US 2016.0015649A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2016/0015649 A1 Chen et al. (43) Pub. Date: Jan. 21, 2016

(54) PHARMACEUTICAL COMPOSITIONS AND in-part of application No. 09/375,636, filed on Aug. DOSAGE FORMS FOR ADMINISTRATION OF 17, 1999, now Pat. No. 6,309.663. HYDROPHOBIC DRUGS Publication Classification Applicant: Lipocine Inc., Salt Lake City, UT (US) (71) (51) Int. Cl. (72) Inventors: Feng-Jing Chen, Danbury, CT (US); A61 K 9/48 (2006.01) Mahesh V. Patel, Salt Lake City, UT A61 K. 3 1/568 (2006.01) (US); David T. Fikstad, Stanford, CA A61 K. 3 1/5685 (2006.01) (US); Huiping Zhang, Malvern, PA A61 K. 3 1/585 (2006.01) (US); Chandrashekar Gillyar, Salt A61R 3 1/57 (2006.01) Lake City, UT (US) A61 K. 3 1/473 (2006.01) (52) U.S. CI. CPC ...... A61K 9/4866 (2013.01); A61K3I/57 (21) Appl. No.: 14/732,342 (2013.01); A61K 9/4858 (2013.01); A61 K 31/473 (2013.01); A61 K3I/5685 (2013.01); (22) Filed: Jun. 5, 2015 A61K3I/585 (2013.01); A61K3I/568 (2013.01) Related U.S. Application Data (57) ABSTRACT (63) Continuation of application No. 12/625,284, filed on Pharmaceutical compositions and dosage forms for adminis Nov. 24, 2009, now abandoned, which is a continu tration of hydrophobic drugs are provided. The pharmaceu ation of application No. 10/444,935, filed on May 22, tical compositions include a therapeutically effective amount 2003, which is a continuation-in-part of application of a hydrophobic drug, preferably a steroid; a solubilizer, and No. 09/716,029, filed on Nov. 17, 2000, now Pat. No. a surfactant. The synergistic effect between the hydrophobic 6,982,281, which is a continuation-in-part of applica drug and the solubilizer results in a pharmaceutical formula tion No. 09/877,541, filed on Jun. 8, 2001, now Pat. tion with improved dispersion of both the active agent and the No. 6,761,903, which is a continuation-in-part of solubilizer. As a result of the improved dispersion, the phar application No. 09/345,615, filed on Jun. 30, 1999, maceutical composition has improved bioavailability upon now Pat. No. 6,267,985, which is a continuation-in administration. Methods of improving the bioavailability of part of application No. 09/751,968, filed on Dec. 29, hydrophobic drugs administered to a patient are also pro 2000, now Pat. No. 6,458,383, which is a continuation vided. US 2016/0015649 A1 Jan. 21, 2016

PHARMACEUTICAL COMPOSITIONS AND follows, and in part will become apparent to those skilled in DOSAGE FORMS FOR ADMINISTRATION OF the art upon examination of the following, or may be learned HYDROPHOBIC DRUGS by practice of the invention. CROSS-REFERENCE INCORPORATION BY REFERENCE [0001] This application is a continuation of Ser. No. [0009] All publications, patents, and patent applications 12/625,284, filed Nov. 24, 2009, which is a continuation of mentioned in this specification are herein incorporated by Ser. No. 10/444,935, filed May 22, 2003, which is a continu reference to the same extent as if each individual publication, ation-in-part of U.S. Pat. No. 6,982,281 filed Nov. 17, 2000, patent, or patent application was specifically and individually and a continuation-in-part of U.S. Pat. No. 6,761,903 filed indicated to be incorporated by reference. Jun. 8, 2001, which is a continuation-in-part of U.S. Pat. No. 6,267,985 filed Jun. 30, 1999, and a continuation-in-part of DETAILED DESCRIPTION OF THE INVENTION U.S. Pat. No. 6,458,383, filed Dec. 29, 2000, which is a continuation-in-part of U.S. Pat. No. 6,309,663 filed Aug. 17, I. Definitions and Nomenclature 1999, the disclosures of which are incorporated herein by [0010] Before the present formulations and dosage forms reference in their entireties. are disclosed and described, it is to be understood that unless otherwise indicated this invention is not limited to specific BACKGROUND OF THE INVENTION dosage forms, solubilizers, or the like, as such may vary. It is [0002) Numerous therapeutic agents are poorly soluble in also to be understood that the terminology used herein is for aqueous medium and present difficult problems in formulat the purpose of describing particular embodiments only and is ing for effective administration to patients. Steroids in par not intended to be limiting. ticular have very low water solubility and are useful thera [0011] It must be noted that, as used in the specification and peutic agents for a wide variety of medical conditions. the appended claims, the singular forms “a,” “an” and “theº Conventional formulations that incorporate these therapeutic include plural referents unless the context clearly dictates agents suffer from several disadvantages such as incomplete otherwise. Thus, for example, reference to “a solubilizer” or slow dissolution and/or highly variable dissolution pro includes a single solubilizer or mixtures of two or more solu files. Furthermore, following oral administration, these con bilizers, reference to “an additive” refers to a single additive ventional formulations exhibit low and/or variable absorp or mixtures of different additives, reference to “an additional tion. A well-designed formulation must, at minimum, be active agent” includes a single additional active agent or capable of presenting a therapeutically effective amount of combinations of two or more additional active agents, and the the active substance to the desired absorption site, in an like. absorbable form. [0012] In this specification and in the claims that follow, reference will be made to a number of terms which shall be SUMMARY OF THE INVENTION defined to have the following meanings: [0013]. “Optional” or “optionally” means that the subse [0003] Accordingly, it is a primary object of the invention quently described circumstance may or may not occur, so that to address the above-mentioned need in the art by providing a the description includes instances where the circumstance pharmaceutical composition and dosage form for orally occurs and instances where it does not. administering hydrophobic therapeutic agents. [0014] The terms “active agent,” “drug” and “pharmaco [0004] It is another object of the invention to provide such logically active agent” are used interchangeably herein to a composition and dosage form comprising a therapeutically refer to a chemical material or compound which, when effective amount of a hydrophobic therapeutic agent and a administered to an organism (human or animal, generally solubilizer. human) induces a desired pharmacologic effect. In the con [0005] It is another object of the invention to provide such text of the present invention, the terms generally refer to a a composition and dosage form wherein the solubilizer com hydrophobic therapeutic active agent, unless the context prises a vitamin E substance, a trialkyl citrate, a lactone, a clearly indicates otherwise. nitrogen-containing solvent or a combination thereof. [0015] By “pharmaceutically acceptable” is meant a carrier [0006] It is still another object of the invention to provide comprised of a material that is not biologically or otherwise such a composition and dosage form wherein the solubilizer undesirable. comprises a phospholipid. It is yet another object of the [0016] “Carrier” or “vehicle” as used herein refer to carrier invention to provide such a composition and dosage form materials suitable for drug administration. Carriers and wherein the solubilizer comprises a glyceryl acetate, a fatty vehicles useful herein include any such materials known in acid esterofan acetylated glyceride or a combination thereof. the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, It is a further object of the invention to provide such a com surfactant, or the like, which is nontoxic and which does not position and dosage form wherein the solubilizer comprises a interact with other components of the composition in a del lower alcohol fatty acid ester. eterious manner. [0007] The present invention also encompasses methods of [0017] The terms “treating” and “treatment” as used herein improving the bioavailabilty of active agents, and steroids in refer to reduction in severity and/or frequency of symptoms, particular, in patients through the administration of the elimination of symptoms and/or underlying cause, prevention claimed pharmaceutical compositions in suitable dosage of the occurrence of symptoms and/or their underlying cause, forms. and improvement or remediation of damage. Thus, for [0008] Additional objects, advantages and novel features of example, “treating” a lipid disorder, as the term “treating” is the invention will be set forth in part in the description which used herein, encompasses both prevention of lipid disorders US 2016/0015649 A1 Jan. 21, 2016 in a predisposed individual and treatment of lipid disorders in tion offenofibrate is already solubilized in the compositions. a clinically symptomatic individual. In addition, the present compositions are not dependent on [0018] “Patient” as used herein refers to a mammalian, lipolysis for the absorption offenofibrate since the composi preferably human, individual who can benefit from the phar tions do not require triglycerides or vegetable oils. maceutical compositions and dosage forms of the present invention. A. Active Agent [0019. The term “vitamin E substance” refers to both vita [0025] The active agentin the present invention is generally min E and derivatives thereof. hydrophobic in nature (log P greater than 2, P is the intrinsic [0020) By the terms “effective amount” or “therapeutically octanol partition coefficient). Preferred classes of active effective amount” of an agent as provided herein are meant a agents from which the hydrophobic drug may be selected nontoxic but sufficient amount of the agent to provide the include the following: analgesics, anti-inflammatory agents, desired therapeutic effect. The exact amount required will anti-helminthics, anti-arrhythmic agents, anti-asthma agents, vary from subject to subject, depending on the age, weight anti-bacterial agents, anti-viral agents, anti-coagulants, anti and general condition of the subject, the severity of the con depressants, anti-diabetics, anti-epileptics, anti-fungal dition being treated, the judgment of the clinician, and the agents, anti-gout agents, anti-hypertensive agents, anti-ma like. Thus, it is not possible to specify an exact “effective larials, anti-migraine agents, anti-muscarinic agents, anti amount.” However, an appropriate “effective amount” in any neoplastic agents, immunosuppressants, anti-protozoal individual case may be determined by one of ordinary skill in agents, anti-thyroid agents, anti-tussives, anxiolytics, seda the art using only routine experimentation. tives, hypnotics, neuroleptics, beta.-blockers, cardiac inotro pic agents, cell adhesion inhibitors, corticosteroids, cytokine II. The Pharmaceutical Composition receptor activity modulators, diuretics, anti-parkinsonian [0021] The present invention overcomes the problems agents, gastro-intestinal agents, histamine H-receptor associated with the conventional approaches for preparing antagonists, keratolytics, lipid regulating agents, muscle formulations containing hydrophobic active agents by pro relaxants, nitrates and other anti-anginal agents, non-steroid viding unique pharmaceutical compositions comprising a anti-asthma agents, nutritional agents, opioid analgesics, sex therapeutically effective amount of an active agent, a solubi hormones, stimulants and anti-erectile dysfunction agents. lizer and, optionally, a dispersing aid, that are more readily [0026] While this approach may be broadly applicable to dispersed upon mixing with an aqueous medium than those many classes of active agents, particularly hydrophobic which would be obtained without the particular combination actives, we have found that drugs in the class of steroids and of solubilizer and active agent. benzoquinones are particularly effective in this regard. [0022] The pharmaceutical compositions described herein [0027] The following lists set forth exemplary active agents contain a hydrophobic therapeutic agent in substantially solu for use in the present invention; those of ordinary skill in the bilized form. The compositions improve the bioavailability of art will readily recognize that suitable active agents may be the active agent after oral administration and/or improve used in the present invention either alone or in combination. patient compliance through an easily followed dosing regi [0028] Steroids are compounds based on the cyclopenta?ol men. The compositions described herein preferably contain phenanthrene structure. Examples of steroids which have the active agent, i.e., fenofibrate, in a substantially solubilized been shown to be suitable for the current invention include form and the effective absorption of the active agent is not those with the androstane structure. Examples of such andros dependent on the dissolution of crystalline material of the tane steroids include cetadiol, clostebol, danazol, dehydroe active agent. piandrosterone (DHEA) (also, prasterone or dehydroisoan [0023] In the art of pharmaceutical formulation, vitamin E drosterone), DHEA sulfate, dianabol, dutasteride, substances have been known for their reducing potential and exemestane, finasteride, nerobol, oxymethol one, stanolone, exclusively used as antioxidant in pharmaceutical composi stanozolol, testosterone, 17-alpha-methyltestosterone, and tions. The inventors have found, however, that vitamin E methyltestosterone enanthate. substances have unexpected solubilization power toward [0029] Another group steroids, which have been shown to fenofibrate and other hydrophobic therapeutic agents. be suitable, are those based on the cholane or cholesterol [0024] The inventors also have surprisingly found that structure. Examples of such steroids are brassicasterol, nitrogen-containing solvents have unexpected solubilization campesterol, chenodeoxycholic acid, clionasterol, desmos power toward fenofibrate and other hydrophobic therapeutic terol, lanosterol, poriferasterol, C-sitosterol-, stigmasterol, agents relative to other commonly used non-nitrogen contain and ursodeoxycholic acid. ing solvents such as glycerol, propylene glycol, and polyeth [0030] Another suitable class of steroids for use in the ylene glycols. With additional research, the inventors have present invention are those steroids based on the estrane further surprisingly found that replacing one or more of the structure. Examples of such estranes include desogestrel, hydroxyl groups of glycerol and propylene glycol with, for equilin, 17-alpha-dihydroeduilin, 17-beta-dihydroeduilin, example, a lower alkyl ester, results in a propylene glycol or 17-alpha-estradiol, 17-beta-estradiol (estradiol), ethinyl glycerol fatty acid ester with an unexpectedly high solubiliz estradiol, estriol, estrone, levonorgestrel, lynestrenol, mestra ing power for fenofibrate. Similarly, additional research has nol, mibolerone, mifegyne, mifepristone, nandrolone, nore yielded other unexpectedly effective solubilizers for fenofi thindrone (or norethistrone), norethindrone acetate (or nore brate including esters of monohydric alcohols such as ethanol thisterone acetate), nortestosterone. and ethylene glycols such as polyethylene glycols with an [0031| Also suitable is the steroid class based on the preg organic acid such as acetic acid, fatty acids and citric acids. In name structure. Examples of such pregnanes include alfaxa contrast to most conventional fenofibrate compositions, the lone, beclomethasone, budesonide, clobetasol, clobetasone, present compositions do not require a separate step for the corticosterone, desoxycorticosterone, cortisol, cortisone, dissolution of crystalline fenofibrate since a significant frac dihydrocortisone, cyproterone, desonide, dexamethasone, US 2016/0015649 A1 Jan. 21, 2016

eplerenone, epoxypregnenolone, flumethasone, megestrol, enem, bicalutamide, bietamiverine, bifonazole, binedaline, melengestrol, prednisolone, prednisone, pregnanediol, preg binifibrate, biricodar, bisacodyl, bisantrene, bisoprolol, nanolone, pregnenolone, allopregnanolone, epiallopreg bitolterol, bopindolol, boswellic acid, bradykinin, bretylium, nanolone, progesterone, medroxyprogesterone, spironolac bromazepam, bromocriptine, bromperidol, brotizolam, tone, and tibolone. brovincamine, buciclate, bucloxic acid, bucumolol, budrala [0032] It is to be understood that steroids suitable for the zine, bufeniode, bufetolol, buflomedil, bufuralol, bumet present invention are not limited to those disclosed herein and anide, bunitrolol, bupranolol, buprenorphine, buproprion, include any secondary steroids, such as for example, vitamin buspirone, busulfan, butalamine, butarphenol, butaverine, D butenafine, butenafine, butidrine hydrochloride, butobarbi [0033] Steroid esters, such as the acetate, benzoate, cypi tone, butoconazole nitrate, butoconazole, butofilol, butorphe onate, decanoate, enanthate, hemisuccinate, hexahydroben nol, butropium bromide, cabergoline, calcifediol, calcipot zoate, 4-methylvalerate, propionate, stearate, Valerate, and riene, calcitriol, caldiribine, cambendazole, camioxirole, undecanoate esters would also be suitable for the present camostat, camposterol, camptothecin, candesartan, candox invention. atril, capecitabine, caprate, capsaicin, captopril, carazolol, [0034] Examples of suitable benzoquinones include carbacephems, carbamates, carbamezepine, carbapenems, ubiquinones, such as coenzyme Q10, embelin, idebenone|2, carbarsone, carbatrol, carbenoxolone, carbimazole, carbro 3-dimethoxy-5-methyl-6-(10-hydroxydec-yl)-1,4-benzo mal, carbuterol, carisoprodol, carotenes, caroverine, car quinone], pyrroloquinoline quinone, and seratrodast [7-(3,5, teolol, carvedilol, cefaclor, cefazolin, cefbuperazone, 6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic cefepime, cefoselis, ceftibuten, celcoxib, celecoxib, celip acid]. rolol, cephaeline, cephalosporin C, cephalosporins, cepha [0035) Examples of other active agents which may be suit mycins, cerivastatin, certoparin, cetamolol, cetiedil, cetiriz able for this invention include, without limitation: abecarnil, ine, cetraxate, chloracizine, chlorambucil, chlorbetamide, acamprostate, acavir, acebutolol, aceclofenac, acemetacin, chlordantoin, chlordiazepoxide, chlormadinone acetate, acetaminophen, acetaminosalol, acetanilide, acetohexamide, chlormethiazole, chloroquine, chlorothiazide, chlorphe acetophenazine maleate, acetophenazine, acetoxolone, niramine, chlorphenoxamide, chlorphentermine, chlor acetoxypregnenolone, acetretin, acrisorcin, acrivastine, acy proguanil, chlorpromazine, chlorpropamide, chlorprothix clovir, adinazolam, adiphenine hydrochloride, adrafinil, ene, chlortetracycline, chlorthalidone, cholecalciferol, adrenolone, agatroban, ahnitrine, akatinol, alatrofloxacin, chromonar, ciclesonide, ciclonicate, cidofivir, ciglitazone, albendazole, albuterol, aldioxa, alendronate, alfentanil, ali cilansetron, cilostazol, cimetidine, cimetropium bromide, bendol, alitretinoin, allopurinol, allylamines, allylestrenol, cinepazet maleate, cinnamedrine, cinnarizine, cinolazepam, alminoprofen, almotriptan, alosetron, aloxiprin, alprazolam, cinoxacin, ciprofibrate, ciprofloxacin, cisapride, cisplatin, alprenolol, amantadine, ambucetamide, amidephrine, amidi citalopram, citicoline, clarithromycin, clebopride, clemas nomycin, amiloride, aminoarylcarboxylic acid derivatives, time, clenbuterol, clidanac, clinofibrate, clioquinol, clobazam, aminoglutethimide, aminoglycosides, aminopentamide, ami clobenfurol, clobenzorex, clofazimine, clofibrate, clofibric nopromazine, aminorex, amiodarone, amiphenazole, ami acid, cloforex, clomipramine, clonazepam, clonidine, cloni prilose, amisuipride, amitriptyline, amlexanox, amlodipine, trate, clopidogrel, clopirac indomethacin, cloranolol, cloric amodiaquine, amosulalol, amotriphene, amoxapine, amox romen, clorprenaline, clortermine, clotiazepam, clotrima icillin, amphecloral, amphetamine, amphomycin, amphoteri zole, cloxacillin, clozapine, cmepazide, codeine methyl cin, ampicillin, ampiroxicam, amprenavir, amrinone, amsa bromide, codeine phosphate, codeine sulfate, codeine, colloi crine, amyl nitrate, amylobarbitone, anagestone acetate, dal bismuth subcitrate, cromafiban, cromolyn, cropropamide, anastrozole, andinocillin, androstenediol, androstenediol-17 crotethamide, curcumin, cyclandelate, cyclarbamate, cycla acetate, androstenediol-17-benzoate, androstenediol-3-ac zocine, cyclexedrine, cyclizine, cyclobenzaprine, cyclodrine, etate, androstenediol-3-acetate-17-benzoate, androstenedi cyclonium iodide, cyclopentamine, cyclosporin, cypionate, one, androsterone acetate, androsterone benzoate, cyproheptadine, cyproterone acetate, cytarabine, dacarba androsterone propionate, androsterone, angiotensin, anidu zine, dalfopristine, dantrolene sodium, dapiprazole, dar lafungin, aniracetam, apazone, apicycline, apoatropine, apo odipine, decanoate, decitabine, decoquinate, dehydroemet morphine, apraclonidine, aprepitant, aprotinin, arbaprostil, ine, delavirdine, delaviridine, demeclocycline, denopamine, ardeparin, aripiprazole, armikacin, arotinolol, arstiinol, ary deramciclone, descitalopram, desipramine, desloratadine, lacetic acid derivatives, arylalkylamines, arylbutyric acid 3-ketodesogestrel, desomorphine, desoxymethasone, deto derivatives, arylcarboxylic acids, arylpiperazines, arylpropi midine, dexamphetamine, dexanabinol, dexchlorphe onic acid derivatives, aspirin, astemizole, atenolol, atomox niramine, dexfenfluramine, dexmethylphenidate, dexrazox etine, atorvastatin, atovaquone, atropine, auranofin, aza ane, dextroamphetamine sulfate, dextroamphetamine, propazone, azathioprine, azelastine, azetazolamide, dextropropoxyphene, DHEA, diacetate, diamorphine, diaz azithromycin, baclofen, bambuterol, bamethan, barbitone, emine, diazepam, diaziquinone, diazoxide, dibromopropami barnidipine, basalazide, beclamide, beclobrate, befimolol, dine, dichlorophen, diclofenac, dicoumarol, didanosine, bemegride, benazepril, bencyclane, bendazac, bendazol, ben dideoxyadenosine, diethylpropion, difemerine, difenami droflumethiazide, benethamine penicillin, benexate hydro zole, diflunisal, digitoxin, digoxin, dihidroergotamine, dihy chloride, benfurodil hemisuccinate, benidipine, benorylate, drocodeine, dihydrocodeinone enol acetate, dihydroergota bentazepam, benzhexol, benziodarone, benznidazole, ben mine mesylate, dihydroergotamine, dihydrogesterone, zoctamine, benzodiazepine derivatives, benzodiazepine, ben dihydromorphine, dihydropyridine derivatives, dihydrostrep zonatate, benzphetamine, benzylmorphine, beperiden, tomycin, dihydrotachysterol, dihydroxyaluminum acetyl bephenium hydroxynaphthoate, bepridil, betahistine, salicylate, diiodohydroxyquinoline, diisopromine, dilazep, betamethasone, betaxolol, bevantolol, bevonium methyl sul dilevalol, dilitazem, diloxanide furoate, diloxanide, dilt fate, bexarotene, bezadoxifine, bezafibrate, bialamicol, biap iazem, dimefline, dimenhydrinate, dimethisterone, dimetof US 2016/0015649 A1 Jan. 21, 2016 rine, dimorpholamine, dinitolmide, dioxaphetyl butyrate, mononitrate, isosorbide dinitrate, isoxsuprine, isradipine, dioxethedrine, diphemethoxidine, diphenhydramine, diphe itasetron, itraconazole, itramintosylate, ivermectin, kallidin, noxylate, diphetarsone, dipivefrin, diponium bromide, dipy kallikrein, kanamycin, ketamine, ketoconazole, ketoprofen, ridamole, dirithromycin, disopyramide, divalproex sodium, ketorolac, ketotifen, labetalol, lafutidine, lamifiban, lamivu dofetilide, domperidone, donezepil, dopexamine, dopradil, dine, lamotrigine, lanatoside c, lansoprazole, lasofoxifene, dosmalfate, doxapram, doxazosin, doxefazepam, doxepin, leflunomide, leminoprazole, lercanadipine, lesopitron, letro doxycycline, drofenine, dromostanolone propionate, dromo zole, leucovorin, levalbuterol, levallorphan, levetiracetam, stanolone, dronabinol, droperidol, droprenilamine, d-threo levetriacetam, levobunolol, levodopa, levofloxacin, methylphenidate, duloxetine, ebrotidine, eburnamonine, eca levophacetoperane, levorphanol, lidocaine, lidoflazine, lifi bet, ecenofloxacin, econazole nitrate, edavarone, edoxudine, brol, limaprost, linezolid, lintitript, liranaftate, lisinopril, efavirenz, effivarenz, efloxate, eledoisin, eletriptan, elgo lisuride, lobeline, lobucavir, lodoxamide, lomefloxacin, lom dipine, ellipticine, emepronium bromide, emetime, enalapril, erizine, lomustine, loperamide, lopinavir, loprazolam, lora enanthate, encainide, enlopitat, enoximone, emprostil, enta carbef, loratadine, lorazepam, lorefloxacin, lormetazepam, capone, epanolol, ephedrine, epinastine, epinephrine, epiru losartan, lovasatain, lovastatin, loxapine succinate, loxapine, bicin, epleronone, eposartan, ergocalciferol, ergoloid mesy 1-threo-methylphenidate, lumiracoxib, lysine acetylsalicy lates, ergotamine, ertapenum, erythromycin, erytlirityl late, lysozyme, lysuride, mabuterol, mafenide, magnesium tetranitrate, esaprazole, escitalopram, esmolol, esomepra acetylsalicylate, malgramostin, mannitol hexanitrate, mapro zole, esonarimod, estazolam, estradiol benzoate, estramus tiline, mazindol, mebendazole, meclizine, meclofenamic time, estriol succinate, estrone acetate, estrone sulfate, acid, mecloxaminepentapiperide, medazepam, medibazine, etafedrine, etafenone, ethacrynic acid, ethamivan, ethi medigoxin, medrogestone, medroxyprogesterone acetate, namate, ethinylestradiol 3-acetate, ethinylestradiol 3-ben mefenamic acid, mefenorex, mefloquin, mefloquine, mege zoate, ethinylestradiol, ethionamide, ethisterone (17.alpha. strol acetate, melengestrol acetate, melphalan, mematine, ethinyltestosterone-), ethopropazine, ethotoin, mepenzolate bromide, meperidine, mephenoxalone, ethoxyphenamine, ethylestrenol, ethylmorphine, ethylmore mephentermine, mepindolol, mepixanox, meprobamate, pinephrine, ethynodiol diacetate, etodolac, etofibrate, etopo meptazinol, mercaptopurine, merropenum, mesalamine, side, etoricoxib, etretinate, everolimus, exalamide, exames mesalazine, mesoridazine besylate, mesoridazine, meta tane, examorelin, ezemitibe, falecalcitriol, famciclovir, clazepam, metamfepramone, metampicillin, metaproterenol, famotidine, fantofarone, farapenum, farglitazar, fasudil, fel metaraminol, methacycline, methadone hydrochloride, bamate, felodipine, femalamide, fenbufen, fenbutrazate, methadone, methamphetamine, methaqualone, metharnphet fendiline, fenfluramine, fenoldopam, fenoprofen, femoterol, amine, methoin, methotrexate, methoxamine, methsuximide, fenoverine, fenoxazoline, fenoxedil, fenpiprane, fempro methylhexaneamine, methylphenidate d-threo-methylpheni porex, fenspiride, fentanyl, fexofenadine, flavoxate, flecain date, methylphenidate, methylphenobarbitone, methylpred ide, flopropione, floredil, floxuridine, fluconazole, flucy nisolone, methysergide, metiazinic acid, metizoline, meto tosine, fludarabine, fludiazepam, fludrocortisone, flufenamic clopramide, metolazone, metoprolol, metoxalone, acid, flunanisone, flunarizine, flunisolide, flunitrazepam, metripranolol, metronidazole, mexiletine, mexilitene, fluocortolone, fluoxetine, flupenthixol decanoate, fluphena metaxalone, mianserin, inibefradil, miconazole, midazolam, zine decanoate, fluphenazine enanthate, fluphenazine, flup midodrine, migitol, milnacipran, milrinone, minoxidil, mir roquazone, flurazepam, flurbiprofen, flurogestone acetate, tazapine, misoprostol, mitomycin, mitotane, mitoxantrone, fluticasone propionate, fluvastatin, fluvoxamine, fominoben, mizolastine, modafinil, mofebutazone, mofetil, molindone formoterol, foscarnet, foscarnet, fosinopril, fosphenytoin, hydrochloride, molindone, molsidomine, monatepil, mon frovatirptan, fudosteine, fumagillin, furazolidone, furazoli telukast, monteplase, moprolol, moricizine, morphine hydro done, furfurylmethyl amphetamine, furosemide, gabapentin, chloride, morphine sulfate, morphine, morpholine salicylate, gabexate, gaboxadol, galanthamine, gallopamil, gamma mosapramine, moxifloxacin, moxisylvyte, moxonidine, parin, ganciclovir, ganglefene, gefarnate, gemcitabine, gem mycophenolate, nabumetone, madolol, nadoxolol, nadro fibrozil, gepirone, gestadene, ghrelin, glatiramer, glaucaru parin, na?amostat, nafronyl, naftopidil, nalbuphine, nalidixic bin, glibenclamide, gliclazide, glimepiride, glipizide, acid, nalmefene, nalorphine, naloxone, maltrexone, man gluconic acid, glutamicacid, glyburide, glyceryl trinitrate, drolone benzoate, nandrolone cyclohexanecarboxylate, man glymepiride, granisetron, grepafloxacin, griseofulvin, guaia drolone cyclohexane-propionate, nandrolone decanoate, zulene, guanabenz, guanfacine, halofantrine, haloperidol nandrolone furylpropionate, nandrolone phenpropionate, decanoate, haloperidol, haloxazolam, hepronicate, hep naphazoline, naproxen, naratriptan, natamycin, nateglinide, tanoate, hexobendine, hexoprenaline, hydramitrazine, nebivalol, nedocromil, nefazodone, nefopam, nelfinavir, hydrazides, hydrochlorothiazide, hydrocodone, hydrocorti nemonapride, neomycin undecylenate, neomycin, neotrofin, sone, hydromorphone, hydroxyamphetamine, hydroxymeth nesiritide, n-ethylamphetamine, nevibulol, nevirapine, nexo ylprogesterone acetate, hydroxymethylprogesterone, pamil, nicametate, nicardipine, nicergoline, nicofibrate, nico hydroxyprogesterone acetate, hydroxyprogesterone furanose, nicomorphine, nicorandil, nicotinyl alcohol, nicou caproate, hydroxyprogesterone, hymecromone, hyos malone, nifedipine, nifemalol, nikethamide, nilutamide, cyamine, ibopamine, ibudilast, ibufenac, ibuprofen, ibutilide, nilvadipine, nimodipine, nimorazole, nipradilol, nisoldipine, idoxuridine, ifenprodil, igmesine, iloprost, imatinib, Ími nitisonone, nitrazepam, nitrofurantoin, nitrofurazone, nitro dapril, imidazoles, imipenem, imipramine, imolamine, glycerin, nizatidine, norastemizole, norepinephrine, nor incadronic acid pergolide, indanazoline, indenolol, indinavir, ethynodrel, norfenefrine, norfloxacin, norgestimate, norg indomethacin, indoramin, inosinepranobex, inositol niaci estrel, norgestrienone, normethadone, normethisterone, nate, iodoquinol, ipidracine, iproniazid, irbesartan, irinote normorphine, norpseudoephedrine, nortriptyline, can, irsogladine, isobutyrate, isocaprate esters, isoetharine, novantrone, nylidrin, nystatin, octamylamine, octodrine, isometheptene, isoproterenol, isosorbide dinitrate, isosorbide octopamine, ofioxacin, olanzapine, olanzapine, olapatadine, US 2016/0015649 A1 Jan. 21, 2016

olmesartan, olopatidine, olsalazine, omapatrilat, omeprazole, sucralfate, sufentanil, sulconazole nitrate, sulfacetamide, sul ondasetron, opium, oprevelkin, orlistat, ornidazole, orno fadiazine, sulfaloxicacid, sulfarside, sulfinalol, sulindac, prostil, oseltamivir, oxaliplatin, oxamniquine, oxandrolone, Suloctidil, sulphabenzamide, sulphacetamide, sulphadiazine, oxantel embonate, oxaprozin, oxatomide pemirolast, oxato sulphadoxine, sulphafurazole, sulphamerazine, sulpha mide, oxazepam, oxcarbazepine, oxfendazole, oxiconazole, methoxazole, sulphapyridine, sulphasalazine, sulphinpyra oxiracetam, oxolinicacid, oxprenolol, oxycodone, oxy zone, Sulpiride, Sulthiame, sultopride, sultroponium, fedrine, oxymetazoline, oxymorphone, oxyphenbutazone, Sumanirole, Sumatriptan, sunepitron, superoxide dismutase, oxyphencyclimine, oxyprenolol, ozagrel, paclitaxel, pal suplatast, suramin sodium, synephrine, tacrine, tacrolimus, onosetron, pantoprazole, papaverine, paracalcitol, tacrolimus, tadalafil, talinolol, talipexole, tamoxifen, tamsu paramethadione, parecoxib, pariprazole, paromomycin, par losin, targretin, tazanolast, tazarotene, tazobactum, tecastim oxetine, parsalmide, pazinaclone, pemoline, penbutolol, pen ezole, teclozan, tedisamil, tegaserod, telenzepine, telmisar ciclovir, penicillin G benzathine, penicillin G procaine, peni tan, temazepam, teniposide, teprenone, terazosin, cillin V, penicillins, pentaerythritol tetranitrate, terbenafine, terbinafine, terbutaline sulfate, terbutaline, ter pentaerythritol tetranitrate, pentapiperide, pentazocine, pen conazole, terfenadine, terodiline, terofenamate, tertatolol, tifylline, pentigetide, pentobarbitone, pentorex, pentoxifyl testolactone, 4-dihydrotestosterone, tetracyclics, tetracy line, pentrinitrol, perbuterol, perenzepine, pergolide, perhex cline, tetrahydrocannabinol, tetrahydrozoline, thalidomide, iline, perindopril erbumine, perospirone, perphenazine theofibrate, thiabendazole, thiazinecarboxamides, thiocar pimozide, perphenazine, phanquinone, phenacemide, phen bamates, thiocarbamizine, thiocarbarsone, thoridazine, thio acetin, phenazopyridine, phencarbamide, phendimetrazine, thixene, tiagabine, tiamenidine, tianeptine, tiaprofenic acid, phenelzine, phenindione, phenmetrazine, phenobarbitone, tiaramide, ticlopidine, tigloidine, tilisolol, timolol, tinida phenoperidine, phenothiazines, phenoxybenzamine, phen zole, tinofedrine, tinzaparin, tioconazole, tipranavir, tira suximide, phentermine, phentolamine, phenyl salicylate, pazamine, tirofiban, tiropramide, titanicene, tizanadine, tiza phenylacetate, phenylbutazone, phenylephrinehydroch nidine, tizinadine, tocainide, tolazamide, tolazoline, bride, phenylpropanolamine hydrochloride, phenylpropano tolbutamide, tolcapone, tolciclate, tolfenamic acid, toliprolol, laminehydrochloride, phenylpropyl-methylamine, pheny tolteridine, tolterodine, tonaberstat, topiramate, topotecan, toin, phloroglucinol, pholedrine, physostigmine salicylate, torasemide, toremifene citrate, toremifene, tosufloxacin, tra physostigmine, phytonadiol, phytosterols, piapenum, picil madol, tramazoline, trandolapril, tranilast, tranylcypromine, orex, piclamilast, picrotoxin, picumast, pifamine, pilsicaim trapidil, traxanox, trazodone, tretoquinol, triacetin, triamci ide, pimagedine, pimeclone, pimecrolimus, pimefylline, nolone, triampterine, triamterine, triazolam, triazoles, tric pimozide, pinaverium bromide, pindolol, pioglitazone, pip romyl, tricyclics, trifluoperazine hydrochloride, trifluopera eracillin, piperazine estrone sulfate, piperazine derivatives, zine, triflupromazine, trifluridine, trihexyphenidyl piperi late, piracetam, pirbuterol, pirenzepine, piribedil, piri hydrochloride, trihexyphenidyl, trimazosin, trimebutine, tri fibrate, piroxicam, pitavastatin, pizotyline, plaunotol, pola metazidine, trimethoprim, trimgestone, trimipramine, trimo prezinc, polybenzarsol, polyestrol phosphate, practolol, pral prostil, trithiozine, troglitazone, trolnitrate phosphate, nacasan, pramipexole, praniukast, pravastatin, prazepam, tromethamine, tropicamide, trovafloxacin, troxipide, tuami praziquantel, prazosin, pregabalin, prenalterol, prenylamine, noheptane, tulobuterol, tymazoline, tyramine, undecanoate, pridinol, pri?inium bromide, primidone, primipramine, undecanoic acid, urinastatin, valacyclovir, Valdecoxib, Valer probenecid, probucol, procainamide, procarbazine, pro ate, valganciclovir, valproic acid, Valsartan, Vancomycin, caterol, prochlorperazine, proguanil, pronethalol, pro vardenafil, venlafaxine, venorelbine, Verapamil, Verapimil, pafenone, propamidine, propatyl nitrate, propentoffyline, vidarabine, vigabatrin, vincamine, vinpocetime, viomycin, propionate, propiram, propoxyphene, propranolol, propyl viduidil, visnadine, vitamin a derivatives, vitamin a, vitamin hexedrine, propylthiouracil, protokylol, protriptyline, prox b2, vitamin d, vitamine, vitamin k, voglibose, Voriconazole, azole, pseudoephedrine, purines, pyrantel embonate, pyra xaliproden, xamoterol, xanthinol niacinate, xenytropium bro zoles, pyrazolones, pyridofylline, pyrimethamine, mide, xibenolol, ximelagatran, xylometazoline, yohimbine, pyrimidines, pyrrolidones, quazepam, quetiapine, quetu zacopride, Zafirlukast, Zafirlukat, zalcitabine, zaleplon, zan apine, quinagolide, quinapril, quinestrol, quinfamide, quini amivir, zatebradine, Ziconotide, zidovudine, zileuton, Zimel dine, quinine sulfate, quinolones, quinupritin, rabalzotan, dine, zinc propionate, ziprasidone, zolimidine, zolmitriptan, rabeprazole sodium, rabeprazole, racefimine, ramatroban, zolpidem, zonisamide, zopiclone. ramipril, ranitidine, ranolazine, ransoprazole, rasagiline, rebamipide, refludan, repaglinide, repinotan, repirinast, [0036) An additional active agent may be administered reproterol, reserpine, retinoids, ribavirin, rifabutine, rifampi with the active agent included in the compositions and dosage cin, rifapentine, rilmenidine, riluzole, rimantadine, rimiterol, forms of the present invention. It is preferred, however, that rioprostil, risperidone, ritanovir, ritapentine, ritipenem, rito the additional active agent is contained within the composi drine, ritonavir, rivastigmine, rizatriptan, rociverine, rofe tion and dosage form. The weight ratio of the primary active coxib, rohypnol, rolipram, romoxipride, ronifibrate, ropin agent to the additional active agent may be varied and will irole, ropivacaine, rosaprostol, rosiglitazone, rosuvastatin, depend upon the effective dose of each ingredient. Each rotinolol, rotraxate, roxatidine acetate, roxindole, rubitecan, active agent contained in the composition ordosage form will salacetamide, salicin, salicylamide, salicylic acid derivatives, be present in a therapeutically effective amount. salmeterol, saquinavir, saquinavir, scopolamine, secnidazole, [0037] Additional active agents may be solubilized or sus selegiline, semotiadil, sertindole, sertraline, sibutramine, pended with or without the presence of an additional solubi sildenafil, simfibrate, simvastatin, siramesine, sirolimus, lizer. For those additional active agents that are ionized or sitaxsentan, sofalcone, somotiadil, sorivudine, sotalol, soter ionizable, the formulations described herein may include a enol, sparfloxacin, spasmolytol, spectinomycin, spiramycin, buffer to facilitate or maintain the presence of a preferred spizofurone, stavudine, streptomycin, succinylsulfathiazole, ionized form of the additional active agent in the formulation. US 2016/0015649 A1 Jan. 21, 2016

B. Solubilizer tocopherol acetate, alpha-tocopherol acid succinate, alpha tocopherol polyethylene glycol succinate and mixtures [0038] The pharmaceutical compositions of the invention thereof. also contain a carrier. At a minimum, the carrier must contain [0042] Another group of solubilizers are monohydric alco a solubilizer. In some instances, the carrier may only contain hol esters of organic acids. The monohydric alcohol can be, one solubilizer without any additional components, i.e., addi for example, ethanol, isopropanol, t-butanol, a fatty alcohol, tives. Alternatively, the carrier may contain one or more phar phenol, cresol, benzyl alcohol or a cycloalkyl alcohol. The maceutically acceptable additives in addition to the solubi organic acid can be, for example, acetic acid, propionic acid, lizer. butyric acid, a fatty acid of 6-22 carbonatoms, bile acid, lactic [0039] In one embodiment, a pharmaceutical composition acid, pyruvic acid, oxalic acid, malic acid, malonic acid, is provided comprising a therapeutically effective amount of succinic acid, maleic acid, fumaric acid, tartaric acid, citric an active agent, a solubilizer and a dispersing aid. The solu acid, benzoic acid, cinnamic acid, mandelic acid and salicylic bilizer is present in an amount such that more of the active acid. Preferred solubilizers in this group include trialkyl cit agent is dispersed; in aqueous medium than that which would rates, lower alcohol fatty acid esters and lactones. Preferred be achieved with the same active agent and dispersing aid trialkyl citrates include triethyl citrate, acetyltriethyl citrate, without the solubilizer. The active agent and the solubilizer tributyl citrate, acetyltributyl citrate and mixtures thereof act synergistically to improve the dispersibility of the solubi with triethyl citrate being particularly preferred. Lower alco lizer itself and the active agent upon dilution in an aqueous hol fatty acid esters, as the name implies, comprise a lower media, thus greatly increasing the amount of active agent alcohol moiety, i.e., containing 2-4 carbon atoms, and a fatty which can be dispersed in a readily absorbably form. Prefer acid moiety of about 6-22 carbon atoms. Particularly pre ably, the solubilizer is present such that after a 100x dilution ferred lower alcohol fatty acid esters include ethyl oleate, of the composition the active agent and/or the solubilizer is at ethyl linoleate, ethyl caprylate, ethyl caprate, isopropyl least 30% dispersed in the aqueous phase, with a dispersion of myristate, isopropyl palmitate and mixtures thereof. Lactones at least 50% being preferred. It is more preferred that the may also serve as a solubilizer. Examples include e-caprolac solubilizer, like the active agent is at least 30% finely dis tone, Ö-valerolactone, fl-butyrolactone, isomers thereof and persed in the aqueous phase, with a fine dispersion of at least mixtures thereof. 50% being most preferred. Thus, the solubilizers as provided [0043] The solubilizer may be a nitrogen-containing sol herein improve the dissolution profile of a hydrophobic thera vent. Preferred nitrogen-containing solvents include dimeth peutic agent and thereby the bioavailability of a hydrophobic ylformamide, dimethylacetamide, N-alkylpyrrolidone, therapeutic agent. N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylca [0040] One type of solubilizer that may be used is a vitamin prolactam and mixtures thereof wherein alkyl is a C1-12 E substance. This group of solubilizers includes a substance branched or straight chain alkyl. Particularly preferred nitro belonging to the group of C-, [-, y-, Ö-, C1-, C2- and e-toco gen-containing solvents include N-methyl 2-pyrrolidone, pherols, their dl, d and 1 forms and their structural analogues, N-ethyl 2-pyrrolidone or a mixture thereof. Alternatively, the such as tocotrienols; which includes substances with the tocol nitrogen-containing solvent may be in the form of a polymer structure [2-methyl-2-(4,8,12-trimethyltridecyl)chroman-6 such as polyvinylpyrrolidone. ol] or the tocotrienol structure [2-methyl-2-(4,8,12-trimeth [0044] Another group of solubilizers includes phospholip yltrideca-3,7,11-trienyl)chroman-6-0-1|, in particular the all ids. Preferred phospholipids include phosphatidylcholine, trans-(E,E) tocotrienols. Particularly preferred vitamin E sub phosphatidylethanolamine, phosphatidylserine, phosphati stances include the mono-, di-, trimethyl-tocol derivatives, dylinositol, lecithins, lysolecithins, lysophosphatidylcholine, commonly known as tocopherols, such as O-tocopherol|5,7, polyethylene glycolated phospholipids/lysophospholipids, 8-trimethyl-], [3-tocopherol|5,8-dimethyl-, y-tocopherol|7, lecithins/lysolecithins and mixtures thereof. 8-dimethyl], C2-tocopherol|5,7-dimethyl-1, Ö-tocopherol|8 [0045] Another group of preferred solubilizers are glycerol methyl-1, q-tocopherol|7-methyl]; and the corresponding acetates and acetylated glycerol fatty acid esters. Preferred mono-, di-, and trimethyltoctrienol derivatives, commonly glycerol acetates include acetin, diacetin, triacetin and mix known as tocotrienols, such as O-tocotrienol (or C1-toco tures thereof, with triacetin being particularly preferred. Pre pherol) [5,7,8-trimethyl-1, 5-tocotrienol (or e-tocopherol) ferred acetylated glycerol fatty acid esters include acetylated [5,8-dimethyl], Y-tocotrienol? 7,8-dimethyl], and 8-tocot monoglycerides, acetylated diglycerides and mixtures rienol? 8-methyl-1. Included are their mixed racemic d1-forms, thereof. In a most preferred embodiment, the acetylated the pure d- and 1-enantiomers and the corresponding deriva monoglyceride is a distilled acetylated monoglyceride. tives, e.g., esters, produced with organic acids; and mixtures [0046) In addition, the solubilizer may be a glycerol fatty thereof. acid ester. The fatty acid component is about 6-22 carbon [0041) One skilled in the art can easily identify vitamin E atoms. The glycerol fatty acid ester can be a monoglyceride, substances that may serve as effective solubilizers by, for diglyceride, triglyceride or mixtures thereof. Preferred glyc example, mixing a particular vitamin E substance with fenofi erol fatty acid esters include monoglycerides, diglycerides, brate and determining the extent of solubility. Preferred vita medium chain triglycerides with fatty acids having about min E substances for use in the present invention include 6-12 carbons and mixtures thereof. Particularly preferred tocopherols, tocotrienols and tocopherol derivatives with glycerol fatty acid esters include medium chain monoglycer organic acids such as acetic acid, propionic acid, bile acid, ides with fatty acids having about 6-12 carbons, medium lactic acid, pyruvic acid, oxalic acid, malic acid, malonic chain diglycerides with fatty acids having about 6-12 carbons acid, succinic acid, maleic acid, fumaric acid, tartaric acid, and mixtures thereof. citric acid, benzoic acid, cinnamic acid, mandelic acid, poly [0047] The solubilizer may be a propylene glycol ester. ethylene glycol succinate and salicylic acid. Particularly pre Preferred propylene glycol esters include propylene carbon ferred vitamin E substances include alpha-tocopherol, alpha ate, propylene glycol monoacetate, propylene glycol diac US 2016/0015649 A1 Jan. 21, 2016

etate, propylene glycol fatty acid esters, acetylated propylene dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 glycol fatty acid esters and mixtures thereof. Alternatively, dioleate; PEG-fatty acid mono- and di-ester mixtures; poly the propylene glycol fatty acid ester may be a propylene ethylene glycol glycerol fatty acid esters such as PEG-20 glycol fatty acid monoester, propylene glycol fatty acid glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl diester or mixture thereof. The fatty acid has about 6-22 laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate; carbon atoms. It is particularly preferred that the propylene alcohol-oil transesterification products such as PEG-35 cas glycol ester is propylene glycol monocaprylate. Other pre tor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cre ferred propylene glycol esters include propylene glycol dica mophor R RH40), polyoxyl 35 castor oil (Cremophor EL), prylate, propylene glycol dicaprate, propylene glycol dica PEG-25 trioleate (TAGATR TO), PEG-60 corn glycerides prylate/dicaprate and mixtures thereof. (Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 [0048] Another group of solubilizers are ethylene glycol palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex esters. Ethylene glycol esters include monoethylene glycol C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), monoacetates, diethylene glycol esters, polyethylene glycol PEG-8 caprylic/capric glycerides (Labrasol R), and PEG-6 esters and mixtures thereof. Additional examples include eth caprylic/capric glycerides (Softigen?& 767); transesterifica ylene glycol monoacetates, ethylene glycol diacetates, ethyl tion products of oils and alcohols; polyglycerized fatty acids ene glycol fatty acid monoesters, ethylene glycol fatty acid such as polyglyceryl oleate (Plurolº Oleigue), polyglyc diesters, and mixtures thereof. Alternatively, the ethylene gly eryl-2 dioleate (Nikkol DGDO), and polyglyceryl-10 tri col ester may be a polyethylene glycol fatty acid monoesters, oleate. Preferred hydrophilic surfactants include polyglyc polyethylene glycol fatty acid diesters or mixtures thereof. eryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 Again, the fatty acid component will contain about 6-22 car oleate (Nikkol Decaglyn 1-0), and polyglyceryl-10 mono, bon atoms. Particularly preferred ethylene glycol esters are dioleate (Caprolº PEG 860); propylene glycol fatty acid those obtained from the transesterification of polyethylene esters such as propylene glycol monolaurate (Lauroglycol glycol with a triglyceride or a vegetable oil or mixture thereof FCC), propylene glycol ricinoleate (Propymuls), propylene and include, for example, those marketed under the Labrafilº glycol monooleate (Myverol R, P-06), propylene glycol dica and Labrasol R names. prylate/dicaprate (CaptexR 200), and propylene glycol dio [0049) Other solubilizers that may be used in the present ctanoate (Captex 800); mixtures of propylene glycol esters invention are disclosed in U.S. Pat. Nos. 6,982,281 and 6,761, and glycerol esters such as a mixture of oleic acid esters of 903, both to Chen et al. Preferred solubilizers that are not propylene glycol and glycerol (Arlacel 186); mono- and dig vitamin E substances for use in the present invention include lycerides such as glyceryl monooleate (Peceol), glyceryl rici fatty acid esters of glycerol, acetylated mono- and diglycer moleate, glyceryl laurate, glyceryl dilaurate (Capmul GDL), ides, fatty acid esters of propylene glycol, trialkyl citrate, glyceryl dioleate (Capmul GDO), glyceryl mono/dioleate glycerol acetate, and lower alcohol fatty acid esters. (Capmul GMO-K), glyceryl caprylate/caprate (Capmul MCM), caprylic acid mono/diglycerides (Imwitor R 988), C. Surfactants and mono- and diacetylated monoglycerides (Myvacet?R [0050] The surfactant in the present invention may be any 9-45); sterol and sterol derivatives such as PEG-24 choles compound containing polar or charged hydrophilic moieties terol ether (Solulan R C-24); polyethylene glycol sorbitan as well as non-polar hydrophobic (lipophilic) moieties; i.e. a fatty acid esters such as PEG-20 sorbitan monolaurate surfactant compound must be amphiphilic. Within the context (Tween(R 20), PEG-20 sorbitan monopalmitate (Tween 40), of the present invention, the hydrophilic surfactant can be any PEG-20 sorbitan monostearate (Tween 60), and PEG-20 sor hydrophilic surfactant suitable for use in pharmaceutical bitan monooleate (polysorbate 80 or Tween 80); polyethylene compositions. Such surfactants can be anionic, cationic, zwit glycol alkyl ethers such as PEG-3 oleyl ether (Volpo 3) and terionic or non-ionic. Mixtures of hydrophilic surfactants are PEG-4 lauryl ether (Brij 30); sugar esters such as sucrose also within the scope of the invention. Similarly, the hydro monopalmitate and sucrose monolaurate; polyethylene gly phobic surfactant can be any hydrophobic surfactant suitable col alkyl phenols; polyoxyethylene-polyoxypropylene block for use in pharmaceutical compositions. Mixtures of hydro copolymers such as Symperonic R PE series (ICI); Pluronicg phobic surfactants are also within the scope of the invention. series (BASF), Emkalyx, Lutrol (BASF), Supronic, Mono Generally, suitable hydrophilic surfactants will have an HLB lan, Pluracare R, and Plurodac; sorbitan fatty acid esters such value greater than about 10 and suitable hydrophobic surfac as sorbitan monolaurate (Arlace18, 20), sorbitan monopalmi tants will have an HLB value less than about 10. The choice of tate (Span-40), sorbitan monooleate (Span-80), sorbitan specific hydrophobic and hydrophilic surfactants should be monostearate, and sorbitan tristearate; lower alcohol fatty made keeping in mind the particular hydrophobic therapeutic acid esters such as hydrophobic surfactants include ethyl agent to be used in the composition, and the range of polarity oleate (Crodamol EO), isopropyl myristate (Crodamol IPM), appropriate for the chosen therapeutic agent. With these gen and isopropyl palmitate (Crodamol IPP); ionic surfactants eral principles in mind, a very broad range of surfactants is such as sodium oleate, sodium lauryl sulfate, sodium lauryl suitable for use in the present invention. sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, [0051] Examples of surfactants suitable for use in the sodium taurocholate, lauroyl carnitine, palmitoyl carnitine, present invention are disclosed in U.S. Pat. No. 6,294,192 to and myristoyl carnitine; unionized ionizable surfactants such Patel et al. and U.S. Pat. No. 6,267,985 to Chen et al. as free fatty acid, particularly Co-C22 fatty acids, and bile Examples of surfactants that may be used in the present acids. invention include polyethoxylated fatty acids such as PEG-8 [0052] Other surfactants for use in the present invention laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 include, without limitation, PEG-400 succinate, PEG 3350, laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, tocopherol polyethyleneglycol (200-8000 MW) succinate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate; PEG tocopherol polyethylene glycol 400 succinate, tocopherol fatty acid diesters such as PEG-20 dilaurate, PEG-20 polyethyleneglycol 1000 succinate (Vitamin E-TPGS, East US 2016/0015649 A1 Jan. 21, 2016

man Chemical Co.), glycerol monolinoleate (Maisine?), The dosage form contains fenofibrate solubilized in the com propylene glycol monocaprylate (Capryol(R 90); capryloca position in an amount of at least about 40 mg, preferably in an proyl macrogol-8 glycerides (Labrosolº), glycerol dibehen amount of at least about 67 mg, and more preferably in an ate (Compritol(R) 888), glycerol distearate (Precirol R), lau amount of at least about 100 mg. royl macrogol-32 glycerides (Gelucire R 44/14), and stearoyl [0056] The amount of solubilizer that can be included in the macrogol-32 glycerides (Gelucire 50/13). dosage forms of the present invention is not particularly lim ited. When the dosage forms are ultimately administered to a D. Additives patient, however, the amount of any given solubilizer is lim [0053] Although not always necessary, the compositions of ited to a bioacceptable amount. Bioacceptable amounts of the present invention may also include one or more additional solubilizers and other components are readily determined by components, i.e., additives. Classes of additives that may be one of skill in the art by using routine experimentation or present in the compositions, include, but are not limited to, searching the literature. In some circumstances, it may be solvents, absorbents, acids, adjuvants, anticaking agent, advantageous to include amounts of solubilizers far in excess glidants, antitacking agents, antifoamers, anticoagulants, of bioacceptable amounts, for example, to maximize the con antimicrobials, antioxidants, antiphlogistics, astringents, centration of the fenofibrate, with excess solubilizer removed antiseptics, bases, binders, chelating agents, sequestrants, prior to providing the composition to a patient. Excess solu coagulants, coating agents, colorants, dyes, pigments, com bilizer may be removed using conventional techniques such patiblizers, complexing agents, softeners, crystal growth as distillation, spray drying, lyophilization or evaporation. regulators, denaturants, dessicants, drying agents, dehydrat Generally, the amount of solubilizer in the composition will ing agents, diluents, dispersants, emollients, emulsifiers, be from about 5 wt.% to about 95 wt.%, preferably between encapsulants, enzymes, fillers, extenders, flavor masking about 20 wt.% to about 70 wt.%. agents, flavorants, fragrances, gelling agents, hardeners, stiff [0057] The amount of additional components in the com ening agents, humectants, lubricants, moisturizers, buffer positions can be determined by one of ordinary skill in the art, ants, pH control agents, plasticizers, soothing agents, demul according to the desired property or properties to be imparted cents, retarding agents, spreading agents, stabilizers, to the composition. For example, the amount of a suspending suspending agents, sweeteners, disintegrants, thickening agent may be determined by adding gradual amounts of the agents, consistency regulators, surfactants, opacifiers, poly agent until the desired homogeneity of undissolved drug par mers, preservatives, antigellants, rheology control agents, ticles in the composition is achieved. For a colorant, the UV absorbers, tonicifiers and viscomodulators. One or more amount of the colorant may determined by adding small additives from any particular class, as well as one or more amounts of the colorant until the desired color of the compo sition is achieved. For a surfactant, the amount of a surfactant different classes of additives, may be present in the compo may determined by adding gradual amounts of the surfactant sitions. Specific examples of additives are well known in the until the desired wetting effect or dispersibility of the com art. position is achieved. The amount of surfactant, when present, III. Determination of Component Amounts and in the composition will generally be up to about 80 wt.%, Preparation of Compositions preferably between about 10 wt.% to about 50 wt.%. [0058] The pharmaceutical compositions of the present [0054] As will be recognized by those skilled in the art, the invention are prepared by conventional methods well known amount or percentage of the active agent present in the com to those skilled in the art. The composition can be prepared by position and dosage forms will vary. Thus, for example, the mixing the active agent, the solubilizer, and optional additive amount of active agent is based, in part, upon the actual need according to methods well known in the art. Excess solvent or of the patient and can be determined by the attending clini solubilizer, added to facilitate solubilization of the active cian. In all cases, however, the amount of the active agent agent and/or mixing of the formulation components, can be present in the composition and dosage forms is an amount removed before administration of the pharmaceutical dosage such that the active agent is significantly solubilized in the form. The compositions can be further processed according to appropriately selected solubilizer or solubilizers so that the conventional processes known to those skilled in the art, such aforementioned advantages of the present invention are as lyophilization, encapsulation, compression, melting, achieved. extrusion, balling, drying, chilling, molding, spraying, spray [0055] Preferably, the compositions are formulated so as to congealing, coating, comminution, mixing, homogenization, contain a sufficient amount, i.e., dose, offenofibrate within a sonication, cryopelletization, spheronization and granulation dosage unit, e.g., a capsule. It is preferred that the amount of to produce the desired dosage form. fenofibrate will be present in the composition so as to provide [0059] For dosage forms substantially free of water, i.e., each dosage form with a unit dosage offrom about 40 to about when the composition is provided in a pre-concentrated form 250 mg, and preferably about 67 to about 200 mg offenofi for administration or for later dispersion in an aqueous sys brate. It is particularly preferred that the entire amount of tem, the composition is prepared by simple mixing of the fenofibrate is solubilized in the composition. However, it is components to form a pre-concentrate. The compositions sometimes necessary to add additional fenofibrate in non comprising solubilized fenofibrate can be further formulated solubilized form when the fenofibrate solubility capacity of a into desirable dosage forms utilizing skills well known in the given composition is exceeded. Therefore, it is also an impor art. For example, compositions in liquid or semi-solid form tant feature of the present invention that the fenofibrate can be filled into soft gelatin capsules using appropriate fill present in the composition is significantly solubilized. Typi ing machines. Alternatively, the composition can also be cally, at least about 50% of the fenofibrate is solubilized in the sprayed, s granulated or coated onto a substrate to become a composition and preferably at least about 75% of the fenofi powder, granule or bead that can be further encapsulated or brate is solubilized in the composition of the dosage form. tableted if the compositions solidify at room temperature with US 2016/0015649 A1 Jan. 21, 2016 or without the addition of appropriate solidifying or binding amount of the composition in, for example, a powder or liquid agents. This approach allows for the creation of a “fused form, to a suitable beverage, e.g., water or juice. mixture,” a “solid solution” or a “eutectic mixture.” [0065] The compositions and dosage forms of the current [0060] As previously indicated, the compositions may invention may be immediate release, releasing the active include additional amounts of fenofibrate over the amount agent and/or excipients in an uncontrolled fashion, or may be that is solubilized in the composition. In such a case, fenofi controlled release. Included in the term “controlled release” brate can be partially suspended in the composition in any are dosage forms or compositions which release the drug desired crystalline or amorphous form. Such partially solu and/or excipients with various release profiles such as bilized and partially suspended fenofibrate compositions can extended or sustained release, delayed release, pulsitile be prepared by adding solids of fenofibrate of desired form release, or combinations of the above such as multi-stage and particle size. For example, micronized crystalline fenofi release achieved by a combination of delayed release com brate having an average particle size of less than 30 microns, positions with variable delay times. nanosized crystalline fenofibrate having an average particle [0066] A preferred dosage form is a capsule containing a size of less than 1 micron or meshed amorphous fenofibrate composition as described herein. The capsule material may may be added to the composition. Such micronized or nano be either hard or soft and is generally made of a suitable sized fenofibrate particles can be obtained by precipitation or compound such as gelatin, starch or a cellulosic material. As size reduction techniques well-known in the art. In addition, is known in the art, use of soft gelatin capsules places a partially suspended fenofibrate compositions may be number of limitations on the compositions that can be encap obtained from a supersaturated fenofibrate solution or by sulated. See, for example, Ebert (1978), “Soft Elastic Gelatin co-precipitation with an additive from a fenofibrate solution. Capsules: A Unique Dosage Form.” Pharmaceutical Technol ogy 1(5). Two-piece hard gelatin capsules are preferably IV. Dosage Forms sealed, such as with gelatin bands or the like. Preparation of various types of pharmaceutical formulations are described, [0061] The pharmaceutical composition of the present for example, in Remington: The Science and Practice of invention can be prepared by mixing the active agent, the Pharmacy, Nineteenth Edition. (1995) cited supra and Ansel solubilizer, the surfactant, and optional additives according to et al., Pharmaceutical Dosage Forms and Drug Delivery Sys methods well known in the art. Alternatively, the active agent, tems, 6th Ed. (Media, PA: Williams & Wilkins, 1995). the solubilizer, and the surfactant may be prepared in separate dosage forms or separated within one dosage form to form a V. Utility and Administration dispersion in situ upon administration and dissolution in the aqueous environment of the gastrointestinal tract. [0067] The pharmaceutical compositions and dosage forms [0062] The claimed pharmaceutical compositions can be have utility in the treatment of patients that may benefit from further processed according to conventional methods known the therapeutic administration of hydrophobic drugs. Such to those skilled in the art, such as lyophilization, encapsula therapies include, for example, steroid therapy or hormone tion, compression, melting, extrusion, balling, drying, chill therapy. Patients suffering from any condition, disease or ing, molding, spraying, spray congealing, coating, comminu disorder that can be effectively treated with any of the active tion, mixing, homogenization, sonication, cryopelletization, agents disclosed herein can benefit from the administration of spheronization and granulation to produce the desired dosage a therapeutically effective amount of the pharmaceutical compositions and dosage forms described herein. An advan form. Excess solvent, added to facilitate incorporation of the tage of the claimed pharmaceutical composition is improve active agent and/or mixing of the formulation components, ment in the oral absorption and bioavailability of the active can be removed before administration of the pharmaceutical agent thereby ensuring that the patient will in fact benefit dosage form. from the prescribed therapy. The improved bioavailability of [0063] The pharmaceutical compositions can be further the active agent is a result of the improved dispersion of the formulated into desirable dosage forms utilizing skills well active agent in the claimed pharmaceutical composition. known in the art. For example, compositions in liquid, semi [0068] The composition may be administered in the form of solid or paste form can be filled into hard gelatin or soft a capsule wherein a patient swallows the entire capsule. Alter gelatin capsules using appropriate filling machines. Alterna natively, the composition may be contained in capsule which tively, the composition can also be extruded, merumerized, is then opened and mixed with an appropriate amount of sprayed, granulated or coated onto a substrate to become a aqueous fluid such as water or juice to form a drink or bever powder, granule or bead that can be further encapsulated or age for administration of the composition. As will be appre tableted with or without the addition of appropriate solidify ciated, the composition need not be contained in a capsule and ing or binding agents. This approach also allows for the may be housed in any suitable container, e.g., packets, creation of a “fused mixture,” a “solid solution” or a “eutectic ampules, etc. Once prepared, the drink or beverage is imbibed mixture.” in its entirety thus effecting administration of the composi [0064] In a preferred embodiment, the pharmaceutical tion. Preparation of the composition-containing drink or bev composition is present in a single dosage form. The dosage erage may be effected by the patient or by another, e.g., a form(s). The dosage forms of the present invention are not caregiver. As will be appreciated by those skilled in the art, limited with respect to size, shape or general configuration, additional modes of administration are available. and may comprise, for example, a capsule, a tablet or a caplet, or a plurality of granules, beads, powders, or pellets that may EXPERIMENTAL or may not be encapsulated. In addition, the dosage form may be a drink or beverage solution or a spray solution that is [0069] The practice of the present invention will employ, administered orally. Thus, for example, the drink or beverage unless otherwise indicated, conventional techniques of phar solution may be formed by adding a therapeutically effective maceutical formulation, medicinal chemistry, and the like, US 2016/0015649 A1 Jan. 21, 2016

which are within the skill of the art. Such techniques are length of 291 mm for tocopherol and 285 mm for tocopherol explained fully in the literature. Preparation of various types acetate tocopherol succinate, and tocopherol polyethyleneg of pharmaceutical formulations are described, for example, in lycol succinate. Samples were diluted 100x in methanol, then Remington: The Science and Practice of Pharmacy, Nine scanned in a quartz cuvette using an Agilent 8453 UV/Vis teenth Edition. (1995) cited supra and Ansel et al., Pharma Spectrophotometer. Calibration was by linear regression of ceutical Dosage Forms and Drug Delivery Systems, 6.sup.th absorbance at the indicated wavelengths with standards of the Ed. (Media, Pa.; Williams & Wilkins, 1995). relevant Vitamin E substance of known concentration. Stan [0070] In the following examples, efforts have been made dards of the drugs or other excipients present in the compo to ensure accuracy with respect to numbers used (e.g., sition at the expected concentrations were also scanned to amounts, temperature, etc.) but some experimental error and confirm selectivity. deviation should be accounted for. Unless indicated other [0075] In cases where the active agent or other excipient wise, temperature is in degrees C. and pressure is at or near caused significant interference at the 285-291 nm wave atmospheric. All components were obtained commercially lengths, assay for Vitamin E substances was by reversed unless otherwise indicated. “Tweene Rº and “Arlace18” com phase HPLC using a Symmetry C 183.6×150mm column, 5p, ponents are available from ICI Americas, Wilmington, Del. with a mobile phase of Methanol 98/2% w/v and detection at “Cremophor Rºº components are available from BASF Corp., 285 nm. Mount Olive, N.J. “Imwitor R." and “Miglyol(R* components are available from Huls AG, Herne, Germany. “Laurogly [0076] Assay of the active agents was by reversed-phase colºr,” “Labrafil R.” “Labrasol®.” “Transcutolº.” HPLC with the column indicated above, a mobile phase of “Maisine Rº and “Capryol(R)” components are available from acetonitrile/water 63/57% w/v, and detection at 204 nm. Gattefosse SA, Saint Priest, France. “Eastman R' compo [0077] Particle size of aqueous dispersions was determined nents are available from Eastman Chemical Products, Inc., using a Nicomp 380 ZLS laser-scattering particle sizer (Par Kingsport, Tenn. “Captex R, and “Capmulº’ components ticle Sizing Systems), with a He—Ne laser at 632.8 nm, fixed are available from Karlshamns USA, Inc., Columbus, Ohio. 90° angle, interrupter at 13.5°, and maximum count rate 5 “Incrocas” and “Crovol” components are available from MHz. Croda, Inc., Parsippany, N.J. [0071] The solubility of drug substances in the composi Example 1 tions was determined using conventional techniques. For example, solubility was in some cases determined gravimetri [0078] This example shows the solubilization and disper cally by incrementally adding drug until the composition sion behavior of a composition including a pregnane steroid, could no longer solubilize additional added drug. Solubility progesterone, a vitamin E substance (d1-alpha-tocopherol, could also be determined by equilibration of the composition Spectrum Chemicals) and a surfactant (polyoxyl 35 castor oil with excess drug during gentle mixing at a controlled tem USP/NF, Cremophor EL, BASF). The compositions shown in perature (25+0.5°C.), centrifugation of the resulting mixture the tables below were prepared by combining the components (15 min at 15,000×g; Beckmann Microfuge Lite), and assay and mixing gently at room temperature. of the clear supernatant. [0072] The dispersibility of the composition was deter TABLE 1-1 mined by diluting the composition in an aqueous medium Compositions such as water, simulated gastric fluid, or simulated intestinal fluid, at a selected dilution factor, preferably 10x to 1000×, Component 1-1 1-2 1–3 1-4 most preferably 100x. The dilution was then gently mixed, dl-alpha 70% 68.25% 63% 60% for example with a rotator at 10 rpm, at an appropriate con tocopherol trolled temperature (typically 37°C.). After a selected dura Polyoxyl 35 30% 29.25% 27% 26% tion (typically 1 hour, but any physiologically realistic dura Castor Oil tion could be appropriate), the aqueous phase was sampled, Progesterone 0% 2.5% 10% 1.59% taking care not to include undispersed oil globules, or non uniformly dispersed particulates. In some cases, the aqueous [0079] Compositions were dispersed in simulated gastric phase was filtered through Nylon or Tuffryn R membrane fluid without enzyme (USP23) at 100x dilution (37+0.5°C.) filters with the appropriate nominal pore size (Whatman or and mixed gently for 1 hour. At 1 hour, the dispersions were Gelman). In all cases, the initial 1-3 ml of filtrate were dis filtered through 0.211 nominal pore size Nylon filters, then the carded, and the absence of significant filter absorption was filtrate was diluted 100x in methanol and assayed for proges confirmed by filtration of standard solutions of known active terone by HPLC and for tocopherol content by UV/Vis spec agent or vitamin E substance concentration in the appropriate trophotometry. Results are shown in Table 1-2 below. matrix, collection of the filtrate, and assay of the filtrate to confirm that there was no change in drug concentration. Other techniques to characterize the extent of dispersion could also TABLE 1-2 be used, such as centrifugation to separate larger particles Fraction of Fraction of from the uniform aqueous dispersion. Drug Loading in Dispersion Solubilizer Drug [0073] The aqueous phase sample or filtrate was then No. Concentrate Appearance Dispersed Dispersed diluted in an appropriate solvent (typically acetonitrile or 1-1 O Non-uniform 14% N/A with large oil methanol; HPLC grade), and assayed for active agent or globules and solubilizer content. visible [0074] Assay for vitamin E substance content in most cases particulates was by UV spectrophotometry with quantification at a wave US 2016/0015649 A1 Jan. 21, 2016 11

TABLE 1-2-continued alcohol (dehydrated alcohol, USP/NF, Quantum). The com positions shown in the tables below were prepared by com Fraction of Fraction of Drug Loading in Dispersion Solubilizer Drug bining the components and mixing gently at room tempera No. Concentrate Appearance Dispersed Dispersed ture. 1-2 25 mg/g Non-uniform 30% 37% TABLE 2–1 with large oil globules and visible Compositions particulates Component 2-1 2-2 2–3 2-4 1–3 100 mg/g Non-uniform 41% 3.6% with a few large dl-alpha 65% 54% - - globules tocopherol 1-4 150 mg/g Uniform milky 63% 62% d-alpha 65% 54% dispersion tocopherol Polyoxyl 35 28% 23% 28% 23% Castor Oil [0080] The results in Table 1-2 show that increasing the Ethanol 7% 69% 7% 69% drug loading from 0 to 15% unexpectedly improves the dis Progesterone 0% 17.5% 0% 17.5% persibility of the formulation. Without the drug, the compo sition does not disperse readily with most of the solubilizer [0082] Compositions were dispersed in simulated gastric present in separate oily globules. With the addition of the fluid without enzyme (USP 23) at 100x dilution (37.4–0.5° active agent, the dispersibility of the formulation is improved C.) and mixed gently for 1 hour. At 1 hour, the dispersions such that the fraction of drug dispersed significantly increases were filtered through 0.2p nominal pore size Nylon filters, with increasing drug loading. The fraction of drug present as then the filtrate was diluted 100x in methanol and assayed for a very fine (<0.2p) dispersion increases from –37% at 25 tocopherol content by UV/Vis spectrophotometry and mg/g drug loading to 62% at 15% drug loading. The improved progesterone content by HPLC. The particle size distribution dispersibility is also shown by the increase in the fraction of of the dispersions was independently determined by laser the solubilizer dispersed as a fine dispersion, increasing from scattering with a Nicomp particle size analyzer for confirma 14% without drug to 63% with 150 mg/g drug. tion. Results are shown in Table 2-2 below. TABLE 2–2

Volume Fraction of Fraction of Fraction of Solubilizer Particles Drug Dispersed <0.21, by Dispersed Vitamin E Dilution in Filtrate laser in Filtrate No. Substance Drug Appearance <0.21 scattering <0.21 2-1 dl-alpha 0 mg/g Non tocopherol uniform Large globules and particles in cloudy solution 2-2 dl-alpha 175 mg/g Fine 66% 79% 100% tocopherol uniform dispersion d-alpha 0 mg/g Non 10% N/A* tocopherol uniform Large globules and particles in cloudy solution 2-4 d-alpha 175 mg/g Fine 83% 8.1% 100% tocopherol uniform dispersion *Particle size cannot be accurately determined for non-uniform samples with very large particles.

Example 2 [0083] The results in Table 2-2 show that not only is the [0081] This example shows the solubilization and disper drug readily soluble in the vitamin E based composition, but sion of a pregnane steroid, progesterone, in compositions the presence of the drug dramatically improves the dispers consisting of vitamin E substances (dl-alpha-tocopherol, ibility of the composition upon aqueous dilution. Without the Spectrum Chemicals; or d-alpha-tocopherol, Archer Daniels, drug, the composition does not form a fine dispersion and Midland Company), a surfactant (polyoxyl 35 castor oil USP/ only ~10% of the vitamin E is incorporated in particles <0.21. NF, Cremophor EL, BASF), and a low-molecular weight With progesterone, the compositions form a very fine uniform US 2016/0015649 A1 Jan. 21, 2016 dispersion, with ~80% of the total vitamin E in particles tables below were prepared by combining the components <0.211. The assay for progesterone in the filtered dispersions and mixing gently at room temperature. shows that the drug is preferentially concentrated in these very small particles with nominal diameter -0.211. TABLE 4-1 Example 3 Compositions [0084] This example shows the solubilization and disper Component 4-1 4-2 4-3 sion of an androstane steroid ((DHEA, Sigma Chemicals), in dl-alpha tocopherol 40.5% 40% 38% compositions consisting of vitamin E substances (dl-alpha Polyoxyl 35 Castor 49.5% 49% 46% tocopherol, Spectrum Chemicals; or d-alpha-tocopherol, Oil Archer Daniels Midland Company), a surfactant (polyoxyl 35 Ethanol 10% 5% 5% castor oil USP/NF, Cremophor EL, BASF), and a low-mo Finasteride 0% 1.1% - lecular weight alcohol (dehydrated alcohol, USP/NF, Quan Ursodiol 0% - 5.9% tum). The compositions shown in the tables below were pre pared by combining the components and mixing gently at [0088] Compositions were dispersed in simulated gastric room temperature. The corresponding placeboes (without fluid without enzyme (USP 23) at 100×(37+0.5° C) and drug) are described in Example 2, compositions 2-1 and 2-3. mixed gently for 1 hour. At 1 hour, the dispersions were filtered through 0.21 nominal pore size Nylon filters and the TABLE 3-1 filtrate diluted 100x in methanol and assayed for tocopherol content by UV/Vis spectrophotometry. Results are shown in Compositions Table 4-2 below. Component 3–1 3–2 TABLE 4–2 dl-alpha tocopherol 54% - d-alpha tocopherol - 54% Fraction of Solubilizer Polyoxyl 35 Castor Oil 23% 23% No. Drug Dilution Appearance Dispersed Ethanol 69% 69% DHEA 17.5% 17.5% 4-1 No drug Non-uniform, large 40% particles and globules 4-2 Finasteride Fine, uniform 86% [0085] Compositions were dispersed in simulated gastric dispersion 4-3 Ursodiol Fine, uniform 93% fluid without enzyme (USP 23) at 100x dilution (37.4–0.5° dispersion C.) and mixed gently for 1 hour. At 1 hour, the dispersions were filtered through 0.21 nominal pore size Nylon filters, then the filtrate was diluted 100x in methanol and assayed for [0089] The results in Table 4-2 show that, as with the other tocopherol content by UVN is spectrophotometry. Results are steroids tested, the incorporation of the steroid active agent shown in Table 3-2 below. has a critical role in achieving good dispersion of the compo sition upon aqueous dilution. TABLE 3–2 Example 5 Fraction of Vitamin E Dilution Solubilizer [0090] This example shows the solubilization and disper No. Substance DHEA Appearance Dispersed sion of progesteronein compositions containing two different 2-1 dl-alpha 0 mg/g Non-uniform 99% tocopherol esters (d-alpha-tocopherol acetate and d-alpha tocopherol Complete phase tocopherol succinate, Archer Daniels Midland Company). separation with The compositions shown in the tables below were prepared large oil globules by combining the components and mixing gently at room 3-1 dl-alpha 175 mg/g Fine, uniform 68% tocopherol dispersion temperature. 2-3 d-alpha 0 mg/g Non-uniform 10% tocopherol Large globules in TABLE 5–1 cloudy solution 3-2 d-alpha 175 mg/g Fine, uniform 70% Compositions tocopherol dispersion Component 5–1 5–2 5–3 5–4 [0086] The results in Table 3-2 show that, as with the preg d-alpha 79% 71% - - name steroid in example 2, the addition of the androstane tocopherol steroid, dehydroepiandrosterone DHEA, dramatically d-alpha - - 68% 62% improves the formation of a fine dispersion of the composi tocopherol tion resulting in compositions with very high drug loading, succinate Polyoxyl 35 14% 1.3% 29% 27% which are then readily dispersed in aqueous media. Castor Oil Ethanol 7% 69% 3% 39% Example 4 Progesterone 0% 10% 0% 8% [0087] This example shows the solubilization and disper sion using Vitamin E/surfactant compositions for additional [0091] Compositions were dispersed in simulated gastric model steroids: an androstane steroid, finasteride; and a fluid without enzyme (USP 23) at 100x dilution (37.4–0.5° cholane steroid, ursodiol. The compositions shown in the C.) and mixed gently for 1 hour. At 1 hour, the dispersions

US 2016/0015649 A1 Jan. 21, 2016 14

TABLE 6–3

Vitamin Fraction of Fraction E:Surfactant Dilution Solubilizer of Drug No. Surfactant(s) Ratio Drug Appearance Dispersed Dispersed 6-1 Polyoxyl 35 Castor 9:1 0 mg/g Complete 0% - Oil phase separation, visible oily ayer, essentially clear aqueous phase 6-4 Polyoxyl 35 Castor 9:1 225 mg/g Hazy 69% 65% Oil dispersion with a few arge visible globules 6–2 Caprylocaproyl 3:7 () mg/g Complete 17.9% - macrogolglycerides phase separation with visible oily globules, cloudy aqueous phase 6-5 Caprylocaproyl 3:7 70 mg/g Hazy 68% 69% macrogolglycerides dispersion with a few large visible globules 6-3 Polysorbate 5.7:1 O Non 44%.” - 80/Medium chain uniform, monoglycerides/E- cloudy with TPGS visible particulates 6-6 Polysorbate 5.7:1 85 mg/g Completely 100%." 100%." 80/Medium chain dispersed monoglycerides/E- in fine, TPGS slightly hazy dispersion

*Filtered with 0.45p1 filter before assay.

[0095] The results in table 6-3 show that for all surfactants TABLE 7-1 and surfactant levels, not only is the drug well solubilized in - - - the vitamin E substance composition, but it also plays a criti- —ºurº cal role in dispersing the composition upon aqueous dilution. Tradename, Component Source 7–1 7-2 7-3 dl-alpha Vitamin EUSP. 65% 65% 65% Example 7 tocopherol Spectrum Polyoxyl 35 Cremophor EL, 28% 28% 28% [0096] This example shows the effect of solubilization and Castor Oil BASF dispersion of progesterone in a compositions consisting of a Ethanol º ºn 7% - - vitamin E substance (d-alpha-tocopherol), a surfactant (poly- Triethyl citrate º - 7% - oxyl 35 castor oil USP/NF) and various hydrophilic and Aldrich hydrophobic solvents (ethanol, triethylcitrate; glycerol triac- Triacetin Triacetin, - - 7% etate (triacetin)).- - The compositions- ... - shown in- the tables below Progesterone N/AEastman 0% 0% 0% were prepared by combining the components and mixing gently at room temperature. US 2016/0015649 A1 Jan. 21, 2016 15

TABLE 7-2 -continued Compositions Exemplary Compositions Tradename, Component Amount (mg) Component Source 7–4 7–5 7–6 EXAMPLE 9 dl-alpha Vitamin E, USP, 59% 59% 59% tocopherol Spectrum dl-alpha tocopherol 55 Polyoxyl 35 Cremophor EL, 25% 25% 25% Cremophor RH40 45 Castor Oil BASF Dutasteride 0.5 Ethanol Ethanol, 200 69% - - EXAMPLE 10 proof, Quantum Triethyl citrate Triethyl citrate, - 69% - dl-alpha tocopherol 200 Aldrich Polysorbate 80 15 Triacetin Triacetin, - - 69% Maisine (Glycerol monolinoleate) 30 Eastman Eplerenone 40 Progesterone N/A 10% 10% 10% EXAMPLE 1.1 dl-alpha tocopherol 300 Capryol 90 (Propylene glycol monocaprylate) 100 [0097] Compositions were dispersed in simulated gastric Cremophor EL 60 fluid without enzyme (USP23) at 100x dilution (37+0.5°C.) Spironolactone 200 and mixed gently for 1 hour. At 1 hour, the dispersions were EXAMPLE 12 filtered through 0.211 nominal pore size Nylon filters, the dl-alpha tocopherol 3.13 Cremophor EL 256 filtrate was then diluted 100x in methanol and assayed for Dehydrated Alcohol 70 tocopherol content by UV/Vis spectrophotometry. Results Progesterone 60 are shown in Table 7-3 below. EXAMPLE 1.3

TABLE 7–3 d-alpha tocopherol succinate 60 E-TPGS 540 Fraction of PEG 8000 60 Dilution Solubilizer Progesterone 100 No. Solvent Drug Appearance Dispersed EXAMPLE 14 7-1 Ethanol 0 mg/g Non uniform 189% d-alpha tocopherol succinate 60 ispersion with E-TPGS 540 large visible PEG 8000 60 globules TestosterOne 100 7–4 Ethanol 100 mg/g Fine uniform 69% EXAMPLE 1.5 ispersion 7-2 Triacetin 0 mg/g Non uniform 24% ispersion with dl-alpha tocopherol 300 large visible Cremophor RH40 300 globules Coenzyme Q10 100 7-5 Triacetin 100 mg/g Fine uniform 47% EXAMPLE 16 ispersion 7-3 Triethyl Citrate 0 mg/g Non uniform 1.59% dl-alpha tocopherol 300 ispersion with Cremophor RH40 300 large visible Idebenone 90 globules EXAMPLE 1.7 7-6 Triethyl Citrate 100 mg/g Fine uniform 45% ispersion d-alpha tocopherol 270 Alpha-tocotrienol 2 Gamma-tocotrienol 23 Cremophor RH40 300 [0098] This example shows that for each of the solvents Idebenone 90 tested, the presence of the steroid drug significantly improves EXAMPLE 1.8 the dispersibility of the composition in aqueous medium. dl-alpha tocopherol 80 Cremophor RH40 400 Example 8-23 Crovol M-40 350 Coenzyme Q10 100 [0099] EXAMPLE 19 Tocoperyl polyethylene glycol 400 succinate 200 Tocopherol polyethylene glycol 1000 succinate 100 Exemplary Compositions PEG 3350 5 Component Bicalutamide 50 Amount (mg) EXAMPLE 2.0 EXAMPLE 8 d-alpha tocopherol succinate 250 dl-alpha tocopherol 520 Cremophor RH40 50 Cremophor EL 430 Capmul MCM 50 DHEA 50 Simvastatin 10 US 2016/0015649 A1 Jan. 21, 2016 16

-continued col fatty acid ester, a trialkylcitrate, a lower alcohol fatty acid ester, a phospholipid, PEG, or a combination Exemplary Compositions thereof. wherein the pharmaceutical composition is free of a trig Component Amount (mg) lyceride; EXAMPLE 21 wherein the pharmaceutical composition is free of a pro pylene glycol fatty acid ester, and d-alpha tocopherol succinate 200 Cremophor RH40 200 wherein bioavailability of the sex hormone is improved Glycerol Dibehenate (Compritol 888) 100 when the pharmaceutical composition is administered Glycerol Distearate (Precirol) 80 as compared to bioavailability of a composition of the Metaxalone 300 sex hormone without an effective solubilizing amount of EXAMPLE 2.2 the solubilizer. d-alpha tocopherol succinate 100 2. The pharmaceutical composition of claim 1, wherein the Hydroxypropyl methyl cellulose, USP 100 solubilizer is a monoglyceride. (Methocel K4M) Microcrystalline cellulose, USP (Avicel PH 200 3. The pharmaceutical composition of claim 1, wherein the 01) solubilizer is a diglyceride. Polyoxyl 40 Hydrogenated Castor Oil, USP 120 4. The pharmaceutical composition of claim 1, wherein the (Cremophor RH 40) surfactant comprises a polyethoxylated fatty acid, an alcohol Polyvinyl pyrrolidone, USP (Kollidon 90F) 45 Talc, USP 8.75 oil transesterification product, a transesterification product of Colloidal Silicon dioxide, USP (Cab-o-Sil 1.25 an oil and alcohol, or a combination thereof. treated) 5. The pharmaceutical composition of claim 4, wherein the Dehydroepiandrosterone 100 surfactant is a polyethoxylated castor oil or polyethoxylated EXAMPLE 23 hydrogenated castor oil. Drug-Containing Granules: 6. The pharmaceutical composition of claim 5, wherein the surfactant comprises polyoxyl 35 castor oil, PEG-40 hydro Spironolactone 100.0 Butylated Hydroxy Anisole USP-NF (BHA) 0.05 genated castor oil, or a combination thereof. Microcrystalline Cellulose USP-NF 100.0 7. The pharmaceutical composition of claim 1, wherein the Crospovidone USP-NF 27.5 surfactant is present in the composition in an amount of from Polyvinyl pyrrolidone USP-NF 40.0 about 12 wt % to about 50 wt %. Talc USP-NF 4.0 Colloidal Silicon dioxide USP-NF 2.0 8. The pharmaceutical composition of claim 1, wherein the Magnesium Stearate USP-NF 2.0 pharmaceutical composition is a liquid, semi-solid, or solid. Solubilizer/Surfactant Granules: 9. The pharmaceutical composition of claim 8, wherein the Cremophor RH40 300 composition is formulated into a capsule. Tocopherol Polyethyleneglycol 400 succinate 50 10. The pharmaceutical composition of claim 1, wherein d-alpha tocopherol succinate 50 the solubilizer increases the rate and extent of absorption of Sodium Starch Glycolate USP-NF 22 the sex hormone. Colloidal Silicon dioxide USP-NF 122 11. The pharmaceutical composition of claim 1, wherein the sex hormone is progesterone, testosterone, or an ester [0100] While preferred embodiments of the present inven thereof. tion have been shown and described herein, it will be obvious 12. The pharmaceutical composition of claim 11, wherein to those skilled in the art that such embodiments are provided the sex hormone is testosterone enanthate, testosterone pro by way of example only. Numerous variations, changes, and pionate, testosterone undecanoate, testosterone palmitate, or substitutions will now occur to those skilled in the art without a combination thereof. departing from the invention. It should be understood that 13. The pharmaceutical composition of claim 11, wherein various alternatives to the embodiments of the invention the testosterone ester is testosterone enanthate. described herein may be employed in practicing the inven 14. The pharmaceutical composition of claim 11, wherein tion. It is intended that the following claims define the scope the testosterone ester is testosterone proprionate. of the invention and that methods and structures within the 15. The pharmaceutical composition of claim 11, wherein scope of these claims and their equivalents be covered the testosterone ester is testosterone undecanoate. thereby. 16. The pharmaceutical composition of claim 11, wherein the testosterone ester is testosterone palmitate. What is claimed is: 17. The pharmaceutical composition of claim 1, wherein 1. A pharmaceutical composition comprising: upon dilution of the composition, the sex hormone increases the extent of dispersion of the vitamin E substance by at least a)atherapeutically effective amount of a sex hormone, said 20% relative to the dispersion of the composition without the amount ranging from about 7% w/w to about 22.5% sex hormone. w/w: 18. A method of providing hormone therapy in a patient b) a surfactant present in an amount ranging from about comprising orally administering to a patient in need thereof a 12% w/w to about 63% w/w; and pharmaceutical composition comprising: c) an effective solubilizing amount of a solubilizer, said a) a therapeutically effective amount of sex hormone; and effective amount ranging from about 27% w/w to about b) an effective solubilizing amount of a solubilizer selected 80.1% w/w, the solubilizer comprising a vitamin E sub from the group consisting of a vitamin E substance, a stance, a monoglyceride, a diglyceride, an ethylene gly monoglyceride, a diglyceride, an ethylene glycol fatty US 2016/0015649 A1 Jan. 21, 2016 17

acid ester, a trialkyl citrate, a lower alcohol fatty acid 28. The method of claim 18 wherein the surfactant is ester, a phospholipid, PEG, or a combination thereof; present in the composition in an amount of from about 10 wt wherein the pharmaceutical composition is free of a trig % to about 50 wt %. lyceride; and 29. The method of claim 18, wherein the pharmaceutical composition is a liquid, semi-solid, or solid. wherein the pharmaceutical composition is free of a pro 30. The method of claim 29, wherein the composition is pylene glycol fatty acid ester. formulated into a capsule. 19. The method of claim 18, wherein the solubilizer is a 31. The method claim 18, wherein bioabsorption of the sex monoglyceride. hormone is enhanced compared to a method of administering 20. The method of claim 18, wherein the solubilizer is a the sex hormone without the solubilizer. diglyceride. 32. The method claim 18, wherein onset and duration of 21. The method of claim 18, wherein the solubilizer is absorption of the sex hormone is increased compared to a method of administering the sex hormone without the solu present in the composition in an amount of from about 5 wt % bilizer. to about 95 wt %. 33. The method claim 18, wherein onset of therapeutic 22. The method of claim 21, wherein the solubilizer is action is more rapid, bioperformance characteristics of the present in the composition in an amount of from about 20 wt sex hormone are better, or a combination thereof compared to % to about 70 wt %. a method of administering the sex hormone without the solu 23. The method of claim 18, further comprising a surfac bilizer. tant. 34. The method claim 18, wherein the sex hormone is 24. The method of claim 23, wherein the surfactant com progesterone, testosterone or an ester thereof. prises a polyethoxylated fatty acid, an alcohol-oil transesteri 35. The method of claim 34, wherein the sex hormone is fication product, a transesterification product of a oil and testosterone enanthate, testosterone propionate, testosterone undecanoate, testosterone palmitate, or a combination alcohol, or a combination thereof. thereof. 25. The method of claim 24, wherein the surfactant is a 36. The method claim 34, wherein the testosterone ester is polyethoxylated castor oil or polyethoxylated hydrogenated testosterone enanthate. castor oil. 37. The method claim 34, wherein the testosterone ester is 26. The method of claim 25, wherein the surfactant com testosterone proprionate. prises polyoxyl 35 castor oil, PEG-40 hydrogenated castor 38. The method claim 34, wherein the testosterone ester is oil, or a combination thereof. testosterone undecanoate. 27. The method of claim 23, wherein the surfactant is 39. The method of claim 34, wherein the testosterone ester present in the composition in an amount of up to about 80 wt is testosterone palmitate. 9%.