Substance with low water Solubility pound, either by spraying the amorphous compound onto an (Cholesteryl beta-glucoside) and a carrier (Silica (Aerosil TM). inert carrier or by micronising the compound. Other attempts 35 The composition is prepared by dissolving the betaglucoside in hot ethanol and Subsequently adding this solution to the have been directed to inclusion complexes with cyclodex aerosol powder and evaporate the solvent from the resulting trins. A common feature of the conventional techniques is that slurry. The resulting composition has a slower release rate the compound is in particulate form, eg. in amorphous form or than conventional formulations. in crystalline form. Both forms still require the initial step of 40 Takeuchi et al relates to the formulation of compositions dissolving the particulate compound before being capable of wherein the drug compound (tolbutamide) is presentinamor penetrating the mucosa of the gastro-intestinal tract. phous form (Takeuchi et al. Spherical solid dispersion con Typical examples of pharmaceutical formulation tech taining amorphous tolbutamide embedded in enteric coating niques which result in particulate forms of lipophilic com polymers or colloidal silica prepared by spray-drying tech pounds in the final composition/dosage form rather than in 45 nique. Chem Pharm Bulletin Pharm Soc Japan. 35, 1987, molecularly dispersed lipophilic compounds are as follows: pages 3800-3806). EP 0474 098 relates to the formulation of solid composi Chowdary Ketal. relates to the formulation of solid dis tions comprising a hardly soluble drug Substance co-precipi persions (powders) prepared by dissolving the drug (Meloxi tated with a carrier comprising a water-soluble excipient cam) in a solvent in the presence of carrier (Silica, Aerosil). (PVP) and a biodegradable excipient (polyactic acid). This 50 The solvent is then evaporated to dryness. The process of formulation technique aims at Solving the problem of provid evaporating the solvent to dryness will result in the drug ing controlled release formulations. precipitating onto the carrier (Chowdary K et al. Enhance U.S. Pat. No. 4,639,370 relates to the formulation of pow ment of dissolution rate of meloxicam. Indian J Pharm Sci, dery compositions comprising a poorly water-soluble drug in 63, 2001, pages 150-154). combination with a water insoluble carrier (cross-linked 55 Nakakami H relates to the formulation of solid dispersions PVP). The compositions are prepared by grinding/milling the comprising poorly water-soluble drugs and non-porous drug substance and the cross-linked PVP without dissolving fumed silicon dioxide as the carrier (Nakakami H. Solid the active drug. dispersions of indomethacin and griseofulvin in non-porous WO 03/04360 relates to the formulation of solid disper fumed silicon dioxide, prepared by melting. Chem Pharm sions comprising a poorly water-soluble drug in combination 60 Bulletin Pharm Sci Japan, 39, 1991, pages 2417-2421). with a carrier (PVP). The compositions are prepared by dis Monkhouse D C et al relates to the formulation of fine solving the drug compound and the carrier (PVP) in a volatile powders of a drug and a carrier (fumed silica). The drug and Solvent and then removing the solvent. the silica are mechanically mixed under addition of an U.S. Pat. No. 6,027,747 relates to the formulation of solid organic volatile solvent (acetone, chloroform or methylene compositions comprising a hardly soluble drug Substance 65 chloride) in order to totally dissolve the drug in the sample. together with a carrier (PVP). The compositions are made by The solvent is then evaporated to dryness. As the solvent is a process including dissolving the drug in a volatile organic evaporated to dryness the drug will precipitate onto the carrier US 8,715,735 B2 3 4 (Monkhouse D C et al. Use of adsorbents in enhancement of In a second aspect, the invention relates to a process for the drug dissolution I. J Pharm Sci, Am Pharm Ass Washington, preparation of a powdery composition of the invention, the 61, 1972, 1430-1435). process comprising the steps of WO 01/52857 relates to the formulation of solid composi a) dissolving in a solvent a lipophilic molecule having a tions comprising drospirenone and an estrogen, wherein the solubility in water at 25° C. lower than 1 mg/ml, such as a drospirenone is initially dissolved in a solvent and then steroidal molecule, in an amount that exceeds the Saturation sprayed onto the Surface of an inert carrier. concentration of that steroidal molecule in the solvent; and b) mixing the resulting Supersaturated solution of step a) Obviously, the administration of a compound that is in the with amorphous silica having a specific Surface area of at least dissolved stage already at the time of administration may be 10 250 m/g. advantageous in terms of ensuring high bioavailability. For A further aspect of the invention relates to a process for the example, by dissolving a compound in a Suitable oil or preparation of a powdery composition comprising a steroidal another lipophilic medium. Unfortunately, it is often found molecule molecularly dispersed in a solvent, where the that the amount of drug which is dissolvable in the lipophilic 15 amount of lipophilic component dissolved equals the satura media is too low, for which reason the oil cannot be admin tion concentration of that lipophilic compound. In this aspect istered in an acceptable form, such as enclosed in a capsule or of the invention the process comprises the steps of the like. a) dissolving in a solvent a steroidal molecule in an amount Supersaturated solutions of lipophilic compounds are that is lower or equals the saturation concentration of that known approaches for making Solutions containing lipophilic steroidal molecule in the solvent; and compounds in a dissolved stage. The concentration of a dis b) mixing the resulting Saturated Solution of step a) with Solved compound in a Supersaturated Solution is higher than amorphous silica having a specific Surface area of at least 250 the solubility of the compound in the actual solvent at room m/g; and temperature. However, the physical stability of the compound c) evaporating off part of the solvent. in Such a Supersaturated Solution is critical in that re-crystal 25 In a still further aspect, the invention relates to a pharma lisation of the compound occurs. Therefore, this technique ceutical dosage form in the form of granules, a tablet, a cannot be applied as a general technique to lipophilic com capsule, or a pill, which comprises the powdery composition pounds as such. as defined herein. Therefore, pharmaceutical dosage forms having the lipo In a still further aspect, the invention relates to the use of philic drug in a readily dissolvable form and which are also 30 amorphous silica with a specific Surface area greater than 250 physically stable (no tendency to crystallisation of the lipo m/g for inhibiting the re-crystallisation of a compound that is philic drug) and which contain the lipophilic drug in a satis present in a solvent in a Supersaturated concentration. factorily high concentration would solve the problems asso ciated with other techniques. DETAILED DESCRIPTION OF THE INVENTION 35 It has been found that lipophilic compounds can be pro SUMMARY OF INVENTION vided in a highly water-soluble form using the technique of Supersaturated Solutions. First of all, the compound is com The present inventors have found a formulation technique pletely dissolved in a suitable solvent by heating, if necessary, of stabilising Supersaturated Solutions of lipophilic drugs by 40 the liquid to high temperatures so as to achieve a Supersatu adding a high Surface amorphous silica to Supersaturated rated solution of the compound. Then, the solvent is adsorbed Solutions of a lipophilic drug compound so as to allow for the onto a Solid carrier characterised by having a very high Sur preparation of powdery compositions with a satisfactorily face area. The resulting solid may be in the form of a powder, high concentration of a lipophilic drug. Furthermore. Such a which comprises the compound completely dissolved and technique also results in physically stable compositions and 45 present in molecularly dispersed form within a thin film of the an extremely fast dissolution rate. Beneficially, the thus solvent that is adsorbed onto the large surface of the solid formed powder can be processed directly into granulates or carrier. Advantageously, it has been discovered that the com processed directly into tablets, in particular by direct tablet pound does not return into its crystalline form, even after long ting. term storage and the resulting powder is applicable for being Now provided is a composition in the form of a powder 50 granulated or otherwise transferred into a suitable solid dos which comprises lipophilic compounds in molecularly dis age form, such as being compressed directly into tablets. persed form, a solvent or at least a residue of a solvent, and a Advantageously, the dissolution rate is very high. carrier which has a specific surface area of at least 250 m/g. Thus, in a first aspect, the invention relates to a powdery It is to be understood that the lipophilic compound is molecu composition comprising a steroidal molecule; and amor larly dispersed in the solvent or in the solvent that remains 55 phous silica having a specific surface area of at least 250 m/g: after evaporation. wherein the steroidal molecule is molecularly dispersed in a solvent. Thus, in a first aspect, the invention relates to a powdery A particular aspect thereof relates to a composition in the composition comprising a lipophilic molecule having a solu form of a powder comprising drospirenone and amorphous bility in water at 25°C. lower than 1 mg/ml, such as a steroidal 60 silica having a specific surface area of at least 250 m/g, molecule; and a carrier, such as amorphous silica, having a wherein the steroidal molecule is molecularly dispersed in a specific surface area of at least 250 m/g; wherein the lipo solvent. philic molecule (such as a steroidal molecule) is molecularly Another particular aspect thereof relates to a composition dispersed in a solvent. in the form of a powder comprising estradiol Valerate and Compounds of the present invention are preferably steroi 65 amorphous silica having a specific Surface area of at least 250 dal molecules and hormones in general. In particular, dro m/g, wherein the steroidal molecule is molecularly dis spirenone and estradiol Valerate are preferred. persed in a solvent. US 8,715,735 B2 5 6 As used herein, the term “molecularly dispersed” or 0.01 mg/ml. Typically, the compound is an active pharmaceu “molecular dispersion' is used to describe any solid, semi tical ingredient, such as a steroidal molecule and/or a hor Solid and liquid system in which the lipophilic compound is mone/anti-hormone in general. A large range of other active dispersed at the molecular level within or on a carrier. That is pharmaceutical ingredients may benefit from the present to say that the lipophilic drug is present in dissolved form in 5 technology. Such as albendazole, aminogluthethimide, ami the Solid phase. That is to say that the lipophilic drug is nosalicylic acids (3- 4- or 5-aminosalicylic acids) amio present in dissolved form in the solvent. The lipophilic com darone, astemizole, azathioprine, beclamide, benorylate, pound cannot be detected in crystalline form, Such as by benperidol, bezafibrate, biotin, bromocriptine, bromocriptine X-ray diffraction, and the lipophilic compound is not detect mesylate, bumetanide, buSulphan, cabergoline, carbam able by microscopy, such as light microscopy or electron 10 azepine, cefixime, chenodeoxycholic acid, chlorambucil, microscopy or by other relevant analysis of the molecular chloroquine, chlorpropamide, chlorprothixene, chlorthali dispersion. That is to say that the lipophilic compound of the done, cinnarizine, cinoxacin, clobazam, clofazimine, clofi invention is neither present in a particulate form nor in a brate, clonazepam, cyclopenthiazide, cyclosporin A, dap crystalline form. In fact, the lipophilic compound is present as Sone, demeclocycline, diazoxide, diflunisal, digitoxin, distinct molecules and if examined under the electron micro 15 digoxin, disulfiram, domperidone, droperidol, enoxacin, Scope no particles are observed. epothilone, ethionamide, etretinate, felodipine, fenbufen, In practice “molecularly dispersed” compositions are fexofenadine, flumazenil, folic acid, furosemide, glipizide, formed by completely dissolving the lipophilic compound in gliquidone, griseofulvin, haloperidol, hydrochlorothiazide, a solvent. Some times the concentration of the lipophilic hydroflumethiazide, ibuprofen, iloprost, indomethacin, iso compound exceeds the amount that can be dissolved at room carboxazid, isosorbide dinitrate, isotretinoin, isradipine, itra temperature. Subsequently, the solvent is mixed with a carrier conazole, ketazolam, ketoconazol, ketoprofen, lanSoprazole, resulting in the lipophilic compound being distributed evenly liothyronine sodium, lisuride, loperamide, loratadine, and homogenously onto the Surface of the carrier at the lorazepam, lovastatin, mebendazole, medazepam, mefe molecular level. That is to say that the lipophilic compound is namic acid, menadione, meduitazine, methotrexate, miso still present in dissolved form in the solvent absorbed onto the 25 prostol, morphine, niclosamide, nifedipine, nimodipine, surface of the carrier. This phenomenon refers to the lipo nitrazepam, omeprazole, oxazepam, oxytetracycline, panto philic compound being molecularly dispersed in the solvent/ prazole, perphenazine, phenylbutaZone, pimozide, pindolol. carrier. probenecid, probucol, pyrantel embonate, pyrimethamine, The term “molecularly dispersed”, when used herein, is retinol, riboflavin, simvastatin, stilboestrol, Sulindac, Sul meant to be interchangeable with the terms “molecular dis 30 phadiazine, Sulphamethoxazole, SulphaSalazine, Sulpiride, persion”, “molecularly dissolved and “molecular dissolu tamoxifen, temazepam, thiabendazole, thioguanine, toco tion”. In the present context the terms "molecularly dis pherol, tolbutamide, tretinoin, triamteren, triazolam, trime solved' and "molecular dissolution' shall not be understood thoprim and Zopiclone. as a simple liquid solution as known in the art. AS Said, a compound of the invention is typically asteroidal The term "saturated solution' is used to describe a solution 35 molecule or otherwise a hormone of which can be mentioned: containing a concentration of the lipophilic compound of the androgens, such as testosterone and esters thereof (test invention that is equal to the amount of compound that maxi osterone enanthate, testosterone undecanoate, testoster mally can be dissolved at room temperature, the so-called one cypionate, testosterone propionate) “saturation concentration'. estrogens/anti-estrogens, such as estradiol and esters The term “supersaturated solution is used to describe a 40 thereof (estradiol Valerate, estradiol enanthate, estradiol Solution containing a concentration of the lipophilic com cypionate, estradiol undecylate), estriol, estrone, conju pound that is higher than its saturation concentration and gated estrogens, equilin, ethinyl estradiol, fenestrel, wherein the full amount of the compound is still completely mestranol, nylestriol, quinestrol, clomifene, estrogen dissolved. Thus, even with the saturated concentrations of receptor alpha agonists, estrogen receptor alpha antago lipophilic compound no crystalline compound can be 45 nists, estrogen receptor beta agonists, estrogen receptor detected by powder X-ray diffraction analysis nor by other beta antagonists, estrogen receptor downregulators. methods. Basically, Supersaturated Solutions are expected to Corticosteroids. Such as cortisones and glucocorticoids, be thermodynamically unstable leading to a saturated Solu e.g. beclomethasone dipropionate, betamethasone, tion containing a recrystallized or precipitated (particulate) betamethasone Valerate, budesonide, clobetasol propi compound. 50 onate, clobetaSone butyrate, cortisone acetate, dexam The term “stabilised supersaturated solution' is used to ethasone, fludrocortisone acetate, prednisolone, pred describe a Supersaturated solution wherein neither a re-crys nisone. tallized drug nor a precipitated (particulate) drug can be progestins/antiandrogens, such as cyproterone, dro detected by powder X-ray diffraction analysis. spirenone, etonogestrel, desogestrel, gestodene, When applied to powder X-ray diffraction, absence of 55 levonorgestrel, norethisterones, norgestimate, norethin diffraction peaks corresponding to those of the crystalline drone, norethindrone acetate, norethynodrel, norgesti drug indicates that the drug is present in a non-crystalline mate, norgestrel, medrogestone, medroxyprogesterone form such as a molecularly dispersed form. acetate, progesterone, progesterone receptor A specific As mentioned, Scanning Electron Microscopy may be ligands, progesterone receptor B specific ligands, meso used to detect whether the lipophilic drug is present in a 60 progestins, antiprogestins, asoprisnil, asoprisnil eca molecularly dispersed form in that no particles may be mate. observed in an electron microscope having a sensitivity below Aldosterone antagonists, such as Spironolactones, the "nano' size range. eplerenone, canrenoate, canrenone, dicirenone, A typical compound of the invention is characterised by meXrenoate, prorenoate, epostane, mespirenone, being lipophilic and/or having a poor solubility in water at 25° 65 oXprenoate, Spirorenone, spiroXasone, prorenone. C. In general, the compound has a solubility lower than 1 Vitamin Dhormones, such as alfacalcidol, calcifediol, cal mg/ml in water at 25°C., such as lower than 0.5,0.1, 0.05, or ciferol, calcitriol. US 8,715,735 B2 7 8 Thus, a steroidal molecule of the invention may be selected Optionally, the solvent may be evaporated or otherwise from estradiol and esters thereof, ethinyl estradiol, conju reduced in an amount So that only sporadical amounts of the gated estrogens, testosterone and esters thereof, cyproterone, Solvent remains in the composition. In the resulting compo drospirenone, etonogestrel, desogestrel, gestodene, sition it is to be understood that the compound is molecularly levonorgestrel, norethisterones, norgestimate, norethindrone, dispersed within the remaining solvent, which is adsorbed as norethindrone acetate, norethynodrel, norgestimate, norg a thin film onto the carrier, the high Surface amorphous silica. estrel, medrogestone, medroxyprogesterone acetate, proges It is also to be understood that in the compositions of the terone, Spironolactones, eplerenone, canrenoate, canrenone, invention the molecular dispersion of the compound is meant dicirenone, meXrenoate, prorenoate, epostane, mespirenone, to define that the compound is in fact dissolved in the solvent, oXprenoate, Spirorenone, spiroXasone, prorenone, asoprisnil, 10 beclomethasone dipropionate, betamethasone, betametha also after the solvent has been adsorbed by the carrier of the Sone Valerate, budesonide, clobetasol propionate, clobeta invention. In one embodiment of the invention, the compound Sone butyrate, cortisone acetate, dexamethasone, fludrocor is present in the solvent in a Supersaturated concentration tisone acetate, prednisolone, prednisone, alfacalcidol. before the solvent is adsorbed onto the silica carrier material. calcifediol, calciferol or calcitriol. 15 The degree of Super-saturation may vary. Typically the degree It is to be understood that the compositions of the invention of Super saturation is above 1.1. Such as above 1.2. In general may comprise more than one active drug Substance, e.g. a it is not possible to reach a degree of Super-saturation greater combination of two ore more drug Substances. For example, than 2.5. a composition of the invention may comprise a therapeutic Further it must be understood that when measuring the effective dose of drospirenone and a therapeutic effective dissolution rate of a composition according to the invention dose of an estrogen. the dissolution rate is very fast. The fast dissolution rate is due In currently interesting embodiments, the compound of the to the fact that the molecularly dispersed compound is already invention is estradiol Valerate and/or drospirenone. present in a dissolved state and that once the composition has As said, the composition of the invention comprises a disintegrated, the release of the compound takes place imme carrier, preferably a pharmaceutically acceptable carrier, 25 diately. The rate-determining step for the release is the disin which is characterised by having a high Surface area. It has tegration time of the composition and not the dissolution step. been found that the carrier should have a specific surface area Suitable solvents for use in the dissolution of the lipophilic greater than 200 m/g, preferably greater than 250 m/g. compound of the invention include but are not limited to: More preferably the carrier should have a specific surface ethanol, isopropanol, glycerol, propylene glycol, transcutol, area greater than 300 m/g. Obviously, the surface area may 30 polyols, citric acid esters, monoglycerides, diglycerides, Veg have an upper limit. It is generally acknowledged that the etable oils, partialsynthetic triglycerides e.g. medium chain upper limit of the surface area is at the most 1000 m?g, such triglycerides (MCT) such as miglyol(R), synthetic triglycer as at the most 800 m/g. ides, mixtures of glycerol fatty acid esters such as Imwitor R, It has been found that such a carrier with a high specific fatty alcohols, fatty alcohol ethers, fatty acids, fatty acid Surface area may be silica dioxide in amorphous form with a 35 esters, waxes, paraffin, purified water or mixtures thereof. specific high surface area of about 300 m/g, such as the silica Preferably, the solvent is selected from ethanol; propylene dioxide marketed under the name Aeroperl R. AeroperlR) is glycol; partial synthetic triglycerides; and vegetable oils. The characterised by being an amorphous granulated fumed silica Vegetable oil is typically a mixture of fatty acid glycerides. with a silicon dioxide content of over 99.8% w/w. Typically, the vegetable oil is selected from olive oil; pea Silica dioxide is a well-known excipient usable for a broad 40 nut oil and castor oil. Typically, olive oil complies with the range of purposes. It has been used as a crystallisation inhibi quality described in Ph. Eur; Olivae oleum raffinatum and/or tor in patch technology and as adsorber, anticaking and free the quality described in USPNF: Olive Oil. Typically, peanut flow agent, defoaming agent, drying agent (desiccant), filler, oil complies with the quality described in Ph. Eur; Arachidis hydrophobizing agent for increasing water resistance, Sus oleum and/or the quality described in USPNF: Peanut oil. pension stabiliser, gel-forming agent or viscosity adjuster. 45 Typically, the castor oil complies with the quality described in AeroperlR) is able to absorb large amounts of oil and even Ph. Eur.; Ricini oleum virginale and/or the quality described then restore its good flowability properties. This renders the in USP; Castor oil. combination of Aeroperl R. and an oil suitable for acting as a Typically, the partial synthetic triglyceride is a medium binder in the preparation of tablets. Due to the relatively large chain triglyceride corresponding to the quality described in particle size of AeroperlR) the excipient has a lower dusting 50 Ph.Eur.; Triglycerida saturate media. Suitable medium-chain and is easier to handle in production. triglycerides may also be known in the art as Bergabest(R), The present inventors have found that amorphous silica Captex R, Crodamol(R), LabrafacR, Myritol(R), Neobee M5(R), dioxide, when applied in a form with high specific Surface Nesatol(R), Wagninol (R) or Miglyol(R). Preferably the medium area, such as above 200 m/g, preferably above 300 m/g, chain triglyceride is known in the art as Miglyol(R), Such as more preferably above 350 m/g, stabilises the molecular 55 Miglyol(R) 810 or Miglyol(R) 812. dispersion of the compound in the composition. By example, The ratio between the solvent and the carrier may be criti crystals could not be detected by X-ray diffraction analyses in cal in terms of achieving a powder with good powder compositions of the invention. Thus, in other terms, the com flowability and stability of the compound. Thus, in some position of the invention does not comprise crystals of the embodiments the weighed ratio between the solvent and the compound. 60 carrier is ranging between 1:100 and 1:0.2, preferably Alternative carriers with similar properties to silica dioxide between 1:50 and 1:0.5, more preferably between 1:20 and may be applicable, for example polyvinylpyrrolidone (Povi 1:0.5. Dependent on the type of solvent, the weighed ratio done(R), Kollidon(R). between the solvent and the carrier is normally in the range of According to the invention, the compound is present in the 1:5 and 1:0.5, preferably about 1:2, 1:1 and 1:0.7. composition in molecularly dispersed form. That is to say that 65 The powdery compositions of the invention may in addi the compound has been completely dissolved in a Suitable tion contain Surfactants and co-solvents, which may be added solvent, which solvent is then adsorbed onto the solid carrier. to the above-mentioned solvents so as to modify the physico US 8,715,735 B2 10 chemical properties of the solvent so as to increase the solu Therefore, a particular aspect of the invention relates to the bility of the lipophilic compound of the invention in the use of amorphous silica with a specific Surface area greater solvent. than 250 m/g for inhibiting re-crystallisation of a steroidal Suitable surfactants include but are not limited to: molecule that is present in a solvent in a Supersaturated con a) Lecithine centration. b) block copolymers of ethylene oxide and propylene oxide It is an advantage of the present invention that it provides an such as Pluronic R and Poloxamer R grades active pharmaceutical ingredient in the form of a powder, c) glycerol esters, and polyoxyethylene glycerol esters, and which can be sieved, mixed with excipients, and encapsulated mixtures thereof such as Gelucire(R) grades into hard gelatine capsules or directly compressed into tablets d) sucrose fatty acid esters such as Sucroesters(R) 10 even without adding a binder. e) Sorbitan fatty acid esters, and polyoxyethylene Sorbitan Thus, in a further aspect, the invention relates to pharma fatty acid esters, and mixtures thereof Such as Span R and ceutical dosage forms, which are in the form of granules, a TweenR) grades tablet, a capsule, or a pill that comprises the powdery com f) polyoxyethylene fatty acid esters, polyoxyethylene fatty 15 position as defined herein. alcohol ethers, and polyoxyethylene mono-, di- and trig The powdery compositions or the pharmaceutical dosage lyceride esters, and mixtures thereof, such as Cremophor(R) forms comprising the powdery compositions are preferably grades. formulated in a manner allowing the compositions to be per As said, the compositions of the invention are Superior to orally administered. That is to say that in one embodiment of those obtained by previously applied formulation techniques. the invention, the composition of the invention is contacted In one embodiment, the invention provides compositions that with the gastric fluid following administration. In another exhibit one or more advantageous properties relative to an embodiment, the compositions are formulated in a manner un-formulated compound. allowing the lipophilic compound or the compositions to pass For example, the in-vitro dissolution rate is high. It may be the gastric fluid without being contacted with the gastric fluid, investigated in an in-vitro dissolution test method using 900 25 Such as formulated with enteric coating material. 1000 mL of dissolution medium that ensures sink condition The composition comprising the molecular dispersion can, Such as water or an aqueous solution of Sodium dodecyl optionally, further comprise excipients selected from the sulfate (37° C., 50-100 rpm) and a dissolution apparatus group comprising disintegrants, lubricants, glidants, artificial according to USP equipped with paddles. It was found that Sweeteners, bulking agents, colorants and one or more fla powdery composition of the invention exhibits fast dissolu 30 VOrantS. tion of the compound in that more than 95% w/w of dro The composition comprising the molecular dispersion can spirenone was dissolved within the first 5 minutes of disso be produced in solid dosage forms. Solid dosage forms lution testing. include tablets, film coated tablets, granules, pellets, pills, Thus, in a particular embodiment of the invention, the capsules and powders including for example any modified composition comprises as the compound drospirenone and at 35 release form of said dosage forms such as dosage forms with least 90% by weight of the drospirenone in the composition is delayed release coatings, Sustained release coatings, enteric dissolved within the first 5 minutes of in-vitro dissolution coatings, immediate release formulations, effervescent dos testing using as the dissolution medium 900-1000 mL of a age forms and chewable forms. Capsules include e.g. soft medium ensuring sink condition, such as water oran aqueous gelatine capsules, hard gelatine capsules, hydroxypropyl solution of sodium dodecyl sulfate (0.4% sodium dodecyl 40 methyl cellulose (HPMC) capsules, and carragenane cap sulfate) equilibrated at 37°C., and as the dissolution appara Sules. tus a USP apparatus equipped with paddles rotating with a In some embodiments, the powdery compositions may be speed of 50 or 100 rpm. suitably formulated for buccal or sublingual administration. Generally, the composition of the invention includes the All dosage forms can be produced by methods well known following Superior properties, but is not limited to one or 45 in the art. more of the following: Typically, the amount of drug in the compositions of the 1. high bioavailability prior art inventions ranges from about 1 to about 75 wt %, 2. low degradation of compound in gastric fluid or a fluid preferably from about 5 to about 50 wt %. When speaking equivalent thereto about the final dosage form the amount of the compound 3. high absorption from the gastric mucosa 50 ranges from about 0.1 to about 5.0 wt % in the pharmaceutical 4 ... high in-vitro dissolution in dissolution media simulating dosage form, such as tablets, granules, pellets or powders, the gastric fluid and/or intestinal fluid. preferably from about 1.0 to about 5.0 wt %. This is to say that ... high in-vitro dissolution in water typically the molecularly dispersed composition is present in ... improved blend uniformity the pharmaceutical dosage form in amounts ranging from ... improved dose uniformity 55 about 5 and 100 wt %, preferably from about 10 and 50 wt %. ... improved flowability of the powdery composition The composition of the invention may comprise a number 9. high load of compound in the compositions of the invention of additional excipients. 10. high physically stability (no formation of precipitates/ Suitable disintegrants are selected from the group consist crystals) of the compound in the powdery composition so ing of croScarmellose sodium (a cross linked polymer of as to allow this powder to be stored for a long term 60 carboxymethylcellulose sodium), crospovidone, starch NF: As stated, the use of the high Surface silica renders it polacrilin Sodium or potassium and Sodium starch glycolate. possible to make stabilised solutions of lipophilic compounds Those skilled in the art will appreciate that it is desirable for dissolved completely at a concentration exceeding the Satu compressible tablets to disintegrate within 30 minutes, more ration level of the compound in the solvent at room tempera desirable within 10 min, most desirable within 5 min; there ture (Supersaturated Solutions) and to transform this solution 65 fore, the disintegrant used preferably results in the disintegra into a powdery composition without forming crystals or pre tion of the tablet within 30 minutes, more preferable within 10 cipitates of the compound, even after long term storage. min, most preferable within 5 min. US 8,715,735 B2 11 12 Suitable lubricants include talc, magnesium Stearate, cal A preferred process for preparing stabilised Supersaturated cium Stearate, Stearic acid, hydrogenated vegetable oils and Solutions of lipophilic drugs such as sex steroids is described the like. Preferably, magnesium Stearate is used. in examples 1-4 and 6. Suitable glidants include pyrogenic silica, talc and the like. From example 6 it will be understood that various formu Suitable bulking agents include xylitol, mannitol, com lations according to examples 1 to 4 exhibit very fast in-vitro pressible Sugars, lactose, calcium phosphate and microcrys dissolution rates with respect to estradiol Valerate and much talline celluloses. faster than that of the micronised estradiol valerate (Dso-5 um). Thus, in-vivo dissolution of the compositions of the Suitable artificial Sweeteners include Saccharin, cycla invention will take place instantly as soon as the disintegra mates and aspartame. tion of the composition has taken place. If desired, known flavorants and known FD & C colorants 10 It was concluded that estradiol Valerate is present in a can be added to the composition. molecularly dispersed form—that is to say—in an already In a further aspect, the invention relates to the use of amor dissolved form. Thus, the in-vitro dissolution test does not phous silica with a specific surface area greater than 250 m/g represent a dissolution procedure but rather reflects the dis for inhibiting re-crystallisation of a compound that is present integration time of the compound. in a solvent in a Supersaturated concentration. 15 Example 7 shows the same result for drospirenone, and the Process for Preparing Molecular Dispersions of Lipophilic above mentioned conclusion was verified by X-ray powder Drugs diffraction: no crystals could be found (example 8). Generally, Super-saturated solutions can be prepared by dissolving a drug compound in a solvent in an amount EXAMPLES exceeding the Saturation concentration of the drug with respect to that solvent by means of heating, ultrasonic treat Example 1 ment, stirring and/or high speed mixing. Without wishing to be limited to any specific mixing tech When dissolving estradiol Valerate in polyethylene glycol nology, stabilized Supersaturated compositions of the inven (PEG) 400 at room temperature, the saturation concentration tion can be prepared by mixing a Supersaturated Solution with 25 was found to be approx. 50 g/L. A Supersaturated Solution of estradiol Valerate is prepared by dissolving 91 g estradiol the powdered carrier. Valerate in 1000 mL polyethylene glycol 400 by stirring at 55° In case of using a volatile solvent, the compositions of the C. The resulting liquid is mixed with 1000 g Aeroperl R300 to invention may be prepared by dissolving a drug compound in give a powder with homogeneously absorbed liquid. 24 mg of a solvent while not exceeding the saturation concentration of the described stabilised supersaturated formulation contains the drug with respect to that solvent and Subsequently mix the 30 resulting solution with the powdered carrier. By subsequent 1 mg estradiol Valerate. evaporation off a part of the solvent a supersaturated solid Example 2 solution is formed. Therefore, a further aspect of the invention relates to a When dissolving estradiol Valerate in peanut oil at room process for the preparation of a powdery composition com 35 temperature, the Saturation concentration was found to be prising a lipophilic compound of the invention, such as a approx. 30g/L. A Supersaturated solution of estradiol Valerate steroidal molecule, molecularly dispersed in a solvent, the is prepared by dissolving 39 g estradiol Valerate in 1000 mL process comprising the steps of peanut oil by stirring at 55° C. The resulting liquid is mixed a) dissolving in a solvent a lipophilic compound (such as a with 1667 g AeroperlR 300 to give a powder with homoge steroidal molecule) in an amount that exceeds the Saturation 40 neously absorbed liquid. 67 mg of the described stabilised concentration of thatlipophilic compound (such as a steroidal Supersaturated formulation contains 1 mg estradiol Valerate. molecule) in the Solvent; and b) mixing the resulting Supersaturated Solution of step a) Example 3 with a carrier as defined herein, Such as amorphous silica having a specific surface area of at least 250 m/g. 45 When dissolving estradiol Valerate in medium chain trig The process may optionally further comprise the step of lycerides (MCT) at room temperature, the saturation concen reducing the amount of solvent, such as by evaporating off the tration was found to be approx. 27 g/L. A Supersaturated solvent so as to achieve a thin film of solvent adsorbed onto Solution of estradiol Valerate is prepared by dissolving 45g the surface of the carrier. estradiol Valerate in 1000 mL medium chain triglycerides by A still further aspect of the invention relates to a process for 50 stirring at 55°C. The resulting liquid is mixed with 1000 g the preparation of a powdery composition comprising a ste AeroperlR 300 to give a powder with homogeneously roidal molecule molecularly dispersed in a solvent, where the absorbed liquid. 44 mg of the described stabilised supersatu amount of lipophilic component dissolved equals the satura rated formulation contains 1 mg estradiol Valerate. tion concentration of that lipophilic compound. In this aspect of the invention the process comprises the steps of 55 Example 4 a) dissolving in a solvent a steroidal molecule in an amount that is lower or equals the saturation concentration of A saturated solution of estradiol Valerate is prepared by that steroidal molecule in the solvent; and dissolving 89 g estradiol Valerate in 1000 mL ethanol by b) mixing the resulting Saturated Solution of step a) with stirring at room temperature. The resulting solution is mixed amorphous silica having a specific Surface area of at 60 with 1000 g AeroperlR 300 giving a dry powder by partly least 250 m/g; and ethanol evaporation. 16 mg of the described stabilized super c) evaporating off a part of the solvent. saturated formulation contains 1 mg estradiol Valerate. The process may be applied to the lipophilic compounds defined herein, in particular applied with respect to steroidal Example 5 molecules drospirenone and estradiol Valerate. Likewise, any 65 Solvent, any carrier and any ratio between solvent and carrier Formulations according to the examples 1 to 4 were inves as defined above may be applied in the process. tigated in an in-vitro dissolution test according to USP US 8,715,735 B2 13 14 XXVIII Paddle apparatus 2 using 1000 mL of an 0.4% aque The invention claimed is: ous solution of sodium dodecyl sulfate as dissolution medium 1. A powdery pharmaceutical composition comprising to ensure sink condition (37° C., 75 rpm). The amount of a steroidal molecule; formulations to be tested was selected so that the composition a pharmaceutically acceptable amorphous silica carrier contains approx. 1 mg of estradiol Valerate. As reference, 1 5 having a specific surface area of greater than 200 m/g: mg unformulated estradiol Valerate was investigated. and a pharmaceutically acceptable solvent said solvent being present on the Surface of said pharma ceutically acceptable carrier and said solvent compris Release estradio Valerate Ing 10 ing an amount of the Steroidal molecule Sufficient to Formulation 3 min 6 min 10 min 15 min 30 min provide a Supersaturated concentration thereof Estradiol valerate O.34 0.41 O.47 O.67 O.76 wherein said powdery pharmaceutical composition is pre (micronised) pared by Formulation according to O.SO O.S2 O.S8 O.63 O.68 a) dissolving said steroidal molecule in said solvent in an example 1 (PEG 400) 15 Formulation according to 0.72 0.75 O.78 0.79 O.80 amount that equals the saturation concentration of the example 2 (peanut oil) steroidal molecule, mixing the resulting saturated Formulation according to O.86 O.90 O.91 0.97 O.99 Solution with said pharmaceutically acceptable car example 3 (MCT) rier and evaporating off a part of the solvent so as to Formulation according to O.92 O.88 O.88 O.89 O.90 example 4 (ethanol) provide a Supersaturated concentration thereof O b) dissolving said steroidal molecule in said solventinan amount that exceeds the Saturation concentration of Example 6 the steroidal molecule 25 and mixing the resulting saturated solution with said A saturated solution of drospirenone is prepared by dis pharmaceutically acceptable carrier so as to provide a solving 17.56 g drospirenone in 1000 mL ethanol by stirring Supersaturated concentration thereof. at room temperature. The resulting Solution is mixed with 2. The composition according to claim 1, wherein the ste 1000 g AeroperlR 300 giving a dry powder by partly ethanol roidal molecule is estradiol or an ester thereof, ethinyl estra evaporation. 61 mg of the described stabilised supersaturated 30 diol, a conjugated estrogen, testosterone or an ester thereof, formulation contains 1 mg drospirenone. cyproterone, drospirenone, etonogestrel, desogestrel, gestodene, levonorgestrel, norethisterones, norgestimate, Example 7 norethindrone, norethindrone acetate, norethynodrel, norges timate, norgestrel, medrogestone, medroxyprogesterone 57 mg of the formulation according to the example 6 was 35 acetate, progesterone, spironolactones, eplerenone, can investigated in an in-vitro dissolution test using 900 mL of renoate, canrenone, dicirenone, mexrenoate, prorenoate, water (37° C., 50 rpm). The following results were found: epostane, mespirenone, oXprenoate, Spirorenone, spiroxas Drospirenone released after 5 min: 97.1%, after 10 min: one, prorenone, asoprisnil, beclomethasone dipropionate, 99.9%, after 15 min: 100.3%, and after 30 min: 100.6%. betamethasone, betamethasone Valerate, budesonide, clobe 40 tasol propionate, clobetaSone butyrate, cortisone acetate, dex Example 8 amethasone, fludrocortisone acetate, prednisolone, pred nisone, alfacalcidol, calcifediol, calciferol or calcitriol. The formulation according to example 6 was investigated 3. The composition according to claim 2, wherein the ste by X-ray powder diffraction (XRPD). Crystals could not be roidal molecule is drospirenone and/or estradiol Valerate. detected. 45 4. The composition according to claim 1, wherein the ste Without further elaboration, it is believed that one skilled roidal molecule is drospirenone. in the art can, using the preceding description, utilize the 5. The composition according to claim 1, wherein the Sol present invention to its fullest extent. The preceding preferred vent is ethanol, partial synthetic triglyceridel, or a vegetable specific embodiments are, therefore, to be construed as oil. merely illustrative, and not limitative of the remainder of the 50 6. The composition according to claim 1, wherein the spe disclosure in any way whatsoever. cific Surface area of said pharmaceutically acceptable carrier In the foregoing and in the examples, all temperatures are is at least 250 m/g. set forth uncorrected in degrees Celsius and, all parts and 7. The composition according to claim 6, wherein the spe percentages are by weight, unless otherwise indicated. cific Surface area of said pharmaceutically acceptable carrier The entire disclosures of all applications, patents and pub 55 is at least 300 m/g. lications, cited herein and of U.S. Provisional Application 8. A powdery pharmaceutical composition according to Ser. No. 60/551.330, filed Mar. 10, 2004, is incorporated by claim 1, wherein part of said solvent is evaporating off after reference herein. mixing. The preceding examples can be repeated with similar Suc 9. A pharmaceutical dosage form in the form of granules, a cess by Substituting the generically or specifically described 60 tablet, a capsule, or a pill comprising the composition as reactants and/or operating conditions of this invention for defined in claim 1. those used in the preceding examples. 10. A process for the preparation of a powdery composition From the foregoing description, one skilled in the art can comprising a steroidal molecule according to claim 1, the easily ascertain the essential characteristics of this invention process comprising and, without departing from the spirit and scope thereof, can 65 a) dissolving completely in a solvent a steroidal molecule make various changes and modifications of the invention to in an amount that exceeds the saturation concentration adapt it to various usages and conditions. of the steroidal molecule in the solvent; and US 8,715,735 B2 15 16 b) mixing the resulting Supersaturated Solution of step a) oXprenoate, Spirorenone, spiroXasone, prorenone, asoprisnil, with a pharmaceutically acceptable carrier having a spe beclomethasone dipropionate, betamethasone, betametha cific surface area of at least 200 m/g. Sone Valerate, budesonide, clobetasol propionate, clobeta 11. A process for the preparation of a powdery composition Sone butyrate, cortisone acetate, dexamethasone, fludrocor comprising a steroidal molecule according to claim 1, the tisone acetate, prednisolone, prednisone, alfacalcidol. process comprising calcifediol, calciferol or calcitriol. a) dissolving completely in a solvent a steroidal molecule 13. The process according to claim 10, wherein the steroi in an amount that equals the saturation concentration of dal molecule is drospirenone and/or estradiol Valerate. the steroidal molecule in the solvent; and 14. The process according to claim 10, wherein the solvent b) mixing the resulting saturated Solution of step a) with a 10 is ethanol, partial synthetic triglyceride, or a vegetable oil. pharmaceutically acceptable carrier having a specific 15. The process according to claim 10, further comprising surface area of at least 200 m/g; and evaporating off the solvent. c) evaporating off a part of the solvent. 16. A powdery composition obtained by the process of 12. The process according to claim 10, wherein the steroi claim 10. dal molecule is estradiolor an ester thereof, ethinyl estradiol, 15 17. A process for preparing a tablet comprising a steroidal a conjugated estrogen, testosterone or an ester thereof, cypro molecule and a pharmaceutically acceptable carrier having a terone, drospirenone, etonogestrel, desogestrel, gestodene, specific surface area of greater than 200 m/g levonorgestrel, norethisterones, norgestimate, norethindrone, comprising: norethindrone acetate, norethynodrel, norgestimate, norg a) preparing a powdery composition according to claim 1: estrel, medrogestone, medroxyprogesterone acetate, proges and terone, Spironolactones, eplerenone, canrenoate, canrenone, c) directly compressing said composition into a tablet. dicirenone, meXrenoate, prorenoate, epostane, mespirenone, k k k k k