US 2003O236236A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0236236A1 Chen et al. (43) Pub. Date: Dec. 25, 2003

(54) PHARMACEUTICAL COMPOSITIONS AND now Pat. No. 6,267,985, and which is a continuation DOSAGE FORMS FOR ADMINISTRATION in-part of application No. 09/751,968, filed on Dec. OF HYDROPHOBC DRUGS 29, 2000, now Pat. No. 6,458,383, which is a con tinuation-in-part of application No. 09/375,636, filed (76) Inventors: Feng-Jing Chen, Salt Lake City, UT on Aug. 17, 1999, now Pat. No. 6,309,663. (US); Mahesh V. Patel, Salt Lake City, UT (US); David T. Fikstad, Salt Lake Publication Classification City, UT (US); Huiping Zhang, Salt Lake City, UT (US); Chandrashekar (51) Int. Cl." ...... A61K 31156; A61K 31/355; Gilyar, Salt Lake City, UT (US) A61K 31/122 (52) U.S. Cl...... 514/171; 514/458; 514/682 Correspondence Address: REED & EBERLE LLP (57) ABSTRACT 800 MENLO AVENUE, SUITE 210 Pharmaceutical compositions and dosage forms for admin MENLO PARK, CA 94025 (US) istration of hydrophobic drugs, particularly Steroids, are provided. The pharmaceutical compositions include a thera (21) Appl. No.: 10/444,935 peutically effective amount of a hydrophobic drug, prefer (22) Filed: May 22, 2003 ably a steroid; a solubilizer, preferably a vitamin E sub stance, and a Surfactant. The Synergistic effect between the Related U.S. Application Data hydrophobic drug and the Vitamin E Substance results in a pharmaceutical formulation with improved dispersion of (63) Continuation-in-part of application No. 09/716,029, both the active agent and the solubilizer. As a result of the filed on Nov. 17, 2000. improved dispersion, the pharamaceutical composition has Continuation-in-part of application No. 09/877,541, improved bioavailability upon administration. Methods of filed on Jun. 8, 2001, which is a continuation-in-part improving the bioavailability of hydrophobic drugs admin of application No. 09/345,615, filed on Jun. 30, 1999, istered to a patient are also provided. US 2003/0236236A1 Dec. 25, 2003

PHARMACEUTICAL COMPOSITIONS AND Micelles, and pharmaceutical compositions containing DOSAGE FORMS FOR ADMINISTRATION OF micelles, have been extensively Studies and are described in HYDROPHOBC DRUGS detail in the literature, See, e.g., Remington's Pharmaceuti cal Sciences, 17" ed. (1985). Although micellar formula REFERENCE TO RELATED APPLICATIONS tions can Solubilize a variety of hydrophobic therapeutic 0001. This application is a continuation-in-part of U.S. agents, the loading capacity of conventional micelle formu patent application Ser. No. 09/716,029, filed Nov. 17, 2000, lations is limited by the Solubility of the therapeutic agent in and a continuation-in-part of U.S. patent application Ser. No. the micelle Surfactant. For many therapeutic agents, Such 09/877,541, filed Jun. 8, 2001, which is a continuation-in solubility is too low to offer formulations that can deliver part of U.S. patent application Ser. No. 09/345,615, filed therapeutically effective doses. Jun. 30, 1999, and a continuation-in-part of U.S. application 0007 Another approach is to solubilize the active sub Ser. No. 09/751,968, filed Dec. 29, 2000, which is a con stance in a triglyceride Solvent, Such as a digestible Veg tinuation-in-part of U.S. application Ser. No. 09/375,636, etable oil. For example, U.S. Pat. No. 4,900,734 to Maxson filed Aug. 17, 1999, the disclosures of which are incorpo et al. discloses a composition in which progesterone is rated herein by reference in their entireties. dissolved in a highly unsaturated edible oil. These triglyc erides are water insoluble themselves and do not normally TECHNICAL FIELD disperse in aqueous environments Such as the gastrointesti 0002 The present invention relates generally to the deliv nal tract. Typically, they must by emulsified by high Shear or ery of hydrophobic drugs, Such as Steroids and benzoquino high temperature homogenization and Stabilized with emul nes. More specifically, the invention relates to novel phar sifiers. In Simplest form, a triglyceride-containing formula maceutical compositions in which a therapeutically effective tion Suitable for delivering hydrophobic agents through an amount of a hydrophobic active agent is combined with a aqueous environment is an oil-in-water emulsion. The col Vitamin E Substance and a Surfactant to form a uniform loidal oil particles are relatively large and will often spon dispersion wherein the active agent is Solubilized in the taneously agglomerate, eventually leading to complete aqueous environment in a readily absorbable form. phase Separation. The large size slows the rate of transport of the colloidal particle and hence the rate of absorption of BACKGROUND the therapeutic agent. Thus these triglyceride compositions are Subject to a number of Significant limitations and dis 0003) Numerous therapeutic agents are poorly soluble in advantages, Such as physical instability and lack of homo aqueous medium and present difficult problems in formu geneity, and are likely to Suffer from poor and variable lating for effective administration to patients. Steroids in absorption. A further disadvantage of triglyceride-contain particular have very low water Solubility and are useful ing compositions is the dependence of the therapeutic agent therapeutic agents for a wide variety of medical conditions. Conventional formulations that incorporate these therapeu absorption on the rate and extent of lipolysis (e.g. See WO tic agents Suffer from Several disadvantages Such as incom 9524893 and WO 97.40823). plete or slow dissolution and/or highly variable dissolution 0008. Other solubilizers of particular utility for hydro profiles. Furthermore, following oral administration, these phobic active agents are described in U.S. patent application conventional formulations exhibit low and/or variable Ser. No. 09/716,029 to Chen et al. The vitamin E substances absorption. A well-designed formulation must, at minimum, disclosed therein include fatty acid esters of glycerol, Such be capable of presenting a therapeutically effective amount as mono-, di-, and triglycerides and acetylated mono- and of the active Substance to the desired absorption Site, in an diglycerides, and mixtures thereof, fatty acid esters of pro absorbable form. pylene glycol, Such as mono- and di-fatty acid esters of 0004. A number of approaches are known for formulating glycerol and mixtures thereof, trialkyl citrate, glyceryl therapeutic agents that are poorly Soluble in water, for both acetate and lower alcohol fatty acid esters. oral and parenteral delivery. 0009 WO 01/49262; U.S. Pat. No. 6,458,373; and U.S. Pat. No. 6,193,985 disclose the use of Solubilizers that 0005 One approach to improving the bioavailability of require high levels of hydrophilic Surfactants, high shear, or Such active Substances is to micronize the particles and to high temperature homogenization to disperse the Solubiliz Suspend them in a pharmaceutically acceptable matrix. For erS Sufficiently to form even a coarse dispersion in an example, U.S. Pat. Nos. 4,196, 188; 4.963,540; and 5,140, adequate medium. Formation of a fine dispersion, which 021 disclose compositions for oral delivery of progesterone would make an effective carrier for oral delivery of the comprising micronized particles of crystalline progesterone active agent, is often difficult or impossible to achieve. AS in triglyceride vehicles. Such Suspensions are difficult to with the triglyceride emulsions, these can be difficult to manufacture, may be physically unstable, and may still manufacture and/or unstable on Storage, and may lead to suffer from poor dissolution and low and/or highly variable absorption. Similarly, compositions utilizing Solid disper poor and variable absorption. sions, such as the approach in FR 2, 647,346, which dis 0010 Thus, there is a need for pharmaceutical composi closes a Solid dispersion of the metastable progesterone II tions for the delivery of therapeutic levels of active agents polymorph in a hydrophilic excipient, are difficult to manu that overcome the Solubility, physical Stability, and absorp facture consistently and may Suffer from physical Stability tion limitations of conventional approaches using microni problems. Additionally this approach may still suffer from Zation, emulsification, or Solubilization. poor dissolution and low and/or highly variable absorption. SUMMARY OF THE INVENTION 0006 Another well-known approach uses surfactant 0011. In the present invention, we have found an unex micelles to Solubilize and transport the therapeutic agent. pected Synergism between an active agent and a Solubilizer. US 2003/0236236A1 Dec. 25, 2003

We have found that for certain therapeutic actives, the active readily absorbable form. A Synergistic combination of an agent has a critical role in improving the dispersion of the appropriate active agent and Solubilizer is observed, Such Solubilizer upon dilution in an aqueous media, allowing for that the presence of the active agent improves the dispersion dispersion of much higher levels of both solubilizer and of the solubilizer (i.e. increases the amount of solubilizer active agent in the aqueous environment. In particular, Such which may be dispersed) and thus further increases the Synergism can be exemplified by compositions comprising amount of active agent which can be dispersed in a readily an active agent, a vitamin ESubstance as the Solubilizer, and absorbable form. a Surfactant as a dispersing aid, wherein the presence of the active agent improves the dispersion of the Solubilizer and 0019. Within the context of the present invention, the thus further increases the amount of active agent which can term “dispersion” is used to refer to the extent to which the be dispersed in a readily absorbable form. This unexpected composition, in particular the active agent and the Solubi Synergism between the active agent, a Vitamin E Substance, lizer, are uniformly distributed in the aqueous phase after and a Surfactant allows for very high drug loading as well as dilution in an aqueous medium, Such as water, Simulated excellent dispersion, keeping the drug Substantially Solubi gastric fluid, or Simulated intestinal fluid. In general, it is lized upon dilution in an aqueous environment Such as the expected that aqueous dispersion of the active agent is gastrointestinal tract in a finely dispersed phase that is critical for oral absorption. The extent of dispersion of the optimal for absorption. composition can be indirectly measured by diluting the composition in an aqueous medium at a Selected dilution 0012. Accordingly, it is a primary object of the invention factor, preferably 100x to 1000x, most preferably 100x; to address the above-mentioned need in the art by providing gently mixing the dilution for a physiologically realistic a pharmaceutical composition and dosage form for orally duration, Sampling from the aqueous phase, and assaying for administering therapeutic agents. either active agent or the Solubilizer. The extent of disper 0013 In a first embodiment of the present invention, a Sion is then defined as the fraction of the total drug or pharmaceutical composition is provided comprising a thera Solubilizer which is distributed in the aqueous phase and peutically effective amount of an active agent, a vitamin E thus readily available for absorption. The undispersed frac Substance and a Surfactant, wherein upon dilution of the tion is the fraction of the total drug or solubilizer would then composition, the active agent increases the extent of disper typically be present in Separate oil or Solid layerS and sion of the vitamin E substance by at least 20% relative to non-uniformly distributed large globules, or large aggre the dispersion of the composition without the active agent. gates of particulates which would be then unavailable for absorption. The characteristics of the dispersion can be 0014. In a second embodiment of the present invention, further assessed by Separating out larger particles or glob a pharmaceutical composition is provided comprising a ules by filtration or centrifugation, then assaying for either therapeutically effective amount of an active agent, a Vita the active agent or the Solubilizer (e.g. vitamin E) or both in min E Substance and a Surfactant, wherein after a 100x the filtrate or Supernatant. dilution of the composition in an aqueous medium, at least 30% of the active agent or the vitamin E substance is 0020. In a preferred embodiment, the composition forms dispersed in an aqueous phase. a "fine dispersion' in which the composition is dispersed such that at least 30% of the active agent or vitamin E 0.015 The present invention also encompasses methods Substance Solubilizer is in particles which will pass through of improving the bioavailability of active agents, and Steroids a filter with 0.45u nominal pore size. in particular, in patients through the administration of the claimed pharmaceutical compositions in Suitable dosage 0021 AS a general rule, it is expected that aqueous forms. dispersion of the active agent is critical for absorption and that the more finely dispersed the active agent is, the more DETAILED DESCRIPTION OF THE effectively it will be absorbed. Other techniques for charac INVENTION terizing the effectiveness of the dispersion may also be used, Such as filtration of the aqueous dispersion with varying 0016 I. Pharmaceutical Compositions nominal pore size and demonstrating an increase in the 0.017. The present invention overcomes the problems fraction of active agent or Solubilizer in the filtrate of any asSociated with the conventional approaches for preparing given size, or centrifugation to demonstrate an increase in formulations containing hydrophobic active agents by pro the fraction of active agent or Solubilizer in aqueous layer. Viding unique pharmaceutical compositions comprising a A Similar comparison may be made based on measuring the therapeutically effective amount of an active agent, a Solu Volume-weighted particle size distribution by photon corre bilizer and, optionally, a dispersing aid, that are more readily lation spectroscopy (dynamic laser light Scattering) and dispersed upon mixing with an aqueous medium than those showing an increase in the fraction of particles with particle which would be obtained without the particular combination diameter below a certain threshold, a decrease in the fraction of Solubilizer and active agent. of particles with diameter above a certain threshold, or a reduction in the Volume-weighted mean particle size. Alter 0.018 Surprisingly, the present inventors have found that natively, an increase in the effectiveness of the dispersion with a composition of an active agent, Such as a Steroid or may be shown by a reduction in the absorbance of light by benzoquinone; a Solubilizer, Such as a vitamin E Substance; an aqueous dilution at visual wavelengths (e.g. 400 nm). and a dispersion aid, Such as a Surfactant, a Synergistic combination results wherein upon dilution in aqueous media 0022. In a preferred first embodiment of the present at an appropriate dilution factor the dispersion of both the invention, a pharmaceutical composition is provided com active agent and the Solubilizer is improved and thus the prising a therapeutically effective amount of an active agent, active agent is Solubilized in the aqueous environment in a a vitamin E Substance and a Surfactant, wherein upon US 2003/0236236A1 Dec. 25, 2003 dilution of the composition, the active agent increases the agent from 0.01% to 30% w/w; solubilizer (vitamin E extent of dispersion of the Vitamin E Substance by at least substance) from 1-95% w/w; and surfactant from 5-85% 20% relative to the dispersion of the composition without W/w. The concentrations of Some exemplary Steroids are the active agent. provided as follows: progesterone-1-300 mg/dosage form 0023. In a preferred second embodiment of the present (0.1% to 30% w/w); testosterone-10 mg to 300 mg/dosage invention, a pharmaceutical composition is provided com form (at least 1% w/w); and DHEA-50 to 300 mg/dosage prising a therapeutically effective amount of an active agent, form (at least 5% w/w). a vitamin E Substance and a Surfactant, wherein after a 100x 0031 Tables 1-2.2-2, 3-2,4-2, 5-2,6-3, 7-2,8-3 and 9-2 dilution of the composition in an aqueous medium, at least from Examples 1-9 show that the synergy between the active 30% of the active agent or the vitamin E substance is agents and the Vitamin E Substances results in a pharma dispersed in an aqueous phase. ceutical composition with a very high percent of dispersion of the active agent and/or the Vitamin E Substance Solubi 0024. In another embodiment, a pharmaceutical compo lizer. Table 1-2 shows that as the concentration of active Sition is provided comprising a therapeutically effective agent is increased from 0% to 15%, the dispersion of both amount of an active agent, a Solubilizer and, optionally, a the active agent and the Vitamin E Substance increase. Table dispersing aid, wherein the amount of active agent improves 8-3 also shows that the careful selection of a solvent or the dispersion of the solubilizer over that which would be coSolubilizer may further increase the dispersion of the achieved with the same Solubilizer without the active agent composition. upon contact with an aqueous medium. 0.025 In yet another embodiment, a pharmaceutical com 0032 Examples 10-25 set forth exemplary compounds position is provided comprising a therapeutically effective that fall within the Scope of the pharmaceutical compositions amount of an active agent, a Solubilizer and a dispersing aid, of the present invention. wherein the Solubilizer is present in an amount Such that 0033 A. Active Agents more of the active agent is dispersed in aqueous medium 0034. The active agent of the present invention is char than that which would be achieved with the same active acterized by the fact that it is Solubilized in aqueous disper agent and dispersing aid without the Solubilizer. Sion by the Solubilizer and has a Synergistic role in improv 0026. In still another embodiment, a pharmaceutical ing the dispersibility of the Solubilizer (and consequently of composition is provided comprising a therapeutically effec the active agent itself) upon dilution in aqueous media. The tive amount of an active agent, a Solubilizer and a dispersing active agent can be said to “improve' the dispersibility of the aid, wherein the active agent is present in an amount Such solubilizer if it is present at levels such that at the selected that at least 30% of the active agent and/or the solubilizer dilution factor it increases the extent of dispersion of the present in the composition is dispersed upon dilution with an solubilizer by at least about 20% relative to the same aqueous medium. composition without the active agent. In one embodiment of the present invention, a pharmaceutical composition is pro 0027. In a further embodiment, a pharmaceutical com Vided comprising a therapeutically effective amount of an position is provided comprising a therapeutically effective active agent, a Solubilizer and, optionally, a dispersing aid, amount of an active agent, a Solubilizer and a dispersing aid, wherein upon dilution of the composition, the active agent wherein the active agent and the Solubilizer are present in is present in an amount to increase dispersion of the Solu amounts Such that the composition forms a more effective bilizer by at least 20% more than that which would be aqueous dispersion than that which would be achieved achieved with the Same composition without the active without the active agent. agent. 0028. In the embodiments set forth above, where appli 0035) Preferably, the active agent is present such that cable, the improvement of the dispersion of either the active after a 100x dilution of the composition the active agent is agent or the Solubilizer or the improvement in the effective at least 30% dispersed in the aqueous phase, with an active ness of the dispersion is on the order of at least 20%, agent dispersion of at least 50% being preferred. More preferably at least 30%, more preferably at least 50%, and preferably, the active agent is present Such that as least 30% the dispersion of the active agent or the Solubilizer is at least of the drug is in fine dispersion. Most preferably the active 30%, with a dispersion of at least 50% preferred, a fine agent is present Such that at least 50% of the drug is in a fine dispersion of at least 30% more preferred, and a fine dispersion. dispersion of at least 50% most preferred. 0036 While this approach may be broadly applicable to 0029. In another embodiment, a pharmaceutical compo many classes of active agents, particularly hydrophobic Sition is provided comprising a therapeutically effective actives, we have found that drugs in the class of Steroids and amount of an active agent, a Solubilizer, and optionally, a benzoquinones are particularly effective in this regard. dispersing aid, wherein the active agent is present in an amount of from about 0.1 to 30% w/w of the composition; 0037. The following lists set forth exemplary active the Solubilizer in the composition is present in an amount of agents for use in the present invention; those of ordinary from about 1 to 99% w/w of the composition; and the skill in the art will readily recognize that Suitable active dispersing aid is present in an amount from about 1 to 99% agents may be used in the present invention either alone or of the composition in combination. 0030 Preferably, the concentrations of each of the active 0038 Steroids are compounds based on the cyclopenta agent, Solubilizer, and Surfactant of the claimed pharmaceu Ophenanthrene structure. Examples of Steroids which have tical composition will have the following ranges: active been shown to be suitable for the current invention include US 2003/0236236A1 Dec. 25, 2003

those with the androstane Structure. Examples of Such aminopentamide, aminopromazine, aminorex, amiodarone, androstane Steroids include cetadiol, clostebol, danazol, amiphenazole, amiprilose, amisui pride, amitriptyline, dehydroepiandrosterone (DHEA) (also, prasterone or dehy amlexanoX, amlodipine, amodiacquine, amoSulalol, amot droisoandrosterone), DHEA Sulfate, dianabol, dutasteride, riphene, amoxapine, amoxicillin, amphecloral, amphet exemestane, finasteride, nerobol, oxymethol one, Stanolone, amine, amphomycin, amphotericin, amplicillin, ampiroxi Stanozolol, testosterone, 17-alpha-methyltestosterone, and cam, amprenavir, amrinone, amsacrine, amyl nitrate, methyltestosterone enanthate. amylobarbitone, anageStone acetate, anastrozole, andinocil 0039. Another group steroids, which have been shown to lin, androstenediol, androstenediol-17-acetate, androstene be Suitable, are those based on the cholane or cholesterol diol-17-benzoate, androstenediol-3-acetate, androstenediol Structure. Examples of Such Steroids are brassicasterol, 3-acetate-17-benzoate, androstenedione, androsterone campesterol, chenodeoxycholic acid, clionasterol, desmos acetate, androsterone benzoate, androsterone propionate, terol, lanosterol, poriferasterol, C-Sitosterol-, Stigmasterol, androsterone, angiotensin, anidulafungin, aniracetam, apa and urSodeoxycholic acid. Zone, apicycline, apoatropine, apomorphine, apraclonidine, 0040 Another suitable class of steroids for use in the aprepitant, aprotinin, arbaprostil, ardeparin, aripiprazole, present invention are those Steroids based on the estrane arnikacin, arotinolol, arstiinol, arylacetic acid derivatives, Structure. Examples of Such estranes include desogestrel, arylalkylamines, arylbutyric acid derivatives, arylcarboxylic equilin, 17-alpha-dihydroeguilin, 17-beta-dihydroequilin, acids, arylpiperazines, arylpropionic acid derivatives, aspi 17-alpha-estradiol, 17-beta-estradiol (estradiol), ethinyl rin, astemizole, atenolol, atomoxetine, atorvastatin, atova estradiol, estriol, estrone, levonorgestrel, lynestrenol, quone, atropine, auranofin, azapropaZone, azathioprine, meStranol, mibolerone, mifegyne, mifepristone, nandrolone, aZelastine, azetazolamide, azithromycin, baclofen, bam buterol, bamethan, barbitone, barnidipine, basalazide, bec norethindrone (or norethistrone), norethindrone acetate (or lamide, beclobrate, befimolol, bemegride, benazepril, ben norethisterone acetate), nortestosterone. cyclane, bendaZac, bendazol, bendroflumethiazide, 0041. Also suitable is the steroid class based on the benethamine penicillin, benexate hydrochloride, benfurodil pregnane Structure. Examples of Such pregnanes include hemisuccinate, benidipine, benorylate, bentazepam, ben alfaxalone, beclomethasone, budesonide, clobetasol, clobe ZheXol, benziodarone, benznidazole, benzoctamine, benzo tasone, corticosterone, desoxycorticosterone, cortisol, corti diazepine derivatives, benzodiazepine, benzonatate, benz Sone, dihydrocortisone, cyproterone, desonide, dexametha phetamine, benzylmorphine, beperiden, bephenium Sone, eplerenone, epoxypregnenolone, flumethasone, hydroxynaphthoate, bepridil, betahistine, betamethasone, megestrol, melengestrol, prednisolone, prednisone, preg betaxolol, bevantolol, bevonium methyl Sulfate, beXaroteine, nanediol, pregnanolone, pregnenolone, allopregnanolone, beZadoxifine, beZafibrate, bialamicol, biapenem, bicaluta epiallopregnanolone, progesterone, medroxyprogesterone, mide, bietamiverine, bifonazole, binedaline, binifibrate, biri Spironolactone, and tibolone. codar, bisacodyl, bisantrene, bisoprolol, bitolterol, bopin 0042. It is to be understood that steroids suitable for the dolol, boSwellic acid, bradykinin, bretylium, bromazepam, present invention are not limited to those disclosed herein bromocriptine, bromperidol, brotizolam, brovincamine, and include any Secondary Steroids, Such as for example, buciclate, bucloxic acid, bucumolol, budralazine, bufeniode, bufetolol, buflomedil, bufuralol, bumetanide, bunitrolol, vitamin D. bupranolol, buprenorphine, buproprion, buSpirone, buSul 0.043 Steroid esters, such as the acetate, benzoate, cypi fan, butalamine, butarphenol, butaverine, butenafine, buten onate, decanoate, enanthate, hemisuccinate, hexahydroben afine, butidrine hydrochloride, butobarbitone, butoconazole Zoate, 4-methylvalerate, propionate, Stearate, Valerate, and nitrate, butoconazole, butofilol, butorphenol, butropium bro undecanoate esters would also be Suitable for the present mide, cabergoline, calcifediol, calcipotriene, calcitriol, invention. caldiribine, cambendazole, camioxirole, camoStat, campos 0044) Examples of Suitable benzoquinones include terol, camptothecin, candesartan, candoxatril, capecitabine, ubiquinones, Such as coenzyme Q10, embelin, idebenone caprate, capsaicin, captopril, carazolol, carbacephems, car 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzo bamates, carbameZepine, carbapenems, carbarSone, carba quinone), pyrroloquinoline quinone, and Seratrodast 7-(3, trol, carbenoXolone, carbimazole, carbromal, carbuterol, 5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic carisoprodol, carotenes, caroverine, carteolol, carvedilol, cefaclor, cefazolin, cefbuperaZone, cefepime, cefoSelis, cef acid. tibuten, celcoxib, celecoxib, celiprolol, cephaeline, cepha 0.045 Examples of other active agents which may be losporin C, cephalosporins, cephamycins, cerivastatin, cer Suitable for this invention include, without limitation: abe toparin, cetamolol, cetiedil, cetirizine, cetraxate, carnil, acamprostate, acavir, acebutolol, aceclofenac, acem chloracizine, chlorambucil, chlorbetamide, chlordantoin, etacin, acetaminophen, acetaminoSalol, acetanilide, aceto chlordiazepoxide, chlormadinone acetate, chlormethiazole, hexamide, acetophenazine maleate, acetophenazine, chloroquine, chlorothiazide, chlorpheniramine, chlorphe acetoxolone, acetoxypregnenolone, acetretin, acrisorcin, noXamide, chlorphentermine, chlorproguanil, chlorprom acrivastine, acyclovir, adinazolam, adiphenine hydrochlo azine, chlorpropamide, chlorprothixene, chlortetracycline, ride, adrafinil, adrenolone, agatroban, ahnitrine, akatinol, chlorthalidone, cholecalciferol, chromonar, cicleSonide, alatrofloxacin, albendazole, albuterol, aldioxa, alendronate, ciclonicate, cidofivir, ciglitaZone, cilansetron, ciloStaZol, alfentanil, alibendol, alitretinoin, allopurinol, allylamines, cimetidine, cimetropium bromide, cinepaZet maleate, cin allylestrenol, alminoprofen, almotriptan, aloSetron, aloX namedrine, cinnarizine, cinolazepam, cinoxacin, ciprofi iprin, alprazolam, alprenolol, amantadine, ambucetamide, brate, ciprofloxacin, cisapride, cisplatin, citalopram, citi amidephrine, amidinomycin, amiloride, aminoarylcarboxy coline, clarithromycin, clebopride, clemastine, clenbuterol, lic acid derivatives, aminoglutethimide, aminoglycosides, clidanac, clinofibrate, clioquinol, clobazam, clobenfurol, US 2003/0236236A1 Dec. 25, 2003

clobenzorex, clofazimine, clofibrate, clofibric acid, cloforex, dil, floxuridine, fluconazole, flucytosine, fludarabine, clomipramine, clonazepam, clonidine, clonitrate, clopi fludiazepam, fludrocortisone, flufenamic acid, flunanisone, dogrel, clopirac indomethacin, cloranolol, cloricromen, clo flunarizine, flunisolide, flunitrazepam, fluocortolone, fluox rprenaline, clortermine, clotiazepam, clotrimazole, cloxacil etine, flupenthixol decanoate, fluphenazine decanoate, lin, clozapine, cmepazide, codeine methyl bromide, codeine fluphenazine enanthate, fluphenazine, flu.proquaZone, flu phosphate, codeine Sulfate, codeine, colloidal bismuth Sub razepam, flurbiprofen, flurogestone acetate, fluticasOne pro citrate, cromafiban, cromolyn, cropropamide, crotethamide, pionate, fluvastatin, fluvoxamine, fominoben, formoterol, curcumin, cyclandelate, cyclarbamate, cyclazocine, foScarnet, foScarnet, fosinopril, foSphenytoin, froVatirptan, cyclexedrine, cyclizine, cyclobenzaprine, cyclodrine, cyclo fudosteine, fumagillin, furazolidone, furazolidone, furfuryl nium iodide, cyclopentamine, cycloSporin, cypionate, methyl amphetamine, furosemide, gabapentin, gabexate, cyproheptadine, cyproterone acetate, cytarabine, dacarba gabOXadol, galanthamine, gallopamil, gammaparin, ganci Zine, dalfopristine, dantrolene Sodium, dapiprazole, dar clovir, ganglefene, gefarnate, gemcitabine, gemfibrozil, odipine, decanoate, decitabine, decoquinate, dehydroemet gepirone, gestadene, ghrelin, glatiramer, glaucarubin, glib ine, delaVirdine, delaviridine, demeclocycline, denopamine, enclamide, gliclazide, glimepiride, glipizide, gluconic acid, deramciclone, descitalopram, desipramine, desloratadine, glutamicacid, glyburide, glyceryl trinitrate, glymepiride, 3-ketodesogestrel, desomorphine, desoxymethasone, deto granisetron, grepafloxacin, griseofulvin, guaiaZulene, gua midine, dexamphetamine, deXanabinol, dexchlorphe nabenz, guanfacine, halofantrine, haloperidol decanoate, niramine, dexfenfluramine, dexmethylphenidate, deXraZOX haloperidol, haloxazolam, hepronicate, heptanoate, heX ane, dextroamphetamine Sulfate, dextroamphetamine, obendine, heXoprenaline, hydramitrazine, hydrazides, dextropropoxyphene, DHEA, diacetate, diamorphine, diaz hydrochlorothiazide, hydrocodone, hydrocortisone, hydro emine, diazepam, diaziquinone, diaZOxide, dibromopropa morphone, hydroxyamphetamine, hydroxymethylprogester midine, dichlorophen, diclofenac, dicoumarol, didanosine, one acetate, hydroxymethylprogesterone, hydroxyprogester dideoxyadenosine, diethylpropion, difemerine, difenami OC acetate, hydroxyprogesterone caproate, Zole, diflunisal, digitoxin, digoxin, dihidroergotamine, dihy hydroxyprogesterone, hymecromone, hyoscyamine, ibo drocodeine, dihydrocodeinone enol acetate, dihydroergota pamine, ibudilast, ibufenac, ibuprofen, ibutilide, idoxuri mine meSylate, dihydroergotamine, dihydrogesterone, dine, ifenprodil, igmesine, iloprost, imatinib, imidapril, imi dihydromorphine, dihydropyridine derivatives, dihydroS dazoles, imipenem, imipramine, imolamine, incadronic acid treptomycin, dihydrotachysterol, dihydroxyaluminum ace pergolide, indanazoline, indenolol, indinavir, indomethacin, tylsalicylate, diiodohydroxyquinoline, diisopromine, indoramin, inoSinepranobeX, inoSitol niacinate, iodoquinol, dilazep, dilevalol, dilitazem, diloxanide furoate, diloxanide, ipidracine, iproniazid, irbeSartan, irinotecan, irSogladine, diltiazem, dimefline, dimenhydrinate, dimethisterone, isobutyrate, isocaprate esters, isoetharine, isometheptene, dimetofrine, dimorpholamine, dinitolmide, dioxaphetyl isoproterenol, isosorbide dinitrate, isosorbide mononitrate, butyrate, dioxethedrine, diphemethoxidine, diphenhy isosorbide dinitrate, isoxSuprine, isradipine, itasetron, itra dramine, diphenoxylate, diphetarSone, diplivefrin, diponium conazole, itramintosylate, ivermectin, kallidin, kallikrein, bromide, dipyridamole, dirithromycin, disopyramide, dival kanamycin, ketamine, ketoconazole, ketoprofen, ketorolac, proex Sodium, dolfetilide, domperidone, doneZepil, dopeX ketotifen, labetalol, lafutidine, lamifiban, lamivudine, lam amine, dopradil, doSmalfate, doxapram, doxazosin, dox otrigine, lanatoside c, lanSoprazole, lasofoXifene, lefluno efazepam, doxepin, doxycycline, drofenine, mide, leminoprazole, lercanadipine, lesopitron, letrozole, dromoStanolone propionate, dromoStanolone, dronabinol, leucovorin, levalbuterol, levallorphan, levetiracetam, droperidol, droprenilamine, d-threo-methylphenidate, levetriacetam, levobunolol, levodopa, levofloxacin, dulloxetine, elbrotidine, eburnamonine, ecabet, ecenofloxa levophacetoperane, levorphanol, lidocaine, lidoflazine, lifi cin, econazole nitrate, edavarone, edoxudine, efavirenz, brol, limaprost, lineZolid, lintitript, liranaftate, lisinopril, effivarenZ, efloxate, eledoisin, eletriptan, elgodipine, ellip lisuride, lobeline, lobucavir, lodoxamide, lomefloxacin, ticine, emepronium bromide, emetine, enalapril, enanthate, lomerizine, lomustine, loperamide, lopinavir, loprazolam, encainide, enlopitat, enoXimone, enprostil, entacapone, loracarbef, loratadine, lorazepam, lorefloxacin, epanolol, ephedrine, epinastine, epinephrine, epirubicin, lormetazepam, losartan, lovasatain, lovastatin, loxapine Suc epleronone, epoSartan, ergocalciferol, ergoloid meSylates, cinate, loxapine, 1-threo-methylphenidate, lumiracoxib, ergotamine, ertapenum, erythromycin, erytlirityl tetranitrate, lysine acetylsalicylate, lysozyme, lySuride, mabuterol, eSaprazole, escitalopram, esmolol, esomeprazole, esonari mafenide, magnesium acetylsalicylate, malgramoStin, man mod, estazolam, estradiol benzoate, estramustine, estriol nitol heXanitrate, maprotiline, mazindol, mebendazole, Succinate, estrone acetate, estrone Sulfate, etafedrine, meclizine, meclofenamic acid, mecloxaminepentapiperide, etafenone, ethacrynic acid, ethamivan, ethinamate, ethi medazepam, medibazine, medigoxin, medrogestone, nylestradiol 3-acetate, ethinyleStradiol 3-benzoate, ethi medroxyprogesterone acetate, mefenamic acid, mefenorex, nylestradiol, ethionamide, ethisterone (17O-ethinyltestoster mefloquin, mefloquine, megestrol acetate, melengestrol one), ethopropazine, ethotoin, ethoxyphenamine, acetate, melphalan, mematine, mepenZolate bromide, mep ethylestrenol, ethylmorphine, ethylnorepinephrine, ethyno eridine, mephenoxalone, mephentermine, mepindolol, diol diacetate, etodolac, etofibrate, etoposide, etoricoxib, mepixanox, meprobamate, meptaZinol, mercaptopurine, etretinate, everolimus, exalamide, exameStane, examorelin, merropenum, meSalamine, meSalazine, mesoridazine besy eZemitibe, falecalcitriol, famciclovir, famotidine, fantofar late, meSoridazine, metaclazepam, metamfepramone, one, farapenum, farglitazar, fasudil, felbamate, felodipine, metampicillin, metaproterenol, metaraminol, methacycline, fenalamide, fenbufen, fenbutrazate, fendiline, fenfluramine, methadone hydrochloride, methadone, methamphetamine, fenoldopam, fenoprofen, fenoterol, fenoverine, fenoxazo methaqualone, metharnphetamine, methoin, methotrexate, line, fenoxedil, fenpiprane, fenproporex, fenspiride, fenta methoxamine, methSuximide, methylhexaneamine, meth nyl, feXofenadine, flavoxate, flecainide, flopropione, flore ylphenidate d-threo-methylphenidate, methylphenidate, US 2003/0236236A1 Dec. 25, 2003 methylphenobarbitone, methylprednisolone, methySergide, tives, piperi late, piracetam, pirbuterol, pirenzepine, piribe metiazinic acid, metizoline, metoclopramide, metolaZone, dil, pirifibrate, piroXicam, pitavastatin, pizotyline, plaunotol, metoprolol, metoxalone, metripranolol, metronidazole, polaprezinc, polybenzarSol, polyestrol phosphate, practolol, mexiletine, mexilitene, metaxalone, mianserin, inibefradil, pralnacasan, pramipexole, praniukast, pravastatin, miconazole, midazolam, midodrine, migitol, milnacipran, prazepam, praZiquantel, praZOSin, pregabalin, prenalterol, milrinone, minoxidil, mirtazapine, misoprostol, mitomycin, prenylamine, pridinol, pri?inium bromide, primidone, primi mitotane, mitoxantrone, mizolastine, modafinil, mofebuta pramine, probenecid, probucol, procainamide, procarbazine, Zone, mofetil, molindone hydrochloride, molindone, molsi procaterol, prochlorperazine, proguanil, pronethalol, pro domine, monatepil, montelukast, monteplase, moprolol, pafenone, propamidine, propatyl nitrate, propentoffyline, moricizine, morphine hydrochloride, morphine Sulfate, mor propionate, propiram, propoxyphene, propranolol, propyl phine, morpholine Salicylate, mosapramine, moxifloxacin, hexedrine, propylthiouracil, protokylol, protriptyline, proX moxisylvyte, moxonidine, mycophenolate, nabumetone, azole, pseudoephedrine, purines, pyrantel embonate, pyra nadolol, nadoxolol, nadroparin, nafamoStat, nafronyl, naf Zoles, pyrazolones, pyridofylline, pyrimethamine, topidil, nalbuphine, nalidixic acid, nalmefene, nalorphine, pyrimidines, pyrrollidones, quaZepam, quetiapine, quetu naloxone, naltrexone, nandrolone benzoate, nandrolone apine, quinagolide, quinapril, quinestrol, quinfamide, quini cyclohexanecarboxylate, nandrolone cyclohexane-propi dine, quinine Sulfate, quinolones, quinupritin, rabalzotan, onate, nandrolone decanoate, nandrolone furylpropionate, rabeprazole Sodium, rabeprazole, racefimine, ramatroban, nandrolone phenpropionate, naphazoline, naproxen, ramipril, ranitidine, ranolazine, ranSoprazole, rasagiline, naratriptan, natamycin, nateglinide, nebivalol, nedocromil, rebamipide, refludan, repaglinide, repinotan, repirinast, nefazodone, nefopam, nelfinavir, nemonapride, neomycin reproterol, reserpine, retinoids, ribavirin, rifabutine, rifampi undecylenate, neomycin, neotrofin, neSiritide, n-ethylam cin, rifapentine, rillmenidine, riluzole, rimantadine, rimiterol, phetamine, nevibulol, nevirapine, neXopamil, nicametate, rioprostil, risperidone, ritanovir, ritapentine, ritipenem, rito nicardipine, nicergoline, nicofibrate, nicofuranose, nicomor drine, ritonavir, rivastigmine, rizatriptan, rociverine, rofe phine, nicorandil, nicotinyl alcohol, nicoumalone, nife coxib, rohypnol, rolipram, romoxipride, ronifibrate, ropin dipine, nifenalol, nikethamide, nilutamide, nilvadipine, irole, ropivacaine, rosaprostol, roSiglitaZone, rosuvastatin, nimodipine, nimorazole, nipradillol, nisoldipine, nitisonone, rotinolol, rotraxate, roXatidine acetate, roXindole, rubitecan, nitrazepam, nitrofurantoin, nitrofuraZone, nitroglycerin, Salacetamide, Salicin, Salicylamide, Salicylic acid deriva nizatidine, norastemizole, norepinephrine, norethynodrel, tives, Salmeterol, Saquinavir, Saquinavir, Scopolamine, Sec norfenefrine, norfloxacin, norgestimate, norgestrel, norg nidazole, Selegiline, Semotiadil, Sertindole, Sertraline, estrienone, normethadone, normethisterone, normorphine, Sibutramine, Sildenafil, Simfibrate, Simvastatin, Siramesine, norpseudoephedrine, nortriptyline, noVantrone, nylidrin, Sirolimus, SitaXSentan, Sofalcone, Somotiadil, Sorivudine, nyStatin, octamylamine, octodrine, octopamine, ofloxacin, Sotalol, Soterenol, Sparfloxacin, Spasmolytol, Spectinomycin, olanzapine, olanzapine, olapatadine, olmesartan, olopati Spiramycin, Spizofurone, Stavudine, Streptomycin, Succinyl dine, olSalazine, omapatrilat, omeprazole, Ondasetron, Sulfathiazole, Sucralfate, Sufentanil, Sulconazole nitrate, Sul opium, oprevelkin, orlistat, ornidazole, ornoprostil, Oselta facetamide, Sulfadiazine, Sulfaloxicacid, Sulfarside, Sulfi mivir, oxaliplatin, OXamniquine, Oxandrolone, OXantel nalol, Sulindac, Suloctidil, Sulphabenzamide, embonate, Oxaprozin, OXatomide pemirolast, OXatomide, Sulphacetamide, Sulphadiazine, Sulphadoxine, Sulphafura oxazepam, oxcarbazepine, Oxfendazole, oxiconazole, Zole, Sulphamerazine, Sulphamethoxazole, Sulphapyridine, oxiracetam, OXolinicacid, OXprenolol, oxycodone, Oxy SulphaSalazine, Sulphinpyrazone, Sulpiride, Sulthiame, Sul fedrine, oxymetazoline, Oxymorphone, oxyphenbutaZone, topride, Sultroponium, Sumanirole, Sumatriptan, Sunepitron, Oxyphencyclimine, oxyprenolol, OZagrel, paclitaxel, pal Superoxide dismutase, Suplatast, Suramin Sodium, Syneph onosetron, pantoprazole, papaverine, paracalcitol, rine, tacrine, tacrolimus, tacrolimus, tadalafil, talinolol, tal paramethadione, parecoxib, pariprazole, paromomycin, par ipexole, tamoxifen, tamsulosin, targretin, taZanolast, tazaro oxetine, parSalmide, paZinaclone, pemoline, penbutolol, tene, taZobactum, tecastimezole, teclozan, tedisamil, penciclovir, penicillin G benzathine, penicillin G procaine, tegaSerod, telenzepine, telmisartan, temazepam, teniposide, penicillin V, penicillins, pentaerythritol tetranitrate, pen teprenone, teraZOsin, terbenafine, terbinafine, terbutaline taerythritol tetranitrate, pentapiperide, pentazocine, pentifyl Sulfate, terbutaline, terconazole, terfenadine, terodiline, line, pentigetide, pentobarbitone, pentorex, pentoxifylline, terofenamate, tertatolol, testolactone, 4-dihydrotestosterone, pentrinitrol, perbuterol, perenzepine, pergolide, perhexiline, tetracyclics, tetracycline, tetrahydrocannabinol, tetrahydro perindopril erbumine, peroSpirone, perphenazine pimozide, Zoline, thalidomide, theofibrate, thiabendazole, thiazinecar perphenazine, phanquinone, phenacemide, phenacetin, boxamides, thiocarbamates, thiocarbamizine, thiocarbar phenazopyridine, phencarbamide, phendimetrazine, Sone, thloridazine, thiothixene, tiagabine, tiamenidine, phenelZine, phenindione, phenmetrazine, phenobarbitone, tianeptine, tiaprofenic acid, tiaramide, ticlopidine, tigloi phenoperidine, phenothiazines, phenoxybenzamine, phen dine, tilisolol, timolol, tinidazole, tinofedrine, tinzaparin, Suximide, phentermine, phentolamine, phenyl Salicylate, tioconazole, tipranavir, tirapazamine, tirofiban, tiropramide, phenylacetate, phenylbutaZone, phenylephrinehydroch titanicene, tizanadine, tizanidine, tizinadine, tocainide, loride, phenylpropanolamine hydrochloride, phenylpro tolaZamide, tolaZoline, tolbutamide, tolcapone, tolciclate, panolaminehydrochloride, phenylpropyl-methylamine, tolfenamic acid, toliprolol, tolteridine, tolterodine, tonaber phenytoin, phloroglucinol, pholedrine, phySoStigmine Sali Stat, topiramate, topotecan, torasemide, toremifene citrate, cylate, phySoStigmine, phytonadiol, phytosterols, piapenum, toremifene, toSufloxacin, tramadol, tramaZoline, trandola picilorex, piclamilast, picrotoxin, picumast, pifamine, pil pril, tranilast, tranylcypromine, trapidil, traXanox, traZ Sicaimide, pimagedine, pimeclone, pimecrolimus, pimefyl odone, tretoquinol, triacetin, triamcinolone, triampterine, line, pimozide, pinaverium bromide, pindolol, pioglitaZone, triamterine, triazolam, triazoles, tricromyl, tricyclics, triflu piperacillin, piperazine estrone Sulfate, piperazine deriva operazine hydrochloride, trifluoperazine, triflu promazine, US 2003/0236236A1 Dec. 25, 2003 trifluridine, trihexyphenidyl hydrochloride, trihexyphenidyl, ylene glycol Succinate and Salicylic acid. Particularly pre trimaZoSin, trimebutine, trimetazidine, trimethoprim, ferred Vitamin ESubstances include alpha-tocopherol, alpha trimgestone, trimipramine, trimoprostil, trithiozine, troglita tocopherol acetate, alpha-tocopherol acid Succinate, alpha Zone, trolnitrate phosphate, tromethamine, tropicamide, tro tocopherol polyethylene glycol Succinate and mixtures vafloxacin, troXipide, tuaminoheptane, tulobuterol, tymazo thereof. line, tyramine, undecanoate, undecanoic acid, urinastatin, Valacyclovir, Valdecoxib, Valerate, Valganciclovir, Valproic 0049 Other solubilizers that may be used in the present acid, Valsartan, Vancomycin, Vardenafil, Venlafaxine, Veno invention are disclosed in U.S. patent application Ser. NoS. relbine, Verapamil, Verapimil, Vidarabine, vigabatrin, Vin 09/716,029 and 09/877,541, both to Chen et al. Preferred camine, Vinpocetine, Viomycin, Vicquidil, Visnadine, Vitamin Solubilizers that are not vitamin E Substances for use in the a derivatives, Vitamina, Vitamin b2, Vitamin d, Vitamine, present invention include fatty acid esters of glycerol, acety Vitamin k, Voglibose, Voriconazole, Xaliproden, Xamoterol, lated mono- and diglycerides, fatty acid esters of propylene Xanthinol niacinate, Xeny tropium bromide, Xibenolol, glycol, trialkyl citrate, glycerol acetate, and lower alcohol Ximelagatran, Xylometazoline, yohimbine, Zacopride, fatty acid esters. Zafirlukast, Zafirlukat, Zalcitabine, Zaleplon, Zanamivir, Zate 0050 C. Surfactants bradine, Ziconotide, Zidovudine, Zileuton, Zimeldine, Zinc propionate, Ziprasidone, Zolimidine, Zolmitriptan, Zolpidem, 0051. The surfactant in the present invention may be any Zonisamide, Zopiclone. compound containing polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e. 0046 B. Solubilizers a surfactant compound must be amphiphilic. Within the 0047. In one embodiment, a pharmaceutical composition context of the present invention, the hydrophilic Surfactant is provided comprising a therapeutically effective amount of can be any hydrophilic Surfactant Suitable for use in phar an active agent, a Solubilizer and a dispersing aid. The maceutical compositions. Such Surfactants can be anionic, Solubilizer is present in an amount Such that more of the cationic, Zwitterionic or non-ionic. Mixtures of hydrophilic active agent is dispersed; in aqueous medium than that Surfactants are also within the Scope of the invention. which would be achieved with the same active agent and Similarly, the hydrophobic Surfactant can be any hydropho dispersing aid without the Solubilizer. AS mentioned above, bic Surfactant Suitable for use in pharmaceutical composi the active agent and the Solubilizer act Synergistically to tions. Mixtures of hydrophobic surfactants are also within improve the dispersibility of the solubilizer itself and the the Scope of the invention. Generally, Suitable hydrophilic active agent upon dilution in an aqueous media, thus greatly surfactants will have an HLB value greater than about 10 increasing the amount of active agent which can be dis and suitable hydrophobic surfactants will have an HLB persed in a readily absorbably form. Preferably, the solubi value less than about 10. The choice of specific hydrophobic lizer is present such that after a 100x dilution of the and hydrophilic Surfactants should be made keeping in mind composition the active agent and/or the Solubilizer is at least the particular hydrophobic therapeutic agent to be used in 30% dispersed in the aqueous phase, with a dispersion of at the composition, and the range of polarity appropriate for the least 50% being preferred. It is more preferred that the chosen therapeutic agent. With these general principles in solubilizer, like the active agent is at least 30% finely mind, a very broad range of Surfactants is Suitable for use in dispersed in the aqueous phase, with a fine dispersion of at the present invention. least 50% being most preferred. 0052 Examples of Surfactants suitable for use in the 0.048. The preferred solubilizer of the present invention is present invention are disclosed in U.S. Pat. No. 6,294,192 to a "vitamin E Substance,” which includes Substances with the Patel et al. and U.S. patent application Ser. No. 09/877,541 tocol structure 2-methyl-2-(4,8,12-trimethyltridecyl)chro to Chen et al. Examples of Surfactants that may be used in man-6-ol) or the tocotrienol structure 2-methyl-2-(4,8,12 the present invention include polyethoxylated fatty acids trimethyltrideca-3,7,11-trienyl)chroman-6-ol, in particular Such as PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, the all trans-(E.E) tocotrienols. Particularly preferred vita PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 min E Substances include the mono-, di-, trimethyl-tocol laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and derivatives, commonly known as tocopherols, Such as C-to PEG-20 oleate; PEG-fatty acid diesters such as PEG-20 copherol 5,7,8-trimethyl-, 3-tocopherol 5,8-dimethyl-, dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 Y-tocopherol 7,8-dimethyl, -tocopherol 5,7-dimethyl-, dilaurate and PEG-32 dioleate; PEG-fatty acid mono- and 8-tocopherol 8-methyl-, q-tocopherol 7-methyl); and the di-ester mixtures, polyethylene glycol glycerol fatty acid corresponding mono-, di-, and trimethyltoctrienol deriva esters such as PEG-20 glyceryl laurate, PEG-30 glyceryl tives, commonly known as tocotrienols, Such as C-tocot laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, rienol (or -tocopherol) 5,7,8-trimethyl-, f-tocotrienol (or and PEG-30 glyceryl oleate; alcohol-oil transesterification e-tocopherol) 5,8-dimethyl), Y-tocotrienol 7,8-dimethyl), products such as PEG-35 castor oil (Incrocas-35), PEG-40 and 8-tocotrienol 8-methyl-. Included are their mixed hydrogenated castor oil (Cremophor(R) RH40), polyoxyl 35 racemic dl-forms, the pure d- and 1-enantiomers and the castor oil (Cremophor EL), PEG-25 trioleate (TAGATE) corresponding derivatives, e.g., esters, produced with TO), PEG-60 corn glycerides (Crovol M70), PEG-60 organic acids, and mixtures thereof. Preferred Vitamin E almond oil (Crovol A70), PEG-40 palm kernel oil (Crovol Substances for use in the present invention include toco PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydro pherols, tocotrienols and tocopherol derivatives with organic genated castor oil (Emalex HC-50), PEG-8 caprylic/capric acids Such as acetic acid, propionic acid, bile acid, lactic glycerides (Labrasol(F), and PEG-6 caprylic/capric glycer acid, pyruvic acid, Oxalic acid, malic acid, malonic acid, ides (Softigen(R) 767); transesterification products of oils and Succinic acid, maleic acid, fumaric acid, tartaric acid, citric alcohols, polyglycerized fatty acids Such as polyglyceryl acid, benzoic acid, cinnamic acid, mandelic acid, polyeth oleate (Plurole Oleigue), polyglyceryl-2 dioleate (Nikkol US 2003/0236236A1 Dec. 25, 2003

DGDO), and polyglyceryl-10 trioleate. Preferred hydro additional components, i.e., additives. Classes of additives philic Surfactants include polyglyceryl-10 laurate (Nikkol that may be present in the compositions, include, but are not Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn limited to, Solvents, absorbents, acids, adjuvants, anticalking 1-0), and polyglyceryl-10 mono, dioleate (Caprol(R) PEG agent, glidants, antitacking agents, antifoamers, anticoagul 860); propylene glycol fatty acid esters such as propylene lants, antimicrobials, antioxidants, antiphlogistics, astrin glycol monolaurate (Lauroglycol FCC), propylene glycol gents, antiseptics, bases, binders, chelating agents, Seques ricinoleate (Propymuls), propylene glycol monooleate trants, coagulants, coating agents, colorants, dyes, pigments, (Myverol(R) P-06), propylene glycol dicaprylate/dicaprate compatiblizers, complexing agents, Softeners, crystal (CapteXCE 200), and propylene glycol dioctanoate (Captex growth regulators, denaturants, dessicants, drying agents, 800); mixtures of propylene glycol esters and glycerol esters dehydrating agents, diluents, dispersants, emollients, emul Such as a mixture of oleic acid esters of propylene glycol and sifiers, encapsulants, enzymes, fillers, extenders, flavor glycerol (Arlacel 186); mono- and diglycerides Such as masking agents, flavorants, fragrances, gelling agents, hard glyceryl monooleate (Peceol), glyceryl ricinoleate, glyceryl eners, Stiffening agents, humectants, lubricants, moisturiz laurate, glyceryl dilaurate (Capmul GDL), glyceryl dioleate ers, bufferants, pH control agents, plasticizers, Soothing (Capmul GDO), glyceryl mono/dioleate (Capmul GMO-K), agents, demulcents, retarding agents, Spreading agents, sta glyceryl caprylate/caprate (Capmul MCM), caprylic acid bilizers, Suspending agents, Sweeteners, disintegrants, thick mono/diglycerides (Imwitor(R) 988), and mono- and diacety ening agents, consistency regulators, Surfactants, opacifiers, lated monoglycerides (Myvacet(R) 9-45); sterol and sterol polymers, preservatives, antigellants, rheology control derivatives such as PEG-24 cholesterol ether (Solulan(R) agents, UV absorbers, tonicifiers and Viscomodulators. One C-24); polyethylene glycol Sorbitan fatty acid esterS Such as or more additives from any particular class, as well as one PEG-20 sorbitan monolaurate (Tween(E) 20), PEG-20 sorbi or more different classes of additives, may be present in the tan monopalmitate (Tween 40), PEG-20 sorbitan monostear compositions. Specific examples of additives are well ate (Tween 60), and PEG-20 sorbitan monooleate (polysor known in the art. bate 80 or Tween 80); polyethylene glycol alkyl ethers such as PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Bri 0057 E. Dosage Forms 30); Sugar esterS Such as Sucrose monopalmitate and Sucrose 0058. The pharmaceutical composition of the present monolaurate; polyethylene glycol alkyl phenols, polyoxy invention can be prepared by mixing the active agent, the ethylene-polyoxypropylene block copolymerS Such as Syn Solubilizer, the Surfactant, and optional additives according peronic(R) PE series (ICI); Pluronicg series (BASF), Emka to methods well known in the art. Alternatively, the active lyx, Lutrol (BASF), Supronic, Monolan, Pluracare(R), and agent, the Solubilizer, and the Surfactant may be prepared in Plurodac, Sorbitan fatty acid esters Such as Sorbitan mono Separate dosage forms or separated within one dosage form laurate (Arlacel(R) 20), sorbitan monopalmitate (Span-40), to form a dispersion in Situ upon administration and disso Sorbitan monooleate (Span-80), Sorbitan monoStearate, and lution in the aqueous environment of the gastrointestinal Sorbitan tristearate; lower alcohol fatty acid esterS Such as tract. hydrophobic surfactants include ethyl oleate (Crodamol 0059. The claimed pharmaceutical compositions can be EO), isopropyl myristate (Crodamol IPM), and isopropyl further processed according to conventional methods known palmitate (Crodamol IPP); ionic surfactants such as sodium to those skilled in the art, Such as lyophilization, encapsu oleate, Sodium lauryl Sulfate, Sodium lauryl Sarcosinate, lation, compression, melting, extrusion, balling, drying, Sodium dioctyl SulfoSuccinate, Sodium cholate, Sodium tau chilling, molding, Spraying, Spray congealing, coating, com rocholate, lauroyl carnitine, palmitoyl carnitine, and myris minution, mixing, homogenization, Sonication, cryopelleti toyl carnitine, unionized ionizable Surfactants Such as free Zation, Spheronization and granulation to produce the fatty acid, particularly C-C fatty acids, and bile acids. desired dosage form. ExceSS Solvent, added to facilitate 0.053 Other surfactants for use in the present invention incorporation of the active agent and/or mixing of the include, without limitation, PEG-400 Succinate, PEG 3350, formulation components, can be removed before adminis tocopherol polyethyleneglycol (200-8000 MW) succinate, tration of the pharmaceutical dosage form. tocopherol polyethylene glycol 400 Succinate, tocopherol 0060. The pharmaceutical compositions can be further polyethyleneglycol 1000 succinate (Vitamin E-TPGS, East formulated into desirable dosage forms utilizing skills well man Chemical Co.), glycerol monolinoleate (Maisine(E), known in the art. For example, compositions in liquid, propylene glycol monocaprylate (Capryol(R 90); capryloca Semi-Solid or paste form can be filled into hard gelatin or Soft proyl macrogol-8 glycerides (LabroSolE), glycerol dibehen gelatin capsules using appropriate filling machines. Alter ate (Compritol(R) 888), glycerol distearate (Precirol(R), lau natively, the composition can also be extruded, merumer royl macrogol-32 glycerides (Gelucire(E 44/14), and ized, Sprayed, granulated or coated onto a Substrate to stearoyl macrogol-32 glycerides (Gelucire 50/13). become a powder, granule or bead that can be further 0054. It is to be understood that within the context of the encapsulated or tableted with or without the addition of present invention, more than one Solubilizer may be used. appropriate Solidifying or binding agents. This approach For example, ethanol may be used in conjunction with also allows for the creation of a “fused mixture,” a “solid Cremophor to improve the solubility of active agent. Pre Solution' or a “eutectic mixture.” ferred Surfactants for use with particular active agents are 0061 The dosage forms of the present invention are not illustrated in the Examples. limited with respect to size, shape or general configuration, and may comprise, for example, a capsule, a tablet or a 0055) D. Other Additives caplet, or a plurality of granules, beads, powders, or pellets 0056 Although not always necessary, the compositions that may or may not be encapsulated. In addition, the dosage of the present invention may also include one or more form may be a drink or beverage Solution or a spray Solution US 2003/0236236A1 Dec. 25, 2003

that is administered orally. Thus, for example, the drink or 0069. The dispersibility of the composition was deter beverage Solution may be formed by adding a therapeuti mined by diluting the composition in an aqueous medium cally effective amount of the composition in, for example, a Such as water, Simulated gastric fluid, or simulated intestinal powder or liquid form, to a Suitable beverage, e.g., water or fluid, at a selected dilution factor, preferably 10x to 1000x, juice. most preferably 100x. The dilution was then gently mixed, for example with a rotator at 10 rpm, at an appropriate 0062) The compositions and dosage forms of the current controlled temperature (typically 37 C.). After a selected invention may be immediate release, releasing the active duration (typically 1 hour, but any physiologically realistic agent and/or excipients in an uncontrolled fashion, or may duration could be appropriate), the aqueous phase was be controlled release. Included in the term “controlled Sampled, taking care not to include undispersed oil globules, release' are dosage forms or compositions which release the or non-uniformly dispersed particulates. In Some cases, the drug and/or excipients with various release profiles Such as acqueous phase was filtered through Nylon or Tuffryn(R) extended or Sustained release, delayed release, pulsitile membrane filters with the appropriate nominal pore size release, or combinations of the above Such as multi-stage (Whatman or Gelman). In all cases, the initial 1-3 ml of release achieved by a combination of delayed release com filtrate were discarded, and the absence of Significant filter positions with variable delay times. absorption was confirmed by filtration of Standard Solutions 0.063 Preparation of various types of pharmaceutical of known active agent or Vitamin E Substance concentration formulations are described, for example, in Remington. The in the appropriate matrix, collection of the filtrate, and assay Science and Practice of Pharmacy, Nineteenth Edition. of the filtrate to confirm that there was no change in drug (1995) cited supra and Ansel et al., Pharmaceutical Dosage concentration. Other techniques to characterize the extent of Forms and Drug Delivery Systems, 6th Ed. (Media, PA: dispersion could also be used, Such as centrifugation to Williams & Wilkins, 1995). Separate larger particles from the uniform aqueous disper 0.064 II. Utility and Administration SO. 0065. The pharmaceutical compositions and dosage 0070 The aqueous phase sample or filtrate was then forms have utility in the treatment of patients that may diluted in an appropriate Solvent (typically acetonitrile or benefit from the therapeutic administration of hydrophobic methanol, HPLC grade), and assayed for active agent or drugs. Such therapies include, for example, Steroid therapy Solubilizer content. or hormone therapy. Patients Suffering from any condition, 0071 Assay for vitamin E substance content in most disease or disorder that can be effectively treated with any of cases was by UV spectrophotometry with quantification at a the active agents disclosed herein can benefit from the wavelength of 291 nm for tocopherol and 285 nm for administration of a therapeutically effective amount of the tocopherol acetate tocopherol Succinate, and tocopherol pharmaceutical compositions and dosage forms described polyethyleneglycol Succinate. Samples were diluted 100x in herein. An advantage of the claimed pharmaceutical com methanol, then Scanned in a quartz cuvette using an Agilent position is improvement in the oral absorption and bioavail 8453 UV/Vis Spectrophotometer. Calibration was by linear ability of the active agent thereby ensuring that the patient regression of absorbance at the indicated wavelengths with will in fact benefit from the prescribed therapy. The standards of the relevant Vitamin E Substance of known improved bioavailability of the active agent is a result of the concentration. Standards of the drugs or other excipients improved dispersion of the active agent in the claimed present in the composition at the expected concentrations pharmaceutical composition. were also Scanned to confirm Selectivity. 0.066. It is to be understood that while the invention has 0072. In cases where the active agent or other excipient been described in conjunction with the preferred specific caused significant interference at the 285-291 nm wave embodiments, the description set forth above as well as the lengths, assay for Vitamin E Substances was by reversed examples that follow are intended only to illustrate the phase HPLC using a Symmetry C 183.6x150 mm column, invention and not limit the scope of the invention. Other 5u, with a mobile phase of Methanol 98/2%v/v and detection aspects, advantages, and modifications within the Scope of at 285 nm. the invention will be apparent to those skilled in the art to 0073 Assay of the active agents was by reversed-phase which the invention pertains. HPLC with the column indicated above, a mobile phase of 0067 All patents, patent applications, and publications acetonitrile/water 63/57%v/v, and detection at 204 nm. mentioned herein, both Supra and infra, are herein incorpo 0074 Particle size of aqueous dispersions was deter rated by reference. mined using a Nicomp 380 ZLS laser-Scattering particle sizer (Particle Sizing Systems), with a He-Ne laser at 632.8 Experimental nm, fixed 90° angle, interrupter at 13.5, and maximum 0068 The solubility of drug Substances in the composi count rate 5 MHZ. tions was determined using conventional techniques. For 0075. The following Examples demonstrate the solubility example, Solubility was in Some cases determined gravi characteristics of various embodiments of the claimed phar metrically by incrementally adding drug until the composi maceutical formulation. tion could no longer Solubilize additional added drug. Solu bility could also be determined by equilibration of the composition with exceSS drug during gentle mixing at a EXAMPLE 1. controlled temperature (25+0.5° C), centrifugation of the 0076. This example shows the solubilization and disper resulting mixture (15 min at 15,000*g; Beckmann Sion behavior of a composition including a pregnane Steroid, Microfuge Lite), and assay of the clear Supernatant. progesterone, a vitamin E Substance (d1-alpha-tocopherol, US 2003/0236236A1 Dec. 25, 2003

Spectrum Chemicals) and a Surfactant (polyoxyl 35 castor solubilizer present in separate oily globules. With the addi oil USP/NF, Cremophor EL, BASF). The compositions tion of the active agent, the dispersibility of the formulatio shown in the tables below were prepared by combining the n.is improved Such that the fraction of drug dispersed components and mixing gently at room temperature. Significantly increases with increasing drug loading. The fraction of drug present as a very fine (<0.2u) dispersion TABLE 1-1 increases from -37% at 25 mg/g drug loading to 62% at 15% drug loading. The improved dispersibility is also shown by Compositions the increase in the fraction of the Solubilizer dispersed as a fine dispersion, increasing from 14% without drug to 63% Component 1-1 1-2 1-3 1-4 with 150 mg/g drug. dl-alpha tocopherol 70% 68.25% 63% 60% Polyoxyl 35 Castor Oil 30% 29.25% 27% 26% EXAMPLE 2 Progesterone O% 2.5% 10% 15% 0079. This example shows the solubilization and disper Sion of a pregnane Steroid, progesterone, in compositions 0.077 Compositions were dispersed in simulated gastric consisting of Vitamin E Substances (dl-alpha-tocopherol, fluid without enzyme (USP23) at 100x dilution (37+0.5° C.) Spectrum Chemicals, or d-alpha-tocopherol, Archer and mixed gently for 1 hour. At 1 hour, the dispersions were Daniels, Midland Company), a surfactant (polyoxyl 35 filtered through 0.2u nominal pore size Nylon filters, then castor oil USP/NF, Cremophor EL, BASF), and a low the filtrate was diluted 100x in methanol and assayed for molecular weight alcohol (dehydrated alcohol, USP/NF, progesterone by HPLC and for tocopherol content by Quantum). The compositions shown in the tables below UV/Vis spectrophotometry. Results are shown in Table 1-2 were prepared by combining the components and mixing below gently at room temperature.

TABLE 1-2 TABLE 2-1 Drug Fraction of Fraction of Loading in Dispersion Solubilizer Drug Compositions No. Concentrate Appearance Dispersed Dispersed Component 2-1 2-2 2-3 2-4 1-1 O Non-uniform with 14% N/A dl-alpha tocopherol 65% 54% large oil glob d-alpha tocopherol 65% 54% ules and visible Polyoxyl 35 Castor Oil 28% 23% 28% 23% particulates Ethanol 7% 6% 7% 6% 1-2 25 mg/g Non-uniform with 30% 37% large oil glob Progesterone O% 17.5% O% 17.5% ules and visible particulates 1-3 100 mg/g Non-uniform 41% 36% 0080 Compositions were dispersed in simulated gastric with a few large globules fluid without enzyme (USP23) at 100x dilution (37+0.5° C.) 1-4 150 mg/g Uniform milky 63% 62% and mixed gently for 1 hour. At 1 hour, the dispersions were dispersion filtered through 0.2u nominal pore size Nylon filters, then the filtrate was diluted 100x in methanol and assayed for tocopherol content by UV/Vis spectrophotometry and 0078. The results in Table 1-2 show that increasing the progesterone content by HPLC. The particle size distribu drug loading from 0 to 15% unexpectedly improves the tion of the dispersions was independently determined by dispersibility of the formulation. Without the drug, the laser Scattering with a Nicomp particle size analyzer for composition does not disperse readily with most of the confirmation. Results are shown in Table 2-2 below

TABLE 2-2

Volume Fraction of Fraction of Fraction Solubilizer Particles of Drug Dispersed <0.2 it, Dispersed Vitamin E Dilution in Filtrate by laser in Filtrate No. Substance Drug Appearance <0.2 it scattering <0.2 it 2-1 d1-alpha 0 mg/g Non-uniform 9% NA* tocopherol Large globules and particles in cloudy solution 2-2 dl-alpha 175 mg/g Fine uniform 66% 79% 100% tocopherol dispersion 2-3 d-alpha 0 mg/g Non-uniform 10% NA* tocopherol Large globules and particles in cloudy solution US 2003/0236236A1 Dec. 25, 2003

TABLE 2-2-continued

Volume Fraction of Fraction of Fraction Solubilizer Particles of Drug Dispersed <0.2 it, Dispersed Vitamin E Dilution in Filtrate by laser in Filtrate No. Substance Drug Appearance <0.2 it scattering <0.2 it 2-4 d-alpha- 175 mg/g Fine uniform 83% 81% 100% tocopherol dispersion *Particle size cannot be accurately determined for non-uniform samples with very large par ticles.

0081. The results in Table 2-2 show that not only is the drug readily Soluble in the Vitamin E based composition, but TABLE 3-2 the presence of the drug dramatically improves the disperS Fraction of ibility of the composition upon aqueous dilution. Without Vitamin E Solubilizer the drug, the composition does not form a fine dispersion No. Substance DHEA Dilution Appearance Dispersed and only ~10% of the vitamin E is incorporated in particles 2-1 d1-alpha 0 mg/g Non-uniform 9% <0.2u. With progesterone, the compositions form a very fine tocopherol Complete phase separation with large uniform dispersion, with ~80% of the total vitamin E in oil globules particles <0.2u. The assay for progesterone in the filtered 3-1 d1-alpha 175 mg/g Fine, uniform 68% dispersions shows that the drug is preferentially concen tocopherol dispersion 2-3 d-alpha 0 mg/g Non-uniform 10% trated in these very Small particles with nominal diameter tocopherol Large globules in <0.2 cloudy solution 3-2 d-alpha 175 mg/g Fine, uniform 70% tocopherol dispersion EXAMPLE 3 0082) This example shows the solubilization and disper Sion of an androstane Steroid ((DHEA, Sigma Chemicals), in 0084. The results in Table 3-2 show that, as with the pregnane Steroid in example 2, the addition of the androStane compositions consisting of Vitamin E Substances (dl-alpha steroid, dehydroepiandrosteroneDHEA, dramatically tocopherol, Spectrum Chemicals, or d-alpha-tocopherol, improves the formation of a fine dispersion of the compo Archer Daniels Midland Company), a Surfactant (polyoxyl Sition resulting in compositions with very high drug loading, 35 castor oil USP/NF, Cremophor EL, BASF), and a low which are then readily dispersed in aqueous media. molecular weight alcohol (dehydrated alcohol, USP/NF, Quantum). The compositions shown in the tables below EXAMPLE 4 were prepared by combining the components and mixing gently at room temperature. The corresponding placeboes 0085. This example shows the solubilization and disper (without drug) are described in Example 2, compositions 2-1 Sion using Vitamin E/Surfactant compositions for additional model Steroids: an androstane Steroid, finasteride; and a and 2-3. cholane Steroid, urSodiol. The compositions shown in the tables below were prepared by combining the components TABLE 3-1 and mixing gently at room temperature. Compositions TABLE 4-1 Component 3-1 3-2 Compositions

dl-alpha tocopherol 54% Component 4-1 4-2 4-3 d-alpha tocopherol 54% Polyoxyl 35 Castor Oil 23% 23% dl-alpha tocopherol 40.5% 40% 38% Polyoxyl 35 Castor Oil 49.5% 49% 46% Ethanol 6% 6% Ethanol 10% 5% 5% DHEA 17.5% 17.5% Finasteride O% 1.1% Ursodiol O% 5.9%

0.083 Compositions were dispersed in simulated gastric 0086 Compositions were dispersed in simulated gastric fluid without enzyme (USP23) at 100x dilution (37+0.5° C.) fluid without enzyme (USP 23) at 100x (37+0.5° C) and and mixed gently for 1 hour. At 1 hour, the dispersions were mixed gently for 1 hour. At 1 hour, the dispersions were filtered through 0.2u nominal pore size Nylon filters, then filtered through 0.2u nominal pore size Nylon filters and the the filtrate was diluted 100x in methanol and assayed for filtrate diluted 100x in methanol and assayed for tocopherol tocopherol content by UVN is spectrophotometry. Results content by UV/Vis spectrophotometry. Results are shown in are shown in Table 3-2 below Table 4-2 below US 2003/0236236A1 Dec. 25, 2003 12

TABLE 4-2 TABLE 5-2-continued

Fraction of Dilution Solubilizer Fraction of No. Drug Appearance Dispersed Vitamin E Dilution Solubilizer No. Substance Drug Appearance Dispersed 4-1 No drug Non-uniform, 40% large parti cles and glob Large globules ules in cloudy 4-2 Finasteride Fine, uniform 86% dispersion solution 4-3 Ursodiol Fine, uniform 93% 5-4 d-alpha tocopherol 84 mg/g Fine uniform 99% dispersion succinate dispersion

0087. The results in Table 4-2 show that, as with the other 0090 The results in Table 5-2 show that both tocopherol Steroids tested, the incorporation of the Steroid active agent esters have excellent Solubilizing capacity for the Steroid and has a critical role in achieving good dispersion of the allow for very high drug loading. The results also show that composition upon aqueous dilution. the Steroid is critical to achieving adequate dispersion of the composition. Without the steroid, the composition is visibly EXAMPLE 5 non-uniform with the bulk of the composition in large 0088. This example shows the solubilization and disper particles or globules (only 30% <0.45u). With the steroid Sion of progesterone in compositions containing two differ drug, the composition is readily dispersed with more 70% of ent tocopherol esters (d-alpha-tocopherol acetate and d-al the particles in a fine dispersion which passes through the pha-tocopherol Succinate, Archer Daniels Midland 0.45u filter. Company). The compositions shown in the tables below were prepared by combining the components and mixing EXAMPLE 6 gently at room temperature. 0091. This example shows the effect of solubilization and TABLE 5-1 dispersion of progesterone in compositions with varying Surfactants and Surfactant levels. The Vitamin E Substances Compositions are d-alpha tocopherol or d-alpha tocopherol acetate (both Component 5-1 5-2 5-3 5-4 from Archer Daniels Midland) with the following surfac tants: polyoxyl 35 castor oil (Cremophor EL, BASF); capry d-alpha tocopherol acetate 79% 71% d-alpha tocopherol succinate 68% 62% locaproyl macrogolglycerides (Labrasol, Gattefosse); Polyoxyl 35 Castor Oil 14% 13% 29% 27% polysorbate 80 (Tween 80, ICI), medium chain monoglyc Ethanol 7% 6% 3% 3% erides (Capmul MCM, Abitec), and tocopherol polyethyl Progesterone O% 10% O% 8% eneglycol 1000 succinate (Vitamin E-TPGS, Eastman). The compositions shown in the tables below were prepared by 0089 Compositions were dispersed in simulated gastric combining the components and mixing gently at room fluid without enzyme (USP23) at 100x dilution (37+0.5° C.) temperature. and mixed gently for 1 hour. At 1 hour, the dispersions were filtered through 0.2u nominal pore size Nylon filters, then TABLE 6-1 the filtrate was diluted 100x in methanol and assayed for Composition tocopherol succinate content by UV/Vis spectrophotometry. Results are shown in Table 5-2 below Component Tradename, Source 6-1 6-2 6-3 dl-alpha tocopherol Vitamin EUSP. 77%. 29% TABLE 5-2 Spectrum dl-alpha tocopherol Vitamin E 6-100, 85% Fraction of acetate ADM Vitamin E Dilution Solubilizer Dehydrated Alcohol Ethanol, 200 proof, 15% 3% No. Substance Drug Appearance Dispersed Quantum Polyoxyl 35 Cremophor EL, BASF 9% 5-1 d-alpha tocopherol 0 mg/g Non- 28% Castor Oil acetate homogeneous Caprylocaproyl Labrasol, Gattefosse 68% dispersion, macrogolglycerides Large globules Polysorbate 80 Tween 80, ICI 5% in cloudy Medium chain Capmul MCM, Abitec 7.5% solution monoglycerides 5-2 d-alpha tocopherol 100 mg/g Fine uniform 72% Tocopherol Vitamin E-TPGS, - 2.5% acetate dispersion polyethylene glycol Eastman 5-3 d-alpha tocopherol 0 mg/g Non- 66% 1000 succinate succinate homogeneous Progesterone N/A O% O% O% dispersion, US 2003/0236236A1 Dec. 25, 2003 13

0092) the Vitamin E Substance composition, but it also plays a critical role in dispersing the composition upon aqueous TABLE 6-2 dilution.

Composition EXAMPLE 7 Component Tradename, Source 6-4 6-5 6-6 0095. This example evaluates the dispersion behavior of d1-alpha tocopherol Vitamin EUSP. 59% 27% an active agent, fenofibrate, in a composition of a tocopherol Spectrum d1-alpha tocopherol Vitamin E 6-100, 77.8% ester (d-alpha-tocopherol acetate, Archer Daniels Midland), acetate ADM and the surfactants, polysorbate 80 (Tween 80, ICI) and Dehydrated Alcohol Ethanol, Quantum 7% 3% medium chain monoglycerides (Capmul MCM, Abitec). The Polyoxyl 35 Cremophor EL, BASF 12% compositions shown in the tables below were prepared by Castor Oil combining the components and mixing gently at room Caprylocaproyl Labrasol, Gattefosse 63% macrogolglycerides temperature. Polysorbate 80 Tween 80, ICI 4.6% Medium chain Capmul MCM, Abitec 6.9% TABLE 7-1 monoglycerides Tocopherol Vitamin E-TPGS, 2.3% Compositions polyethylene glycol Eastman 1000 succinate Component 7-1 7-2 Progesterone N/A 22.5% 7% 8.5% d-alpha tocopherol 85% 79% acetate Polysorbate 80 8.6% 8% 0.093 Compositions were dispersed in simulated gastric Medium chain 6.4% 6% fluid without enzyme (USP23) at 100x dilution (37+0.5° C.) monoglycerides and mixed gently for 1 hour. At 1 hour, the bulk aqueous Fenofibrate O% 7% phase was Sampled, taking care not to disturb the oily phase. The sample was then diluted 100x in methanol and assayed for tocopherol and drug content by UV/Vis spectrophotom 0096 Compositions were dispersed in simulated gastric etry or HPLC. Results are shown in Table 6-3 below fluid without enzyme (USP23) at 100x dilution (3710.5° C.)

TABLE 6-3

Vitamin E: Fraction of Fraction Surfactant Dilution Solubilizer of Drug No. Surfactant(s) Ratio Drug Appearance Dispersed Dispersed 6-1 Polyoxyl 35 Castor 9:1 0 mg/g Complete phase O% Oil separation, visible oily layer, essentially clear aqueous phase 6-4 Polyoxyl 35 Castor 9:1 225 mg/g Hazy dispersion 69% 65% Oil with a few large visible globules 6-2 Caprylocaproyl 3:7 0 mg/g Complete phase 17% macrogolglycerides separation with visible oily globules, cloudy aqueous phase 6-5 Caprylocaproyl 3:7 70 mg/g Hazy dispersion 68% 69% macrogolglycerides with a few large visible globules 6-3 Polysorbate 5.7:1 O Non uniform, 44%a 80/Medium chain cloudy monoglycerides/E- with visible TPGS particulates 6-6 Polysorbate 5.7:1 85 mg/g Completely 100%a 100%a 80/Medium chain dispersed in fine, monoglycerides/E- slightly hazy TPGS dispersion Filtered with 0.45 u filter before assay.

0094. The results in table 6-3 show that for all surfactants and mixed gently for 1 hour. At 1 hour, the dispersions were and Surfactant levels, not only is the drug well Solubilized in filtered through 0.2u nominal pore size Nylon filters, then US 2003/0236236A1 Dec. 25, 2003

the filtrate was diluted 100x in methanol and assayed for 0100 Compositions were dispersed in simulated gastric tocopherol acetate content by HPLC. Results are shown in fluid without enzyme (USP23) at 100x dilution (37+0.5° C.) Table 7-2 below and mixed gently for 1 hour. At 1 hour, the dispersions were filtered through 0.2u nominal pore size Nylon filters, the TABLE 7-2 filtrate was then diluted 100x in methanol and assayed for Fraction of tocopherol content by UV/Vis spectrophotometry. Results Drug Dilution Solubilizer are shown in Table 8-3 below. No. Substance Drug Appearance Dispersed 7-1 Placebo 0 mg/g Non-uniform 23% TABLE 8-2 Large globules in cloudy Fraction of aqueous phase 7-2 Fenofibrate 70 mg/g Non-uniform 22% Dilution Solubilizer Large globules No. Solvent Drug Appearance Dispersed in cloudy aqueous phase 8-1 Ethanol 0 mg/g Non uniform 18% dispersion with large visible 0097. The results in Table 7-2 show that fenofibrate globules shows no synergism with the Vitamin ESubstance Solubilizer 8-4 Ethanol 100 mg/g Fine uniform 69% upon aqueous dilution and is not dispersed adequately in the dispersion aqueous medium for effective absorption. 8-2 Triacetin 0 mg/g Non uniform 24% dispersion with EXAMPLE 8 large visible globules 0098. This example shows the effect of solubilization and 8-5 Triacetin 100 mg/g Fine uniform 47% dispersion of progesterone in a compositions consisting of a dispersion Vitamin E Substance (d-alpha-tocopherol), a Surfactant 8-3 Triethyl 0 mg/g Non uniform 15% (polyoxyl 35 castor oil USP/NF) and various hydrophilic Citrate dispersion with and hydrophobic Solvents (ethanol, triethyl citrate; glycerol large visible triacetate (triacetin)). The compositions shown in the tables globules below were prepared by combining the components and 8-6 Triethyl 100 mg/g Fine uniform 45% mixing gently at room temperature. Citrate dispersion

TABLE 8-1 Compositions 0101 This example shows that for each of the solvents tested, the presence of the Steroid drug significantly Component Tradename, Source 8-1 8-2 8-3 improves the dispersibility of the composition in aqueous dl-alpha Vitamin EUSP. 65% 65% 65% medium. tocopherol Spectrum Polyoxyl 35 Cremophor EL, BASF 28% 28% 28% Castor Oil EXAMPLE 9 Ethanol Ethanol, 200 proof, 7% Quantum 0102) This example shows the solubilization and disper Triethyl Triethyl citrate, 7% citrate Aldrich Sion of a water insoluble benzoquinone, Coenzyme QIO, in Triacetin Triacetin, Eastman 7% a composition consisting of a Vitamin E Substance (dl-alpha Progesterone N/A O% O% O% tocopherol, BASF), and surfactant (Cremophor EL, BASF). Results are shown in Table 9-1. The corresponding compo 0099) Sition without drug is in Example 1, Composition 1-1. TABLE 9-1 TABLE 8-2 Composition Tradename, Compositions Component 9-1 Component Source 8-4 8-5 8-6 dl-alpha tocopherol 63% Cremophor EL 27 dl-alpha Vitamin E, USP, 59% 59% 59% tocopherol Spectrum Coenzyme Q10 10% Polyoxyl 35 Cremophor EL, 25% 25% 25% Castor Oil BASF Ethanol Ethanol, 200 proof, 6% Quantum 0.103 Compositions were dispersed in simulated gastric Triethyl citrate Triethyl citrate, 6% fluid without enzyme (USP23) at 100x dilution (37+0.5° C.) Aldrich and mixed gently for 1 hour. At 1 hour, the aqueous phase Triacetin Triacetin, Eastman 6% Progesterone N/A 10% 10% 10% was filtered through an 0.45u filter. The filtrate was then diluted 100x in methanol and assayed for tocopherol content by HPLC. Results are shown in Table 9-2 below. US 2003/0236236A1 Dec. 25, 2003 15

TABLE 9-2 -continued

Fraction of Exemplary Compositions Dilution Solubilizer No. Drug Appearance Dispersed Component Amount (mg) 1-1 0 mg/g Non-uniform 14% EXAMPLE 17 with large oil globules and dl-alpha tocopherol visible Cremophor RH40 particulates Coenzyme Q10 9-1 100 mg/g Uniform, fine 100% EXAMPLE 1.8 dispersion dl-alpha tocopherol 3OO Cremophor RH40 3OO Idebenone 90 0104. The results in Table 9-2 show that the benzo EXAMPLE 19 quinone, coenzyme Q10, Synergistically improves the dis persion of the solubilizer. Without the active agent, the d-alpha tocopherol 270 Alpha-tocotrienol composition does not disperse in the aqueous environment Gamma-tocotrienol 23 (<14% of the solubilizer present as a fine dispersion <0.45u). Cremophor RH40 3OO With the active agent, the composition readily disperses to Idebenone 90 form a fine dispersion with 100%.<0.45u. EXAMPLE 20 dl-alpha tocopherol 8O EXAMPLES 10-25 Cremophor RH40 400 Crowo M-40 350 01.05 Coenzyme Q10 1OO EXAMPLE 21

Tocoperyl polyethylene 2OO Exemplary Compositions glycol 400 succinate Tocopherol polyethylene Component Amount (mg) glycol 1000 succinate PEG 3350 EXAMPLE 10 Bicalutamide EXAMPLE 22 dl-alpha tocopherol 52O Cremophor EL 430 d-alpha tocopherol succinate 250 DHEA 50 Cremophor RH40 50 EXAMPLE 11 Capmul MCM 50 Simvastatin 1O dl-alpha tocopherol 55 EXAMPLE 23 Cremophor RH40 45 Dutasteride 0.5 d-alpha tocopherol succinate EXAMPLE 12 Cremophor RH40 Glycerol Dibehenate dl-alpha tocopherol 2OO (Compritol 888) Polysorbate 80 15 Glycerol Distearate Maisine (Glycerol 3O (Precirol) monolinoleate) Metaxalone Eplerenone 40 EXAMPLE 24 EXAMPLE 13 d-alpha tocopherol succinate dl-alpha tocopherol Hydroxypropyl methyl cellulose, Capryol 90 (Propylene USP (Methocel K4M) glycol monocaprylate) Microcrystalline cellulose, USP Cremophor EL 60 (Avicel PH 101) Spironolactone 2OO Polyoxyl 40 Hydrogenated Castor EXAMPLE 1.4 Oil, USP (Cremophor RH 40) Polyvinyl pyrrolidone, USP dl-alpha tocopherol 313 (Kollidon 90F) Cremophor EL 256 Talc, USP 8.75 Dehydrated Alcohol 70 Colloidal Silicon dioxide, USP 1.25 Progesterone 60 (Cab-o-Sil treated) EXAMPLE 1.5 Dehydroepiandrosterone EXAMPLE 25 d-alpha tocopherol succinate 60 E-TPGS 540 Drug-Containing Granules: PEG 8OOO 60 Progesterone 1OO Spironolactone EXAMPLE 16 Butylated Hydroxy Anisole USP NF (BHA) d-alpha tocopherol succinate 60 Microcrystalline Cellulose USP E-TPGS 540 NF PEG 8OOO 60 Crospovidone USP-NF 27.5 Testosterone 1OO Polyvinyl pyrrolidone USP-NF 40.O US 2003/0236236A1 Dec. 25, 2003 16

10. The pharmaceutical composition according to claim 8, -continued wherein at least 30% of the active agent or the vitamin E Exemplary Compositions Substance is finely dispersed in the aqueous phase. 11. The pharmaceutical composition according to claim Component Amount (mg) 10, wherein at least 50% of the active agent or the vitamin Tac USP-NF 4.0 E. Substance is finely dispersed in the aqueous phase. Colloidal Silicon dioxide USP-NF 2.O Magnesium Stearate USP-NF 2.O 12. The pharmaceutical composition of claim 8, wherein Solubilizer/Surfactant Granules: the Steroid is present in an amount ranging from 0.01% to Cremophor RH40 3OO 30% w/w of the composition, the vitamin E substance is Tocopherol Polyethyleneglycol 50 present in an amount ranging from about 1% to 95% w/w of 400 succinate the composition, and the Surfactant is present in an amount d-alpha tocopherol succinate 50 Sodium Starch Glycolate USP-NF 22 ranging from about 5 to 85% w/w of the composition. Colloidal Silicon dioxide USP-NF 122 13. The pharmaceutical composition of claim 12, wherein the Steroid is progesterone. 14. The pharmaceutical composition of claim 12, wherein What is claimed is: the Steroid is testosterone. 1. A pharmaceutical composition comprising: 15. The pharmaceutical composition of claim 12, wherein a. an active agent; the Steroid is dehydroepiantrosterone. b. a Vitamin E Substance; and 16. The pharmaceutical composition of claim 8, wherein the Vitamin E Substance is Selected from the group consist c. a Surfactant, ing of alpha tocopherol, alpha tocopherol acetate, alpha wherein upon dilution of the composition, the active tocopherol Succinate, and alpha tocopherol polyethyleneg agent increases the extent of dispersion of the Vita lycol Succinate. min E substance by at least 20% relative to the 17. The pharmaceutical composition of claim 16, wherein dispersion of the composition without the active the Vitamin E Substance is Selected from the group consist agent. ing of d-alpha tocopherol, d1-alpha tocopherol, d-alpha 2. The pharmaceutical composition of claim 1, wherein tocopherol acetate, di-alpha tocopherol acetate, d-alpha the active agent is a hydrophobic drug. tocopherol Succinate, and di-alpha tocopherol Succinate. 3. The pharmaceutical composition of claim 2, wherein 18. The pharmaceutical composition of claim 8, wherein the hydrophobic drug is a Steroid. the Surfactant is Selected from the group consisting of 4. The pharmaceutical composition of claim 2, wherein polyoxyl 35 castor oil, PEG-40 hydrogenated castor oil, the hydrophobic drug is a benzoquinone. caprylocaproyl macrogol-8 glycerides, polySorbate 80, lau 5. The pharmaceutical composition of claim 1, wherein royl macrogol-32 glycerides, Stearoyl macrogol-32 glycer the Vitamin E Substance is Selected from the group consist ing of alpha tocopherol, alpha tocopherol acetate, alpha ides, and tocopherol polyethyleneglycol 1000 Succinate. tocopherol Succinate, and alpha tocopherol polyethyleneg 19. The pharmaceutical composition of claim 8, wherein lycol Succinate. the Steroid is progesterone, the Vitamin E Substance is alpha 6. The pharmaceutical composition of claim 5, wherein tocopherol, and the Surfactant is polyoxyl 35 castor oil. the Vitamin E Substance is Selected from the group consist 20. The pharmaceutical composition of claim 19, wherein ing of d-alpha tocopherol, d1-alpha tocopherol, d-alpha the progesterone is present in an amount ranging from about tocopherol acetate, d1-alpha tocopherol acetate, d-alpha 0.1% to 30% w/w. tocopherol Succinate, and dl-alpha tocopherol Succinate. 7. The pharmaceutical composition of claim 1, wherein 21. The pharmaceutical composition of claim 20, wherein the Surfactant is Selected from the group consisting of the progesterone is present in an amount ranging from about polyoxyl 35 castor oil, PEG-40 hydrogenated castor oil, 0.01% to 0.3% w/w. caprylocaproyl macrogol-8 glycerides, polySorbate 80, lau 22. The pharmaceutical composition of claim 8, wherein royl macrogol-32 glycerides, Stearoyl macrogol-32 glycer the Steroid is dehydroepiantrosterone, the Vitamin E Sub ides, and tocopherol polyethyleneglycol 1000 Succinate. stance is alpha.tocopherol, and the Surfactant is polyoxyl 35 8. A pharmaceutical composition comprising: castor oil. 23. The pharmaceutical composition of claim 22, wherein a. a steroid; the dehydroepianitrosterone is present in an amount of at b. a Vitamin E Substance; and least 5% w/w. c. a Surfactant, 24. The pharmaceutical composition of claim 8, wherein the Steroid is testosterone, the Vitamin E Substance is alpha wherein after a 100x dilution of the composition in an acqueous medium, at least 30% of the hydrophobic tocopherol Succinate, and the Surfactant is tocopherol poly drug or the Vitamin E Substance is dispersed in the ethyleneglycol 1000 succinate. aqueous phase. 25. The pharmaceutical composition of claim 24, wherein 9. The pharmaceutical composition according to claim 8, the testosterone is present in an amount of at least 1% W/w. wherein at least 50% of the active agent or the vitamin E 26. The pharmaceutical composition of claim 8, wherein Substance is dispersed in the aqueous phase. the Steroid is progesterone, the Vitamin E Substance is alpha US 2003/0236236A1 Dec. 25, 2003 tocopherol Succinate, and the Surfactant is tocopherol poly the pharmaceutical composition of claim 2 in a Suitable ethyleneglycol 1000 succinate. dosage form. 27. The pharmaceutical composition of claim 26, wherein 29. A method of improving the bioavailability of a steroid the progesterone is present in an amount ranging from about administered to a patient comprising administering to Said 1% to 30%. patient a therapeutically effective amount of the pharmaceu 28. A method of improving the bioavailability of a hydro tical composition of claim 8 in a Suitable dosage form. phobic drug administered to a patient comprising adminis tering to Said patient a therapeutically effective amount of k k k k k