US 20050207990A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0207990 A1 Funke et al. (43) Pub. Date: Sep. 22, 2005

(54) STABILISED SUPERSATURATED SOLIDS OF Related U.S. Application Data LIPOPHILIC DRUGS (60) Provisional application No. 60/551.330, filed on Mar. (76) Inventors: Adrian Funke, Berlin (DE); Torsten 10, 2004. Wagner, Berlin (DE); Ralph Lipp, Zionsville, IN (US) Publication Classification Correspondence Address: (51) Int. Cl...... A61L 9/04; A61K 9/14; MILLEN, WHITE, ZELANO & BRANIGAN, A61K 31/56 P.C. (52) U.S. Cl...... 424/46; 514/169 2200 CLARENDON BILVD. SUTE 1400 (57) ABSTRACT ARLINGTON, VA 22201 (US) Methods for improving solubility and bioavailability of (21) Appl. No.: 11/076,022 lipophilic compounds are described. Particularly, described are Stabilized SuperStaturated Solid Solutions, particularly in (22) Filed: Mar. 10, 2005 power form, of lipophilic drugs, Such as Steroidal molecules. US 2005/0207990 A1 Sep. 22, 2005

STABLISED SUPERSATURATED SOLIDS OF pared by dissolving the drug compound and the carrier LIPOPHILIC DRUGS (PVP) in a volatile solvent and then removing the solvent. 0001. This application claims the benefit of the filing date 0009 U.S. Pat. No. 6,027,747 relates to the formulation of U.S. Provisional Application Ser. No. 60/551.330 filed of Solid compositions comprising a hardly Soluble drug Mar. 10, 2004. substance together with a carrier (PVP). The compositions are made by a process including dissolving the drug in a FIELD OF INVENTION Volatile organic Solvent together with a hydrophilic polymer and evaporating the Solvent to dryneSS to form a co-precipi 0002 The present invention relates to the field of phar tate of the drug with the hydrophilic polymer. maceutical formulation Science, in particular with respect to methods of improving solubility and bioavailability of lipo 0010 Khougaz Ketal. relates to the formulation of solid philic compounds. The Specific formulation technique of the dispersions comprising a hardly Soluble drug Substance present invention relates to Stabilised SuperSaturated Solid together with a carrier (PVP), wherein the drug substance is Solutions of lipophilic drugs, Such as Steroidal molecules and present in amorphous form or in crystalline form (Khougaz hormones in general. The Solid Solutions are Suitable for K et al. Crystallisation inhibition in solid dispersions of being processed into tablets or other Solid dosage forms. MK-0591 and PVP polymers, J Pharm Sci vol 89, October 2000, pages 1325-1334). BACKGROUND 0011 Watanabe Tet al. relates to the formulation of solid compositions comprising indomethacin and Silica. The 0.003 Poor bioavailability of lipophilic compounds is a indomethacin is physically mixed with the Silica by co well-known problem, in particular in connection with per grinding or melting resulting in amorphous form of oral administration, wherein the compound is to be dis solved in the gastric fluid and/or intestinal fluid before being indometacin (Watanabe T et al. Stability of amorphous absorbed from the gastro-intestinal tract into the blood indomethacin compounded with silica, Int J Pharm, 226, circulation. Thus, the rate-limiting Step in the absorption of 2001, pages 81-91). compounds from the gastro-intestinal tract is often the 0012 Watanabe Tet al. also relates to the formulation of dissolution rate of the compound in water and other liquids, Solid compositions comprising indomethacin and Silica. The which are similar to the ones found in the gastro-intestinal indomethacin is physically mixed with the Silica by co tract. grinding or melting resulting in amorphous form of indometacin (Watanabe T et al. Prediction of apparent 0004. Many attempts at increasing the solubility of a equilibrium Solubility of indometacin compounded with lipophilic compound have been Suggested and used in the past years. Examples are attempts to increase the Surface silica by 13C solid state NMR, Int J Pharm, 248, 2002, area of a compound, either by Spraying the amorphous pages 123-129). compound onto an inert carrier or by micronising the 0013 Watanabe Tetal relates to the formulation of solid compound. Other attempts have been directed to inclusion compositions comprising indomethacin and Silica or PVP. complexes with cyclodextrins. A common feature of the The indomethacin is physically mixed with the silica or PVP conventional techniques is that the compound is in particu by co-grinding or melting resulting in amorphous form of late form, eg. in amorphous form or in crystalline form. Both indometacin (Watanabe Tet al. Comparision between Poly forms still require the initial Step of dissolving the particu Vinylpyrrolidone and Silica nano particles as carriers for late compound before being capable of penetrating the indomethacin in a solid state dispersion. Int J Pharm, 250, mucosa of the gastro-intestinal tract. 2003, pages 283-286). 0005 Typical examples of pharmaceutical formulation 0014 GB 1365 661 relates to the formulation of solid techniques which result in particulate forms of lipophilic compositions comprising a drug Substance with low water compounds in the final composition/dosage form rather than solubility (Cholesteryl beta-glucoside) and a carrier (Silica in molecularly dispersed lipophilic compounds are as fol (Aerosil"M). The composition is prepared by dissolving the lows: betaglucoside in hot ethanol and Subsequently adding this Solution to the aerosol powder and evaporate the Solvent 0006 EP 0474 098 relates to the formulation of solid from the resulting Slurry. The resulting composition has a compositions comprising a hardly Soluble drug Substance slower release rate than conventional formulations. co-precipitated with a carrier comprising a water-Soluble excipient (PVP) and a biodegradable excipient (polyactic 0015 Takeuchi et al relates to the formulation of com acid). This formulation technique aims at Solving the prob positions wherein the drug compound (tolbutamide) is lem of providing controlled release formulations. present in amorphous form (Takeuchi et al. Spherical Solid dispersion containing amorphous tolbutamide embedded in 0007 U.S. Pat. No. 4,639,370 relates to the formulation enteric coating polymers or colloidal Silica prepared by of powdery compositions comprising a poorly water-Soluble spray-drying technique. Chem Pharm Bulletin Pharm Soc drug in combination with a water insoluble carrier (cross Japan. 35, 1987, pages 3800-3806). linked PVP). The compositions are prepared by grinding/ milling the drug substance and the cross-linked PVP without 0016 Chowdary K et al. relates to the formulation of dissolving the active drug. Solid dispersions (powders) prepared by dissolving the drug (Meloxicam) in a Solvent in the presence of carrier (Silica, 0008 WO 03/04360 relates to the formulation of solid Aerosil). The solvent is then evaporated to dryness. The dispersions comprising a poorly water-Soluble drug in com process of evaporating the Solvent to dryneSS will result in bination with a carrier (PVP). The compositions are pre the drug precipitating onto the carrier (Chowdary K et al. US 2005/0207990 A1 Sep. 22, 2005

Enhancement of dissolution rate of meloxicam. Indian J 0024 Now provided is a composition in the form of a Pharm Sci, 63, 2001, pages 150-154). powder which comprises lipophilic compounds in molecu 0017 Nakakami H relates to the formulation of Solid larly dispersed form, a Solvent or at least a residue of a dispersions comprising poorly water-Soluble drugs and non Solvent, and a carrier which has a specific Surface area of at porous fumed Silicon dioxide as the carrier (Nakakami H. least 250 m/g. It is to be understood that the lipophilic Solid dispersions of indomethacin and griseofulvin in non compound is molecularly dispersed in the Solvent or in the porous fumed Silicon dioxide, prepared by melting. Chem Solvent that remains after evaporation. Pharm Bulletin Pharm Sci Japan, 39, 1991, pages 2417 0025 Thus, in a first aspect, the invention relates to a 2421). powdery composition comprising a lipophilic molecule hav 0018 Monkhouse D C et all relates to the formulation of ing a solubility in water at 25 C. lower than 1 mg/ml, such fine powders of a drug and a carrier (fumed silica). The drug as a Steroidal molecule; and a carrier, Such as amorphous and the Silica are mechanically mixed under addition of an silica, having a specific Surface area of at least 250 m/g; organic volatile Solvent (acetone, chloroform or methylene wherein the lipophilic molecule (Such as a steroidal mol chloride) in order to totally dissolve the drug in the sample. ecule) is molecularly dispersed in a Solvent. The Solvent is then evaporated to dryness. AS the Solvent is 0026 Compounds of the present invention are preferably evaporated to dryneSS the drug will precipitate onto the Steroidal molecules and hormones in general. In particular, carrier (Monkhouse D C et al. Use of adsorbents in enhance droSpire none and estradiol Valerate are preferred. ment of drug dissolution I. J Pharm Sci, Am Pharm ASS 0027. In a second aspect, the invention relates to a Washington, 61, 1972, 1430-1435). process for the preparation of a powdery composition of the 0019 WO 01/52857 relates to the formulation of solid invention, the proceSS comprising the Steps of compositions comprising droSpirenone and an estrogen, 0028 a) dissolving in a solvent a lipophilic mol wherein the droSpire none is initially dissolved in a Solvent ecule having a solubility in water at 25 C. lower and then Sprayed onto the Surface of an inert carrier. than 1 mg/ml, Such as a Steroidal molecule, in an 0020 Obviously, the administration of a compound that amount that exceeds the Saturation concentration of is in the dissolved Stage already at the time of administration that Steroidal molecule in the Solvent; and may be advantageous in terms of ensuring high bioavail ability. For example, by dissolving a compound in a Suitable 0029 b) mixing the resulting supersaturated solu oil or another lipophilic medium. Unfortunately, it is often tion of step a) with amorphous silica having a found that the amount of drug which is dissolvable in the specific Surface area of at least 250 m/g. lipophilic media is too low, for which reason the oil cannot 0030) A further aspect of the invention relates to a be administered in an acceptable form, Such as enclosed in process for the preparation of a powdery composition com a capsule or the like. prising a steroidal molecule molecularly dispersed in a 0021 Supersaturated solutions of lipophilic compounds Solvent, where the amount of lipophilic component dis are known approaches for making Solutions containing Solved equals the Saturation concentration of that lipophilic lipophilic compounds in a dissolved Stage. The concentra compound. In this aspect of the invention the process tion of a dissolved compound in a SuperSaturated Solution is comprises the Steps of higher than the Solubility of the compound in the actual Solvent at room temperature. However, the physical Stability 0031) a) dissolving in a solvent a steroidal molecule of the compound in Such a SuperSaturated Solution is critical in an amount that is lower or equals the Saturation in that re-crystallisation of the compound occurs. Therefore, concentration of that Steroidal molecule in the Sol this technique cannot be applied as a general technique to vent; and lipophilic compounds as Such. 0032) b) mixing the resulting saturated solution of 0022. Therefore, pharmaceutical dosage forms having Step a) with amorphous Silica having a specific the lipophilic drug in a readily dissolvable form and which Surface area of at least 250 m/g; and are also physically stable (no tendency to crystallisation of 0033) c) evaporating off part of the Solvent. the lipophilic drug) and which contain the lipophilic drug in a Satisfactorily high concentration would Solve the problems 0034. In a still further aspect, the invention relates to a asSociated with other techniques. pharmaceutical dosage form in the form of granules, a tablet, a capsule, or a pill, which comprises the powdery compo SUMMARY OF INVENTION Sition as defined herein. 0023 The present inventors have found a formulation 0035) In a still further aspect, the invention relates to the technique of Stabilising SuperSaturated Solutions of lipo use of amorphous Silica with a specific Surface area greater philic drugs by adding a high Surface amorphous Silica to than 250 m/g for inhibiting the re-crystallisation of a SuperSaturated Solutions of a lipophilic drug compound So as compound that is present in a Solvent in a SuperSaturated to allow for the preparation of powdery compositions with concentration. a Satisfactorily high concentration of a lipophilic drug. Furthermore, Such a technique also results in physically DETAILED DESCRIPTION OF THE Stable compositions and an extremely fast dissolution rate. INVENTION Beneficially, the thus formed powder can be processed 0036. It has been found that lipophilic compounds can be directly into granulates or processed directly into tablets, in provided in a highly water-Soluble form using the technique particular by direct tabletting. of SuperSaturated Solutions. First of all, the compound is US 2005/0207990 A1 Sep. 22, 2005

completely dissolved in a Suitable Solvent by heating, if “molecular dissolution”. In the present context the terms necessary, the liquid to high temperatures So as to achieve a “molecularly dissolved” and “molecular dissolution” shall SuperSaturated Solution of the compound. Then, the Solvent not be understood as a simple liquid Solution as known in the is adsorbed onto a Solid carrier characterised by having a art. very high Surface area. The resulting Solid may be in the form of a powder, which comprises the compound com 0043. The term “saturated solution” is used to describe a pletely dissolved and present in molecularly dispersed form Solution containing a concentration of the lipophilic com within a thin film of the Solvent that is adsorbed onto the pound of the invention that is equal to the amount of large Surface of the Solid carrier. Advantageously, it has been compound that maximally can be dissolved at room tem discovered that the compound does not return into its perature, the So-called “Saturation concentration'. crystalline form, even after long term Storage and the 0044) The term “supersaturated solution” is used to resulting powder is applicable for being granulated or oth describe a Solution containing a concentration of the lipo erwise transferred into a Suitable Solid dosage form, Such as philic compound that is higher than its Saturation concen being compressed directly into tablets. Advantageously, the tration and wherein the full amount of the compound is still dissolution rate is very high. completely dissolved. Thus, even with the Saturated con 0037 Thus, in a first aspect, the invention relates to a centrations of lipophilic compound no crystalline compound powdery composition comprising a Steroidal molecule; and can be detected by powder X-ray diffraction analysis nor by other methods. Basically, SuperSaturated Solutions are amorphous Silica having a specific Surface area of at least expected to be thermodynamically unstable leading to a 250 m/g; wherein the steroidal molecule is molecularly Saturated Solution containing a recrystallized or precipitated dispersed in a Solvent. (particulate) compound. 0.038 A particular aspect thereof relates to a composition in the form of a powder comprising droSpirenone and 004.5 The term “stabilised Supersaturated solution” is amorphous Silica having a specific Surface area of at least used to describe a SuperSaturated Solution wherein neither a 250 m/g, wherein the steroidal molecule is molecularly re-crystallized drug nor a precipitated (particulate) drug can dispersed in a Solvent. be detected by powder X-ray diffraction analysis. 0039. Another particular aspect thereof relates to a com 0046) When applied to powder X-ray diffraction, absence position in the form of a powder comprising estradiol of diffraction peaks corresponding to those of the crystalline Valerate and amorphous silica having a specific Surface area drug indicates that the drug is present in a non-crystalline of at least 250 m/g, wherein the steroidal molecule is form Such as a molecularly dispersed form. molecularly dispersed in a Solvent. 0047 As mentioned, Scanning Electron Microscopy may 0040 AS used herein, the term “molecularly dispersed” be used to detect whether the lipophilic drug is present in a or "molecular dispersion' is used to describe any Solid, molecularly dispersed form in that no particles may be Semi-Solid and liquid System in which the lipophilic com observed in an electron microScope having a Sensitivity pound is dispersed at the molecular level within or on a below the "nano' Size range. carrier. That is to Say that the lipophilic drug is present in 0048. A typical compound of the invention is character dissolved form in the solid phase. That is to say that the ised by being lipophilic and/or having a poor Solubility in lipophilic drug is present in dissolved form in the Solvent. water at 25 C. In general, the compound has a solubility The lipophilic compound cannot be detected in crystalline lower than 1 mg/ml in water at 25 C., such as lower than form, Such as by X-ray diffraction, and the lipophilic com 0.5, 0.1, 0.05, or 0.01 mg/ml. Typically, the compound is an pound is not detectable by microScopy, Such as light microS active pharmaceutical ingredient, Such as a Steroidal mol copy or electron microscopy or by other relevant analysis of ecule and/or a hormone/anti-hormone in general. A large the molecular dispersion. That is to Say that the lipophilic range of other active pharmaceutical ingredients may benefit compound of the invention is neither present in a particulate from the present technology, Such as albendazole, amino form nor in a crystalline form. In fact, the lipophilic com gluthethimide, aminosalicylic acids (3-4- or 5-aminosali pound is present as distinct molecules and if examined under cylic acids) amiodarone, astemizole, azathioprine, becla the electron microScope no particles are observed. mide, benorylate, benperidol, beZafibrate, biotin, 0041. In practice “molecularly dispersed” compositions bromocriptine, bromocriptine meSylate, bumetanide, buSul are formed by completely dissolving the lipophilic com phan, cabergoline, carbamazepine, cefixime, chenodeoxy pound in a Solvent. Some times the concentration of the cholic acid, chlorambucil, chloroquine, chlorpropamide, lipophilic compound exceeds the amount that can be dis chlorprothixene, chlorthalidone, cinnarizine, cinoxacin, clo Solved at room temperature. Subsequently, the Solvent is bazam, clofazimine, clofibrate, clonazepam, cyclopenthiaz mixed with a carrier resulting in the lipophilic compound ide, cycloSporin A, dapsone, demeclocycline, diaZOxide, being distributed evenly and homogenously onto the Surface diflunisal, digitoxin, digoxin, disulfiram, domperidone, dro of the carrier at the molecular level. That is to say that the peridol, enoxacin, epothilone, ethionamide, etretinate, felo lipophilic compound is still present in dissolved form in the dipine, fenbufen, feXofenadine, flumazenil, folic acid, furo solvent absorbed onto the surface of the carrier. This phe Semide, glipizide, gliquidone, griseofulvin, haloperidol, nomenon refers to the lipophilic compound being molecu hydrochlorothiazide, hydroflumethiazide, ibuprofen, ilo larly dispersed in the Solvent/carrier. prost, indomethacin, isocarboxazid, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketazolam, ketocona 0042. The term “molecularly dispersed”, when used Zol, ketoprofen, lanSoprazole, liothyronine Sodium, lisuride, herein, is meant to be interchangeable with the terms loperamide, loratadine, lorazepam, lovastatin, mebendazole, “molecular dispersion”, “molecularly dissolved” and medazepam, mefenamic acid, menadione, mecquitazine, US 2005/0207990 A1 Sep. 22, 2005 methotrexate, misoprostol, morphine, niclosamide, nife dexamethasone, fludrocortisone acetate, prednisolone, pred dipine, nimodipine, nitrazepam, omeprazole, oxazepam, nisone, alfacalcidol, calcifediol, calciferol or calcitriol. Oxytetracycline, pantoprazole, perphenazine, phenylbuta Zone, pimozide, pindolol, probenecid, probucol, pyrantel 0057. It is to be understood that the compositions of the embonate, pyrimethamine, retinol, riboflavin, Simvastatin, invention may comprise more than one active drug Sub Stilboestrol, Sulindac, Sulphadiazine, Sulphamethoxazole, stance, e.g. a combination of two ore more drug Substances. SulphaSalazine, Sulpiride, tamoxifen, temazepam, thiabenda For example, a composition of the invention may comprise Zole, thioguanine, tocopherol, tolbutamide, tretinoin, triam a therapeutic effective dose of droSpire none and a therapeu teren, triazolam, trimethoprim and Zopiclone. tic effective dose of an estrogen. 0049. As said, a compound of the invention is typically a 0058. In currently interesting embodiments, the com steroidal molecule or otherwise a hormone of which can be pound of the invention is estradiol Valerate and/or dro mentioned: spirenone. 0059 AS said, the composition of the invention com 0050 androgens, such as testosterone and esters prises a carrier, preferably a pharmaceutically acceptable thereof (testosterone enanthate, testosterone unde carrier, which is characterised by having a high Surface area. canoate, testosterone cypionate, testosterone propi It has been found that the carrier should have a specific onate) Surface area greater than 200 m/g, preferably greater than 0051) estrogens/anti-estrogens, Such as estradiol and 250 m/g. More preferably the carrier should have a specific esters thereof (estradiol Valerate, estradiol enanthate, surface area greater than 300 m/g. Obviously, the surface estradiol cypionate, estradiol undecylate), estriol, area may have an upper limit. It is generally acknowledged estrone, conjugated estrogens, equilin, ethinyl estra that the upper limit of the surface area is at the most 1000 diol, fenestrel, mestranol, nylestriol, quineStrol, clo m°/g, such as at the most 800 m /g. mifene, estrogen receptor alpha agonists, estrogen 0060. It has been found that such a carrier with a high receptor alpha antagonists, estrogen receptor beta Specific Surface area may be Silica dioxide in amorphous agonists, estrogen receptor beta antagonists, estrogen form with a specific high surface area of about 300 m/g, receptor downregulators. Such as the Silica dioxide marketed under the name Aerop 0052 Corticosteroids, such as cortisones and gluco erlE). Aeroperle) is characterised by being an amorphous corticoids, e.g. beclomethasone dipropionate, granulated fumed Silica with a Silicon dioxide content of betamethasone, betamethasone Valerate, budeSonide, over 99.8% w/w. clobetasol propionate, clobetasone butyrate, corti 0061 Silica dioxide is a well-known excipient usable for Sone acetate, dexamethasone, fluidrocortisone a broad range of purposes. It has been used as a crystalli acetate, prednisolone, prednisone. sation inhibitor in patch technology and as adsorber, anti 0053 progestins/antiandrogens, Such as cyproter caking and free flow agent, defoaming agent, drying agent one, droSpire none, etonogestrel, desogestrel, (desiccant), filler, hydrophobizing agent for increasing water gestodene, levonorgestrel, norethisterones, norgesti resistance, Suspension Stabiliser, gel-forming agent or vis mate, norethindrone, norethindrone acetate, nor cosity adjuster. ethynodrel, norgestimate, norgestrel, medrogestone, 0062 Aeroperle) is able to absorb large amounts of oil medroxyprogesterone acetate, progesterone, proges and even then restore its good flowability properties. This terone receptor A Specific ligands, progesterone renders the combination of Aeroperl(R) and an oil suitable for receptor B Specific ligands, mesoprogestins, anti acting as a binder in the preparation of tablets. Due to the progestins, asoprisnil, asopriSnil ecamate. relatively large particle size of Aeroperlf the excipient has 0054 Aldosterone antagonists, such as spironolac a lower dusting and is easier to handle in production. tones, eplerenone, canrenoate, canrenone, dicir 0063. The present inventors have found that amorphous enOne, meXrenoate, prorenoate, epOStane, Silica dioxide, when applied in a form with high Specific meSpire none, Oxprenoate, Spirorenone, SpiroXaSone, surface area, such as above 200 m/g, preferably above 300 prorenone. m°/g, more preferably above 350 m /g, stabilises the molecular dispersion of the compound in the composition. 0055 Vitamin D hormones, such as alfacalcidol, By example, crystals could not be detected by X-ray dif calcifediol, calciferol, calcitriol. fraction analyses in compositions of the invention. Thus, in 0056 Thus, a steroidal molecule of the invention may be other terms, the composition of the invention does not Selected from estradiol and esters thereof, ethinyl estradiol, comprise crystals of the compound. conjugated estrogens, testosterone and esters thereof, cypro terone, droSpire none, etonogeStrel, desogeStrel, gestodene, 0064. Alternative carriers with similar properties to silica levonorgestrel, norethisterones, norgestimate, norethin dioxide may be applicable, for example polyvinylpyrroli drone, norethindrone acetate, norethynodrel, norgestimate, done (Povidone(R), Kollidon(R). norgestrel, medrogestone, medroxyprogesterone acetate, 0065 According to the invention, the compound is progesterone, Spironolactones, eplerenone, canrenoate, can present in the composition in molecularly dispersed form. renone, dicire none, meXrenoate, prorenoate, epoStane, That is to Say that the compound has been completely meSpire none, Oxprenoate, Spirorenone, SpiroXaSone, pro dissolved in a Suitable solvent, which Solvent is then renone, asoprisnil, beclomethasone dipropionate, adsorbed onto the Solid carrier. Optionally, the Solvent may betamethasone, betamethasone Valerate, budesonide, clobe be evaporated or otherwise reduced in an amount So that tasol propionate, clobetaSone butyrate, cortisone acetate, only Sporadical amounts of the Solvent remains in the US 2005/0207990 A1 Sep. 22, 2005 composition. In the resulting composition it is to be under 1:0.5. Dependent on the type of solvent, the weighed ratio stood that the compound is molecularly dispersed within the between the Solvent and the carrier is normally in the range remaining Solvent, which is adsorbed as a thin film onto the of 1:5 and 1:0.5, preferably about 1:2, 1:1 and 1:0.7. carrier, the high Surface amorphous Silica. 0073. The powdery compositions of the invention may in 0.066. It is also to be understood that in the compositions addition contain Surfactants and co-Solvents, which may be of the invention the molecular dispersion of the compound added to the above-mentioned solvents so as to modify the is meant to define that the compound is in fact dissolved in physico-chemical properties of the Solvent So as to increase the solvent, also after the solvent has been adsorbed by the the solubility of the lipophilic compound of the invention in carrier of the invention. In one embodiment of the invention, the solvent. the compound is present in the Solvent in a SuperSaturated concentration before the Solvent is adsorbed onto the Silica 0074 Suitable surfactants include but are not limited to: carrier material. The degree of Super-Saturation may vary. 0075) a) Lecithine Typically the degree of Super Saturation is above 1.1, Such as above 1.2. In general it is not possible to reach a degree of 0076 b) block copolymers of ethylene oxide and propylene oxide such as Pluronic(R) and Poloxamer(R) Super-Saturation greater than 2.5. grades 0067 Further it must be understood that when measuring the dissolution rate of a composition according to the 0077 c) glycerol esters, and polyoxyethylene glyc invention the dissolution rate is very fast. The fast dissolu erol esters, and mixtures thereof Such as Gelucire(R) tion rate is due to the fact that the molecularly dispersed grades compound is already present in a dissolved State and that 0078 d) sucrose fatty acid esters such as once the composition has disintegrated, the release of the Sucroesters(E) compound takes place immediately. The rate-determining Step for the release is the disintegration time of the compo 0079 e) Sorbitan fatty acid esters, and polyoxyeth Sition and not the dissolution Step. ylene Sorbitan fatty acid esters, and mixtures thereof such as Span(R) and Tween(R) grades 0068 Suitable solvents for use in the dissolution of the lipophilic compound of the invention include but are not 0080 f) polyoxyethylene fatty acid esters, polyoxy limited to: ethanol, isopropanol, glycerol, propylene glycol, ethylene fatty alcohol ethers, and polyoxyethylene transcutol, polyols, citric acid esters, monoglycerides, dig mono-, di- and triglyceride esters, and mixtures lycerides, vegetable oils, partialsynthetic triglycerides e.g. thereof, Such as Cremophor(R) grades. medium chain triglycerides (MCT) Such as miglyol(F), Syn 0081. As said, the compositions of the invention are thetic triglycerides, mixtures of glycerol fatty acid esters Superior to those obtained by previously applied formulation such as Imwitor(R), fatty alcohols, fatty alcohol ethers, fatty techniques. In one embodiment, the invention provides acids, fatty acid esters, waxes, paraffin, purified water or compositions that exhibit one or more advantageous prop mixtures thereof. erties relative to an un-formulated compound. 0069 Preferably, the solvent is selected from ethanol; 0082 For example, the in-vitro dissolution rate is high. It propylene glycol, partial Synthetic triglycerides, and Veg may be investigated in an in-vitro dissolution test method etable oils. The vegetable oil is typically a mixture of fatty using 900-1000 mL of dissolution medium that ensures sink acid glycerides. condition Such as water or an aqueous Solution of Sodium 0070 Typically, the vegetable oil is selected from olive dodecyl sulfate (37° C., 50-100 rpm) and a dissolution oil, peanut oil and castor oil. Typically, olive oil complies apparatus according to USP equipped with paddles. It was with the quality described in Ph. Eur.; Olivae oleum raffi found that powdery composition of the invention exhibits natum and/or the quality described in USPNF: Olive Oil. fast dissolution of the compound in that more than 95% w/w Typically, peanut oil complies with the quality described in of drospirenone was dissolved within the first 5 minutes of Ph. Eur.; Arachidis oleum and/or the quality described in dissolution testing. USPNF; Peanut oil. Typically, the castor oil complies with 0083. Thus, in a particular embodiment of the invention, the quality described in Ph. Eur.; Ricini oleum virginale the composition comprises as the compound droSpirenone and/or the quality described in USP; Castor oil. and at least 90% by weight of the drospirenone in the 0.071) Typically, the partial synthetic triglyceride is a composition is dissolved within the first 5 minutes of medium-chain triglyceride corresponding to the quality in-vitro dissolution testing using as the dissolution medium described in Ph. Eur.; Triglycerida Saturate media. Suitable 900-1000 mL of a medium ensuring sink condition, such as medium-chain triglycerides may also be known in the art as water or an aqueous Solution of Sodium dodecyl Sulfate BergabestCE), Captex(R), Crodamol(R), Labrafac(R), Myritol(R), (0.4% sodium dodecyl sulfate) equilibrated at 37 C., and as Neobee M5(R), Nesatol(R), Wagninol (R) or Miglyol(R). Prefer the dissolution apparatus a USP apparatus equipped with ably the medium-chain triglyceride is known in the art as paddles rotating with a speed of 50 or 100 rpm. Miglyol(R), such as Miglyol(R) 810 or Miglyol(R) 812. 0084 Generally, the composition of the invention 0.072 The ratio between the solvent and the carrier may includes the following Superior properties, but is not limited be critical in terms of achieving a powder with good powder to one or more of the following: flowability and stability of the compound. Thus, in some 0085 1. high bioavailability embodiments the weighed ratio between the solvent and the carrier is ranging between 1:100 and 1:0.2, preferably 0086 2. low degradation of compound in gastric between 1:50 and 1:0.5, more preferably between 1:20 and fluid or a fluid equivalent thereto US 2005/0207990 A1 Sep. 22, 2005

0087 3. high absorption from the gastric mucosa modified release form of Said dosage forms Such as dosage forms with delayed release coatings, Sustained release coat 0088 4. high in-vitro dissolution in dissolution ings, enteric coatings, immediate release formulations, effer media simulating the gastric fluid and/or intestinal Vescent dosage forms and chewable forms. Capsules include fluid. e.g. Soft gelatine capsules, hard gelatine capsules, hydrox 0089) 5. high in-vitro dissolution in water ypropyl methyl cellulose (HPMC) capsules, and carra genane capsules. 0090. 6. improved blend uniformity 0102) In some embodiments, the powdery compositions 0091) 7. improved dose uniformity may be Suitably formulated for buccal or Sublingual admin 0092 8. improved flowability of the powdery com istration. position 0.103 All dosage forms can be produced by methods well 0093 9. high load of compound in the compositions known in the art. of the invention 0104 Typically, the amount of drug in the compositions 0094) 10. high physically stability (no formation of of the prior art inventions ranges from about 1 to about 75 precipitates/crystals) of the compound in the pow wt %, preferably from about 5 to about 50 wt %. When dery composition So as to allow this powder to be Speaking about the final dosage form the amount of the compound ranges from about 0.1 to about 5.0 wt % in the Stored for a long term pharmaceutical dosage form, Such as tablets, granules, pel 0.095 AS stated, the use of the high surface silica renders lets or powders, preferably from about 1.0 to about 5.0 wt %. it possible to make Stabilised Solutions of lipophilic com This is to say that typically the molecularly dispersed pounds dissolved completely at a concentration exceeding composition is present in the pharmaceutical dosage form in the Saturation level of the compound in the Solvent at room amounts ranging from about 5 and 100 wt %, preferably temperature (SuperSaturated Solutions) and to transform this from about 10 and 50 wt %. Solution into a powdery composition without forming crys tals or precipitates of the compound, even after long term 0105 The composition of the invention may comprise a Storage. number of additional excipients. 0096. Therefore, a particular aspect of the invention 0106 Suitable disintegrants are selected from the group relates to the use of amorphous Silica with a specific Surface consisting of croScarmellose Sodium (a cross linked poly area greater than 250 m/g for inhibiting re-crystallisation of mer of carboxymethylcellulose Sodium), crospovidone, a Steroidal molecule that is present in a Solvent in a Super Starch NF; polacrilin Sodium or potassium and Sodium Starch Saturated concentration. glycolate. Those skilled in the art will appreciate that it is desirable for compressible tablets to disintegrate within 30 0097. It is an advantage of the present invention that it minutes, more desirable within 10 min, most desirable provides an active pharmaceutical ingredient in the form of within 5 min; therefore, the disintegrant used preferably a powder, which can be Sieved, mixed with excipients, and results in the disintegration of the tablet within 30 minutes, encapsulated into hard gelatine capsules or directly com more preferable within 10 min, most preferable within 5 pressed into tablets even without adding a binder. . 0.098 Thus, in a further aspect, the invention relates to 0107 Suitable lubricants include talc, magnesium stear pharmaceutical dosage forms, which are in the form of ate, calcium Stearate, Stearic acid, hydrogenated vegetable granules, a tablet, a capsule, or a pill that comprises the oils and the like. Preferably, magnesium Stearate is used. powdery composition as defined herein. 0099. The powdery compositions or the pharmaceutical 0.108 Suitable glidants include pyrogenic silica, talc and dosage forms comprising the powdery compositions are the like. preferably formulated in a manner allowing the composi 0109 Suitable bulking agents include xylitol, mannitol, tions to be per orally administered. That is to Say that in one compressible Sugars, lactose, calcium phosphate and micro embodiment of the invention, the composition of the inven crystalline celluloses. tion is contacted with the gastric fluid following adminis tration. In another embodiment, the compositions are for 0110 Suitable artificial Sweeteners include Saccharin, mulated in a manner allowing the lipophilic compound or cyclamates and aspartame. the compositions to pass the gastric fluid without being 0111. If desired, known flavorants and known FD & C contacted with the gastric fluid, Such as formulated with colorants can be added to the composition. enteric coating material. 0112 In a further aspect, the invention relates to the use 0100. The composition comprising the molecular disper of amorphous Silica with a specific Surface area greater than Sion can, optionally, further comprise excipients Selected 250 ml/g for inhibiting re-crystallisation of a compound that from the group comprising disintegrants, lubricants, is present in a Solvent in a SuperSaturated concentration. glidants, artificial Sweeteners, bulking agents, colorants and one or more flavorants. 0113 Process for Preparing Molecular Dispersions of Lipophilic Drugs 0101 The composition comprising the molecular disper Sion can be produced in Solid dosage forms. Solid dosage 0114 Generally, Super-Saturated Solutions can be pre forms include tablets, film coated tablets, granules, pellets, pared by dissolving a drug compound in a Solvent in an pills, capsules and powders including for example any amount exceeding the Saturation concentration of the drug US 2005/0207990 A1 Sep. 22, 2005

with respect to that Solvent by means of heating, ultrasonic and much faster than that of the micronised estradiol Valer treatment, Stirring and/or high Speed mixing. ate (Dso-5 um). Thus, in-vivo dissolution of the composi 0115 Without wishing to be limited to any specific tions of the invention will take place instantly as Soon as the mixing technology, Stabilized SuperSaturated compositions disintegration of the composition has taken place. of the invention can be prepared by mixing a SuperSaturated 0128. It was concluded that estradiol valerate is present in Solution with the powdered carrier. a molecularly dispersed form-that is to Say-in an already 0116. In case of using a volatile solvent, the compositions dissolved form. Thus, the in-vitro dissolution test does not of the invention may be prepared by dissolving a drug represent a dissolution procedure but rather reflects the compound in a Solvent while not exceeding the Saturation disintegration time of the compound. concentration of the drug with respect to that Solvent and 0129. Example 7 shows the same result for drospirenone, Subsequently mix the resulting Solution with the powdered and the above mentioned conclusion was verified by X-ray carrier. By Subsequent evaporation off a part of the Solvent powder diffraction: no crystals could be found (example 8). a SuperSaturated Solid Solution is formed. 0117 Therefore, a further aspect of the invention relates EXAMPLES to a proceSS for the preparation of a powdery composition Example 1 comprising a lipophilic compound of the invention, Such as a Steroidal molecule, molecularly dispersed in a Solvent, the 0.130. When dissolving estradiol valerate in polyethylene proceSS comprising the Steps of glycol (PEG) 400 at room temperature, the saturation con centration was found to be approx. 50 g/L. A SuperSaturated 0118 a) dissolving in a solvent a lipophilic com Solution of estradiol Valerate is prepared by dissolving 91 g pound (Such as a steroidal molecule) in an amount estradiol valerate in 1000 mL polyethylene glycol 400 by that exceeds the Saturation concentration of that stirring at 55 C. The resulting liquid is mixed with 1000 g lipophilic compound (Such as a steroidal molecule) Aeroperl(R) 300 to give a powder with homogeneously in the Solvent, and absorbed liquid. 24 mg of the described stabilised super 0119 b) mixing the resulting supersaturated solution Saturated formulation contains 1 mg estradiol Valerate. of step a) with a carrier as defined herein, Such as amorphous Silica having a specific Surface area of at Example 2 least 250 m /g. 0131 When dissolving estradiol valerate in peanut oil at 0120) The process may optionally further comprise the room temperature, the Saturation concentration was found to Step of reducing the amount of Solvent, Such as by evapo be approx. 30 g/L. A SuperSaturated Solution of estradiol rating off the solvent so as to achieve a thin film of solvent Valerate is prepared by dissolving 39 g estradiol Valerate in adsorbed onto the Surface of the carrier. 1000 mL peanut oil by stirring at 55 C. The resulting liquid 0121 A still further aspect of the invention relates to a is mixed with 1667 g Aeroperl(R) 300 to give a powder with proceSS for the preparation of a powdery composition com homogeneously absorbed liquid. 67 mg of the described prising a steroidal molecule molecularly dispersed in a Stabilised SuperSaturated formulation contains 1 mg estra Solvent, where the amount of lipophilic component dis diol Valerate. Solved equals the Saturation concentration of that lipophilic Example 3 compound. In this aspect of the invention the proceSS comprises the Steps of 0.132. When dissolving estradiol Valerate in medium chain triglycerides (MCT) at room temperature, the Satura 0122) a) dissolving in a solvent a steroidal molecule tion concentration was found to be approx. 27 g/L. A in an amount that is lower or equals the Saturation SuperSaturated Solution of estradiol Valerate is prepared by concentration of that Steroidal molecule in the Sol dissolving 45 gestradiol valerate in 1000 mL medium chain vent; and triglycerides by stirring at 55 C. The resulting liquid is 0123 b) mixing the resulting saturated solution of mixed with 1000 g Aeroperle) 300 to give a powder with Step a) with amorphous Silica having a specific homogeneously absorbed liquid. 44 mg of the described Surface area of at least 250 m/g; and Stabilised SuperSaturated formulation contains 1 mg estra diol Valerate. 0124 c) evaporating off a part of the Solvent. 0.125 The process may be applied to the lipophilic com Example 4 pounds defined herein, in particular applied with respect to 0.133 A Saturated solution of estradiol valerate is pre Steroidal molecules droSpire none and estradiol Valerate. pared by dissolving 89 g estradiol valerate in 1000 mL Likewise, any Solvent, any carrier and any ratio between ethanol by Stirring at room temperature. The resulting Solu Solvent and carrier as defined above may be applied in the tion is mixed with 1000 g Aeroperle) 300 giving a dry proceSS. powder by partly ethanol evaporation. 16 mg of the 0.126 A preferred process for preparing Stabilised Super described Stabilized SuperSaturated formulation contains 1 Saturated Solutions of lipophilic drugs. Such as Sex Steroids is mg estradiol Valerate. described in examples 1-4 and 6. Example 5 0127. From example 6 it will be understood that various formulations according to examples 1 to 4 exhibit very fast 0134) Formulations according to the examples 1 to 4 in-vitro dissolution rates with respect to estradiol Valerate were investigated in an in-vitro dissolution test according to US 2005/0207990 A1 Sep. 22, 2005

USPXXVIII Paddle apparatus 2 using 1000 mL of an 0.4% 0142. From the foregoing description, one skilled in the aqueous Solution of Sodium dodecyl Sulfate as dissolution art can easily ascertain the essential characteristics of this medium to ensure sink condition (37° C., 75 rpm). The invention and, without departing from the Spirit and Scope amount of formulations to be tested was Selected So that the thereof, can make various changes and modifications of the composition contains approx. 1 mg of estradiol Valerate. AS invention to adapt it to various usages and conditions. reference, 1 mg unformulated estradiol Valerate was inves tigated. 1. A powdery composition comprising a Steroidal mol ecule; and amorphous Silica having a specific Surface area of at least 250 m/g; wherein the steroidal molecule is molecu larly dispersed in a Solvent. Release estradiol Valerate Img 2. The composition according to claim 1, wherein the Steroidal molecule is Selected from the group consisting of Formulation 3 min 6 min 10 min 15 min 30 min estradiol and esters thereof, ethinyl estradiol, conjugated Estradiol valerate O.34 O41 O.47 O.67 O.76 estrogens, testosterone and esters thereof, cyproterone, dro (micronised) Spire none, etonogeStrel, desogestrel, gestodene, levonorg Formulation according to O.SO 0.52 O.58 O.63 O.68 example 1 (PEG 400) estrel, norethisterones, norgestimate, norethindrone, nore Formulation according to 0.72 O.75 0.78 O.79 O.80 thindrone acetate, norethynodrel, norgestimate, norgestrel, example 2 (peanut oil) medrogestone, medroxyprogesterone acetate, progesterone, Formulation according to O.86 O.90 O.91 0.97 O.99 Spironolactones, eplerenone, canrenoate, canrenone, dicir example 3 (MCT) Formulation according to O.92 O.88 O.88 O.89 O.90 enone, mexrenoate, prorenoate, epoStane, meSpire none, example 4 (ethanol) OXprenoate, Spirorenone, SpiroXasone, prorenone, asoprisnil, beclomethasone dipropionate, betamethasone, betametha Sone Valerate, budesonide, clobetasol propionate, clobeta Sone butyrate, cortisone acetate, dexamethasone, fludrocor Example 6 tisone acetate, prednisolone, prednisone, alfacalcidol, 0135 A Saturated solution of drospirenone is prepared by calcifediol, calciferol and calcitriol. dissolving 17.56 g drospirenone in 1000 mL ethanol by 3. The composition according to claim 2, wherein the Stirring at room temperature. The resulting Solution is mixed Steroidal molecule is droSpirenone and/or estradiol Valerate. with 1000 g Aeroperl(R) 300 giving a dry powder by partly 4. The composition according to claim 1, wherein the ethanol evaporation. 61 mg of the described stabilised Steroidal molecule is present in the Solvent in a SuperSatu SuperSaturated formulation contains 1 mg droSpire none. rated concentration. 5. The composition according to claim 1, wherein the Example 7 Solvent is ethanol; partial Synthetic triglyceride; or a Veg 0.136 57 mg of the formulation according to the example etable oil. 6 was investigated in an in-vitro dissolution test using 900 6. A process for the preparation of a powdery composition mL of water (37° C., 50 rpm). The following results were comprising a Steroidal molecule, the proceSS comprising the found: Drospirenone released after 5 min: 97.1%, after 10 Steps of min: 99.9%, after 15 min: 100.3%, and after 30 min: a) dissolving completely in a Solvent a steroidal molecule 100.6%. in an amount that exceed the Saturation concentration of the steroidal molecule in the solvent; and Example 8 b) mixing the resulting Supersaturated Solution of step a) 0.137 The formulation according to example 6 was inves with amorphous Silica having a Specific Surface area of tigated by X-ray powder diffraction (XRPD). Crystals could at least 250 m/g. not be detected. 7. A process for the preparation of a powdery composition 0138. Without further elaboration, it is believed that one comprising a Steroidal molecule, the proceSS comprising the skilled in the art can, using the preceding description, utilize Steps of the present invention to its fullest extent. The preceding a) dissolving completely in a Solvent a steroidal molecule preferred Specific embodiments are, therefore, to be con in an amount that equals the Saturation concentration of Strued as merely illustrative, and not limitative of the the Steroidal molecule in the Solvent; and remainder of the disclosure in any way whatsoever. b) mixing the resulting Saturated Solution of Step a) with 0.139. In the foregoing and in the examples, all tempera amorphous Silica having a specific Surface area of at tures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indi least 250 m/g; and cated. c) evaporating off a part of the Solvent. 8. The process according to claim 6, wherein the Steroidal 0140. The entire disclosures of all applications, patents molecule is Selected from the group consisting of estradiol and publications, cited herein and of U.S. Provisional Appli and esters thereof, ethinyl estradiol, conjugated estrogens, cation Ser. No. 60/551.330, filed Mar. 10, 2004, is incorpo testosterone and esters thereof, cyproterone, droSpirenone, rated by reference herein. etonogeStrel, desogestrel, gestodene, levonorgestrel, nore 0.141. The preceding examples can be repeated with thisterones, norgestimate, norethindrone, norethindrone Similar SucceSS by Substituting the generically or Specifically acetate, norethynodrel, norgestimate, norgestrel, medroge described reactants and/or operating conditions of this Stone, medroxyprogesterone acetate, progesterone, Spirono invention for those used in the preceding examples. lactones, eplerenone, canrenoate, canrenone, dicire none, US 2005/0207990 A1 Sep. 22, 2005

meXrenOate, prorenoate, epOStane, meSpirenone, 11. The process according to claim 6, further comprising OXprenoate, Spirorenone, SpiroXaSone, prorenone, asoprisnil, the Step of evaporating off the Solvent. beclomethasone dipropionate, betamethasone, betametha 12. A powdery composition obtained by the process as defined in claim 6. Sone Valerate, budesonide, clobetaSol propionate, clobeta 13. A pharmaceutical dosage form in the form of granules, Sone butyrate, cortisone acetate, dexamethasone, fludrocor a tablet, a capsule, or a pill comprising the composition as tisone acetate, prednisolone, prednisone, alfacalcidol, defined in claim 1. calcifediol, calciferol and calcitriol. 14. Use of amorphous Silica with a specific Surface area 9. The process according to claim 6, wherein the Steroidal greater than 250 m/g for inhibiting re-crystallisation of a molecule is droSpire none and/or estradiol Valerate. Steroidal molecule that is present in a Solvent in a Super 10. The process according to claim 6, wherein the solvent Saturated concentration. is ethanol; partial Synthetic triglyceride, or a vegetable oil. k k k k k