US 200601 10444A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110444 A1 Holm et al. (43) Pub. Date: May 25, 2006

(54) SOLID DOSAGE FORM COMPRISINGA Mar. 23, 2004 (DK)...... PA 2004 OO464 FIBRATE Jun. 25, 2004 (DK)...... PA 2004 O1 OO6 (76) Inventors: Per Holm, Vanlose (DK); Tomas Publication Classification Norling, Lyngby (DK) (51) Int. Cl. Correspondence Address: A6IR 9/20 (2006.01) CHERYL, H AGRIS PHD A6II 3L/92 (2006.01) PO BOX 806 (52) U.S. Cl...... 424/464: 514/571 PELHAM, NY 10803 (US) (21) Appl. No.: 10/513,807 (57) ABSTRACT

(22) PCT Filed: Oct. 1, 2004 The invention provides stable, Solid dosage forms and (86). PCT No.: pharmaceutical compositions in particulate form comprising a fibrate, for example fenofibrate, dissolved in an non (30) Foreign Application Priority Data aqueous vehicle in order to ensure improved bioavailability of the active ingredient upon oral administration relative to Oct. 10, 2003 (DK)...... PA 2003 O1503 known fibrate formulations. US 2006/01 10444 A1 May 25, 2006

SOLID DOSAGE FORM COMPRISING A FIBRATE 0006 Fenofibrate is also effective in the treatment of Diabetes Type II and metabolic syndrome. 0001. The present invention relates to novel solid dosage forms and pharmaceutical compositions comprising a 0007 Fenofibrate is also indicated as adjunctive therapy fibrate, notably fenofibrate. Particularly, the invention dis to diet for treatment of adult patients with hypertriglyceri closes solid dosage forms having increased bioavailability. demia (Fredrickson Types IV and V hyperlipedemia). The solid dosage forms of the invention comprise fibrate Improving glycemic control in diabetic patients showing dissolved in a suitable vehicle or mixture of vehicles. The fasting chylomicronemia will usually reduce fasting triglyc dosage forms are especially intended for oral use and exhibit erides and eliminate chylomicronemia and thereby obviating excellent storage stability, i.e. are stable. The invention also the need for pharmacologic intervention. relates to methods for preparation of the Solid dosage forms 0008 Fibrates are drug substances known to be are and pharmaceutical compositions and the use thereof. poorly and variably absorbed after oral administration. Nor mally they are prescribed to be taken with food in order to BACKGROUND OF THE INVENTION increase the bioavailability. 0002 Fibrates are lipid regulating agents. Examples of 0009. There have been a number of improvements in fibrates include gemifibrozil, fenofibrate, bezafibrate, clofi dosage form of the currently most used fibrate, fenofibrate, brate and ciprofibrate. The compounds are regarded as in an effort to increase the bioavailability of the drug and prodrugs and are metabolised in Vivo to their active metabo hence its efficacy. However, there is still a need for lites. For illustrative purposes only, the following is based on improved dosage forms relative to the currently available a specific example of a fibrate, namely fenofibrate. Fenofi compositions and dosage forms, which provide crystalline brate is chemically named 2-4-(4-chlorobenzoyl-2-me fenofibrate in micronized form. In particular, there remains thyl-propanoic acid, 1-methylethyl ester and has the follow a need for a composition and a dosage form exhibiting a ing structural formula: suitable bioavailability, which substantially can reduce or overcome the differential between the bioavailability of the drug in patients who are fasted versus the bioavailability of O CH the drug in patients who are fed, and/or which substantially can reduce or overcome the intra- and/or inter-individual C O -N variations observed with the current treatment with the O CH available commercial products. Furthermore, there is also a H3C CH3 need for novel dosage forms and/or compositions that enable reduction in observed side-effects. O 00.10 Especially, there is an unmet need for developing a solid composition in particulate form in which the fibrate is in a dissolved state and that appears as a composition that is 0003) Fenofibrate is a white solid. The compound is in the form of a powder, granules, granulates, particles, insoluble in water. The melting point is 79-82° C. Fenofi beads, pellets or other forms for particulate material and not brate is metabolised to the active substance fenofibric acid. in the form of a soft dosage form containing a liquid Fenofibric acid has an elimination half-life of about 20 medium. hours. Measurement of the detected amount of fenofibric acid in the blood of a patient can reflect the efficacy of SUMMARY OF THE INVENTION fenofibrate uptake. Fenofibric acid produces reductions in total cholesterol (total-C), LDL-C, apo-lipoprotein B, total 0011. The inventors have now found that the bioavail triglycerides, and triglyceride rich lipoprotein (VLDL) in abilty of fenofibrate can be significantly enhanced by dis treated patients. In addition, treatment with fenofibrate solving a fibrate, for example fenofibrate, in a suitable results in increases in high density lipoprotein (HDL) and vehicle and using the resulting composition for preparing a apo-lipoprotein apoAl and apo All. Fenofibrate acts as a Solid dosage form, i.e. a dosage form excluding material in potent lipid regulating agent offering unique and clinical liquid form. Fibrate, especially fenofibrate, is known to be advantages over existing products in the fibrate family of insoluble in water, but the present invention provides phar drug Substances. Fenofibrate produces Substantial reduction maceutical compositions and formulations exhibiting imme in plasma triglyceride levels in hypertriglyceridemic diate release profiles which are comtemplated having sig patients and in plasma cholesterol and LDL-C in hypercho nificantly increased in vivo bioavailability in patients in lesterolemic and mixed dyslipidemic patients. need thereof. Especially, the inventors have succeeded in preparing a solid dosage form, such as a tablet, comprising 0004 Fenofibrate also reduces serum uric acid levels in the fibrate in dissolved form. The advantages of a solid and hyperuricemic and normal Subjects by increasing the urinary stable dosage form useful for oral administration are well excretion of uric acid. known. 0005 Clinical studies have demonstrated that elevated 0012. Accordingly, in a first aspect the present invention levels of total cholesterol, low density lipoprotein choles relates to a Solid oral dosage form comprising a fibrate terol (LDL-C), and apo-lipoprotein B (apo B) are associated dissolved in a vehicle, which is hydrophobic, hydrophilic or with human atherosclerosis. Decreased levels of high den water-miscible. Useful solid dosage forms are in the form of sity lipoprotein cholesterol (HDL-C) and its transport com tablets, beads, capsules, grains, pills, granulates, granules, plex, apolipoprotein A (apo Al and apo All) are associated powder, pellets, Sachets or troches, and useful fibrates are, with the development of atherosclerosis. fenofibrate, bezafibrate, clofibrate, ciprofibrate and active US 2006/01 10444 A1 May 25, 2006 metabolites and analogues thereof including any relevant 0020. In the present context, the term “hydrophobic' fibric acid such as fenofibric acid. denotes a compound tending to be electrically neutral and non-polar, and thus preferring other neutral and nonpolar 0013 In a second aspect, the invention relates to a pharmaceutical composition comprising a fibrate dissolved Solvents or molecular environments. in a vehicle, which is hydrophobic, hydrophilic or water 0021. As used herein, the term “water-miscible' denotes miscible; and in a further aspect, the invention relates to a a compound being fully or partly miscible with water. For Solid pharmaceutical composition in particulate form com example, certain polar lipids are partly water-miscible. prising a fibrate, a hydrophobic or a hydrophilic or water 0022. As used herein, the term “vehicle' means any miscible vehicle and an oil-sorption material, which com Solvent or carrier in a pharmaceutical product that has no position exhibits an oil threshold value of at least 10%. pharmacological role. For example, water is the vehicle for 0014. In yet another aspect, the invention relates to a Xilocaine and propylene glycol is the vehicle for many method of manufacturing the Solid oral dosage form or the antibiotics. pharmaceutical composition of the invention. 0023. In the present context, the term "solid dispersion' 0.015 Further aspects of the invention are evident from denotes a drug or active ingredient or Substance dispersed on the following description. Comparison in vivo tests in dogs a particulate level in an inert vehicle, carrier, diluent or have shown, cf. the examples herein, that solid dosage forms matrix in the Solid State, i.e. usually a fine particulate and compositions of the invention exhibit significantly dispersion. enhanced bioavailability of fenofibrate compared to com mercially available Solid dosage forms containing the same 0024. In the present context, the term "solid solution' active ingredient, i.e. to Tricor R tablet and Lipanthyl(R) denotes a drug or active ingredient or Substance dissolved on capsules. a molecular level in an inert vehicle, carrier, diluent or matrix in the Solid state. 0016 Further, it is strongly believed that the present invention provides solid dosage forms and/or compositions 0025. As used herein, the term “analogue' means a of fibrate capable of significantly reducing the intra- and/or chemical compound that is structurally similar to another. inter-individual variation normally observed after oral 0026. The term “drug' means a compound intended for administration. Furthermore, compositions and/or dosage use in diagnosis, cure, mitigation, treatment, or prevention forms according to the invention provide for a significant of disease in man or other animals. reduced food effect, i.e. the absorption is relatively inde pendent on whether the patient takes the composition or 0027. In this context, the term “dosage form a means the dosage form together with or without any meal. It is con form in which the drug is delivered to the patient. This could templated that a modified release of the fibrate may reduce be parenteral, topical, tablet, oral (liquid or dissolved pow the number of gastro-intestinal related side effects. Further der), Suppository, inhalation, transdermal, etc. more, it is contemplated that a significantly larger amount of 0028. As used herein, the term “bioavailability” denotes the fibrate is absorbed and, accordingly, an equally less the degree means to which a drug or other Substance amount is excreted unchanged via feces. becomes available to the target tissue after administration. DETAILED DESCRIPTION 0029. As used herein, the term “bioequivalency” denotes a scientific basis on which generic and brand name drugs are Definitions compared with one another. For example, drugs are 0017. As used herein, the term “active ingredient’ or bioequivalent if they enter circulation at the same rate when “active pharmaceutical ingredient’ means any component given in similar doses under similar conditions. Parameters that is intended to furnish pharmacological activity or other often used in bioeduivalence studies are ta. C. AUCo direct effect in the diagnosis, cure, mitigation, treatment, or infinity, AUC. Other relevant parameters may be Wso, Wis prevention of disease, or to affect the structure or any and/or MRT. Accordingly, at least one of these parameters function of the body of man or other animals. The term may be applied when determining whether bioeduivalence is includes those components that may undergo chemical present. Furthermore, in the present context, two composi change in the manufacture of the drug product and are tions are regarded as bioequivalent if the value of the present in the drug product in a modified form intended to parameter used is within 80-125% of that of Prograf R or a furnish the specified activity or effect. similar commercially available tacrolimus-containing prod uct used in the test. 0018. In the present context, the term “hydrophilic' describes that something likes water, i.e. a hydrophilic 0030. In the present context “t denotes the time to molecule or portion of a molecule is one that typically is reach the maximal plasma concentration (c) after admin electrically polarized and capable of forming hydrogen istration; AUConni or AUC denotes the area under the bonds with water molecules, enabling it dissolve more plasma concentration versus time curve from time 0 to readily in water than in oil or other “non-polar solvents. infinity; AUC denotes the area under the plasma concen tration versus time curve from time 0 to time t; Wso denotes 0019. In the present context, the term "amphiphilic' the time where the plasma concentration is 50% or more of describes a molecule (as a surfactant) having a polar water C.; W.7s denotes the time where the plasma concentration soluble group attached to a water-insoluble hydrocarbon is 75% or more of C.; and MRT denotes mean residence chain. Thus, one end of the molecule is hydrophilic (polar) time for a fibrate Such as fenofibrate (and/or an analogue and the other is hydrophobic (non-polar). thereof. US 2006/01 10444 A1 May 25, 2006

0031. In this context, the term “medicine” means a com in the dosage form or the pharmaceutical compostion fully pound used to treat disease, injury or pain. Medicine is justly dissolved in the vehicle or the vehicle system. distributed into “prophylactic, i.e. the art of preserving 0036). In addition to the content of fibrate, the dosage health, and “therapeutic”, i.e. the art of restoring health. forms and pharmaceutical compositions of the invention 0032. In the present context, the terms “controlled may comprise further active drug Substances, preferably one release' and “modified release' are intended to be equiva additional drug Substances. Preferably, such an additional lent terms covering any type of release of tacrolimus from a drug Substance is of a type normally employed for the same composition of the invention that is appropriate to obtain a indications as fibrate. A specific example is eZetimibe. specific therapeutic or prophylactic response after adminis However, combination products with three or even four drug tration to a Subject. A person skilled in the art knows how Substances used for the same indication are contemplated as controlled release/modified release differs from the release well as combination products comprising two, three or four of plain tablets or capsules. The terms “release in a con active ingredients for different indications or therapies. trolled manner” or “release in a modified manner” have the 0037 Examples of additional drug substances are other same meaning as stated above. The terms include slow antilipidemic agents like statins; lipid regulators like: acipi release (that results in a lower C and later t, but t2 is mox, binifibrate, etofibrate, niceritrol, nicofibrate, pirozadil, unchanged), extended release (that results in a lower C. ronifibrate, tocoferil nicotinate; combination with cardiovas later t, but apparent t is longer); delayed release (that cular drugs like ace inhibitors: alacepril, benazepril, capto result in an unchanged Ca. but lag time and, accordingly, pril, cilaZapril, delapril, enalapril, enalaprilat, fosinopril, t is delayed, and t2 is unchanged) as well as pulsatile imidapril, lisinopril, moexipril, perindopril, quinapril, rami release, burst release, Sustained release, prolonged release, pril, spirapril, temocapril, teprotide, trandolapril. Zofenopril; chrono-optimized release, fast release (to obtain an calcium channel blockers like: amlodipine, aranidipine, enhanced onset of action) etc. Included in the terms is also aZelnidipine, barnidipine, benidipine, bepridil, cilnidipine, e.g. utilization of specific conditions within the body e.g. diltiazem, efonidipine, felodipine, gallopamil. isradipine, different enzymes or pH changes in order to control the lacidipine, lercanidipine, manidipine, mibefradil, nicar release of the drug Substance. dipine, nifedipine, nilvadipine, nimodipine, nisoldipine, 0033. In this context, the term “erosion” or “eroding nitrendipine, Verapamil: alpha-blockers like: alfuZosin, means a gradual breakdown of the Surface of a material or bunaZosin, doxazosin, indoramin, naftopidil, phenoxyben structure, for example of a tablet or the coating of a tablet. Zamine, phentolamine, prazosin, tamsulosin, teraZosin, thy moxamine, tolazoline, urapidil; beta-blockers like: acebu The Active Drug Substance tolol, alprenolol, amoSulalol, arotinolol, atenolol, befunolol. 0034. The drug or active substance of the dosage forms betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, and pharmaceutical compositions of this invention is a bunitrolol, bupranolol, carazolol, carteolol, carvedilol, celip rolol, esmolol, indenolol, labetalol, landiolol, levobetaxolol, fibrate. Examples of useful fibrates are bezafibrate, ciprofi levobunolol, mepindolol, metipranolol, metoprolol, nadolol. brate, clinofibrate, clofibrate, etofylline, clofibrate, fenofi nebivolol, nipradillol, Oxprenolol, penbutolol, pindolol, pro brate, gemfibrozil, pirifibrate, simfibrate and tocofibrate; pranolol, Sotalol, talinolol, tertatolol, timolol; angiotensin ii particularly useful are gemfibrozil, fenofibrate, bezafibrate, blockers like: candesartan, eprosartan, irbesartan, losartan, clofibrate, ciprofibrate and active metabolites and analogues olmesartan, tasosartan, ref. telmisartan, Valsartan; vasodila thereof including any relevant fibric acid such as fenofibric tors like: cadralazine, diazoxide, dihydralazine, endralazine, acid. In a preferred embodiment, the fibrate is fenofibrate or hydralazine, minoxidil, todralazine, tolazoline, car an analogue thereof. However, the dosage forms and com bocromen, cinepazet, ref cloridarol, dilaZep, etafenone, positions of the invention may also comprise a mixture of fendiline, hexobendine, oxyfedrine, trapidil, trimetazidine, two, three or even four different fibrates and/or fibric acids. aZapetine, bamethan, bencyclane, buflomedil, butalamine, 0035. The concentration offibrate in the vehicle is at least calcitonin gene-related peptide, cetiedil, cinepazide, cycla 10% w/w, based on the total weight of the fibrate and the indelate, di-isopropylammonium ichloroacetate, fasudil, vehicle; preferably at least 15% w/w, or at least 16% w/w, ifenprodil, inositol nicotinate, naftidrofuryl, nicotinyl alco or at least 17% w/w, or at least 20% w/w, or at least 25% hol, Oxpentifylline pentoxifylline pentifylline, pipratecol, w/w, or at least 30% w/w, especially at least 35% w/w, based propentofylline, raubasine, Xantinolicotinat, centrally acting on the total weight of the fibrate and the vehicle; and the hypertensives: apraclonidine, brimonidine, clonidine, gua concentration of fibrate in the vehicle is at the most 90% nabenz, guanfacine, methyldopa, moxonidine, rillmenidine, w/w, based on the total weight of the fibrate and the vehicle, tiamenidine; antiarrhythmic drugs like: ajmaline, cibenzo or at the most 80% w/w, or at the most 75% w/w, or at the line, disopyramide, hydroquinidine, pirmenol, procaina most 70% w/w, or at the most 60% w/w, or at the most 50% mide, quinidine, aprindine, mexiletine, tocainide, wfw, or at the most 40% w/w, or not above 35% w/w, based diprafenone, encainide, flecainide, lorcainide, pilsicainide, on the total weight of the fibrate and the vehicle. Preferably, propafenone, bretylium, acecainide, amiodarone, azimilide, the fibrate is fully dissolved in the non-aqueous vehicle. bretylium, cibenzoline, dofetilide, ibutilide, nifekalant, However, a minor occurrence of crystalline or microcrys Sotalol, cibenzoline, Verapamil; anti platelets like: abcix talline active drug may not influence on the enhanced imab, aspirin, ciloStaZol, clopidogrel, cloricromen, dipy bioavailability of the Solid dosage forms and pharmaceutical ridamole, ditazole, eptifibatide, indobufen, lamfliban, orbo compositions of the invention. Accordingly, at least 90% fiban, picotamide, Sarpogrelate, sibrafiban, ticlopidine, w/w of the fenofibrate is dissolved in the vehicle, preferably tirofiban, trapidil, triflusal, xemilofiban; diuretics like: aceta is at least 93% w/w, or at least 95% w/w, or at least 97% Zolamide, brinzolamide, diclofenamide, dorzolamide, met wfw, or at least 98% w/w, or at least 99% w/w, or at least haZolamide, azosemide, bumetanide, etacrynic acid, etoZo 99.5% w/w, or at least 99.9% w/w, of the fenofibrate present lin, frusemide, piretanide, torasemide, isosorbide, mannitol, US 2006/01 10444 A1 May 25, 2006 amiloride, canrenone, potassium canrenoate, spironolac (Eudragit RS: Eudragit RL, Eudragit NE, Eudragit E), tone, triamterene, altizide, bemetizide, bendrofluazide, ben myristyl alcohol, cellulose derivatives including hydrox Zthiazide, butizide, chlorothiazide, chlortalidone, clopam ypropyl methyl-cellulose (HPMC), hydroxypropyl cellulose ide, cyclopenthiazide, cycloithiazide, epitizide, (HPC), methylcellulose, sodium carboxymethylcellulose, hydrochlorothiazide, hydroflumethiazide, indapamide, hydroxyethyl cellulose, pectins, cyclodextrins, galactoman mebutizide, mefruside, methyclothiazide, meticrane, meto nans, alginates, carragenates, Xanthan gums and mixtures laZone, polythiazide, quinethaZone, teclothiazide, trichlo thereof. rmethiazide, tripamide, Xipamide; antidiabetic drugs like: acarbose acetohexamide biguanide antidiabetics buformin 0044) The vehicle is preferably a mixture of two or more carbutamide chlorpropamide epalrestat glibenclamide gli Substances. bomuride gliclaZide glimepiride glipizide gliquidone glisen 0045. The vehicle may also be an oily material as defined tide glisolamide glisoxepide glybuzole glyclopyramide gly and described below. cyclamide glymidine sodium mefformin hydrochloride midaglizole miglitol nateglinide phenformin hydrochloride 0046 Preferably, the melting point of the vehicle is pimagedine pioglitaZone hydrochloride pramlintide repa preferably in the range of 10°C. to 250° C., preferably in the glinide rosiglitaZone sorbinil tolaZamide tolbutamide trogli range of 30° C. to 100° C., more preferably in the range of taZone Voglibose Substances like: q10, Vitamins (nicotina 40° C. to 75° C., especially in the range of 40° C. to 70° C. mid, pyridoxine hcl, b12, tocopheroles, ascorbic acids, and 0047. In a preferred embodiment of the invention, the others), and antioxidants in general are also included in the vehicle is polyethylene glycol (PEG), preferably having an useful combinations. average molecular weight of at least 3000, more preferably 0038. The additional drug substance or substances may at least 4000, optionally in admixture with a poloxamer such also be included in or used in combination with drugs that as e.g. poloxamer 188, in a preferred weight ratio of between may lead to an undesired level of triglycerides and/or 1:3 and 10:1, preferably between 1:1 and 5:1, more prefer cholesterol. Thus, a composition according to the invention ably between and 3:24:1, especially between 2:1 and 3:1, in may be included in or used in combination with drugs like particular about 7:3. e.g. isotretinoin or a retroviral protease inhibitor like HIV Bioavailability protease inhibitors, with an antipsychotic like olanzapine 0048. In general, it is known that the absorption and and others. bioavailability of a therapeuticcally active substance can be 0039. As mentioned, combination products with fibrates affected by a variety of factors when administered orally. are not limited to combinations of two active Substances, Such factors include the presence of food in the gastrointes triple or quadruple therapies could also be of particular tinal tract and, in general, the gastric residence time of a drug interest. Substance is significantly longer in the presence of food than in the fasted state. If the bioavailability of a drug substance The Vehicle is affected beyond a certain point due to the presence of food 0040 Vehicles useful in the present context are vehicles, in the gastrointestinal tract, the drug Substance is said to which are water-miscible, hydrophilic or hydrophobic. Use exhibit a food effect. Food effects are important because ful vehicles are non-aqueous Substances. there is a risk associated with administering the drug Sub 0041 Examples of hydrophobic vehicles useful in the stance to a patient who has eaten recently. The risk derives present invention are straight chain Saturated hydrocarbons, from the potential that absorption into the bloodstream may paraffins; fats and oils such as cacao butter, beef tallow, lard; be adversely affected to the point that the patient risks higher fatty acid such as Stearic acid, myristic acid, palmitic insufficient absorption to remedy the condition for which the drug was administered. In the case of e.g. fenofibrate the acid; hydrogenated tallow, Substituted and/or unsubstituted situation is different in that food increases the uptake. Thus, triglycerides, yellow beeswax, white beeswax, carnauba lack of intake of food simultaneously with the drug sub wax, castor wax, japan wax, and mixtures thereof. stances may lead to insufficient absorption. The extent of 0.042 Examples of water-miscible vehicles useful in the absorption of a commercially available product Tricor(R) present invention are water-miscible polar lipids such as containing fenofibrate (from Abbott) is increased by Sorbitan esters, polyether glycol esters; higher alcohols such approximately 35% under fed as compared to fasting con as cetanol, Stearyl alcohol; glyceryl monooleate, Substituted ditions. and/or unsubstituted monoglycerides, Substituted and/or unsubstituted diglycerides, and mixtures thereof. In a more 0049. As described above, there remains a need for new preferred embodiment, the vehicle is hydrophilic or water pharmaceutical compositions comprising one or more miscible. Preferably, the vehicle is selected from the group fibrates exhibiting, suitable bioavailability of the active consisting of polyethylene glycols, polyoxyethylene oxides, compound and/or reduced or eliminated food effect. In the poloxamers, polyoxyethylene Stearates, poly-epsilon capro present context, the term "suitable bioavailability” is intended to mean that administration of a composition lactone and mixtures thereof. However, the vehicle may according to the invention will result in a bioavailability that advantageously also be a polyglycolized glyceride Such as is improved compared to the bioavailability obtained after one of the numerous products sold under the registered trade administration of the active Substance(s) in a plain tablet; or mark GelucireR), for example Gelucire 44/14. the bioavailability is at least the same or improved compared 0043. Examples of useful hydrophilic or water-miscible to the bioavailability obtained after administration of a vehicles are polyvinylpyrrolidones, polyvinylpolyvinylac commercially available product containing the same active etate copolymers (PVP-PVA), polyvinyl alcohol (PVA), Substance(s) in the same amounts. In particular it is desired PVP polymers, acrylic polymers, polymethacrylic polymers to obtain more complete uptake of the active compound, and US 2006/01 10444 A1 May 25, 2006 thereby provide for a possible reduction of the administered fibrates, wherein the composition or Solid dosage form upon dosages. Further, pharmaceutical compositions and dosage oral administration to a mammal in need thereof does not forms comprising a fibrate may also reduce or negate the exhibit a significant adverse food effect as evidenced by a need for food to be takes simultaneously with the dosage value of (AUC/AUC) of at least about 0.85 with a form thereby allowing patients more freedom on when the lower 90% confidence limit of at least 0.75. In a specific drug is taken. Also, improved or enhanced bioavailability embodiment, the pharmaceutical composition or Solid dos will lead to an improved treatment because it will be age form of the invention has a value of (AUC/AUC) possible to obtain the same therapeutic response with a that is about 0.9 or more such as, e.g., about 0.95 or more, decreased dose and/or a less frequent administration and less about 0.97 or more or about 1 or more. variability in plasma levels and no food restrictions. Another way of obtaining an improved treatment of conditions where 0055. In other words, the difference between a bioequiva e.g. fenofibrate is indicated is by balancing the release of lence parameter measured after oral administration to a fenofibrate to the gastro-intestinal tract in Such a manner that mammal with and without food, respectively, is less than an enhanced plasma concentration offenofibrate is obtained 25% such as, e.g., less than 20%, less than 15%, less than initially or delayed with respect to the time of administra 10% or less than 5%. tion, i.e. by applying modified or delayed release composi 0056. In another aspect, the invention relates to a phar tions containing one or more fibrates. maceutical composition in particulate form or Solid dosage 0050. In one embodiment, the invention relates to a form comprising a fibrate, wherein the composition upon pharmaceutical composition in particulate form or Solid oral administration to a mammal in need thereof is essen dosage form comprising one or more fibrates, wherein the tially bioequivalent with a commercially available product composition upon oral administration to a mammal in need containing the same fibrate when administered in the same thereof exhibits an AUC/AUCc value of at least about or lower dose as the commercially available product con 1.0, the AUC, being determined using a commercially taining the same fibrate. In specific embodiments thereof, available product containing the same fibrate, and the AUC the dose is at the most about 98% w/w such as, e.g., at the values being determined under similar conditions. most about 95% w/w, at the most about 90% w/w, at the most about 85% w/w, at the most about 80% w/w, at the 0051. No absolute bioavailability databased on an inject most about 75% w/w, at the most about 70% w/w, at the able composition are available e.g. for fenofibrate (most most about 65% w/w, at the most about 60% w/w, at the likely due to solubility problems in aqueous media). The most about 55% w/w or at the most about 50% w/w of the commercially available compositions containing fenofibrate dose of the fibrate administered in the form of a commer include Surface-active agents and/or e.g. a lipophilic cially available product containing the same fibrate. medium. The Surface-active agents may impart improved bioavailability and therefore, the bioavailability of such a 0057 Normally, the bioequivalence is determined by composition may be sufficient already. However, there is means of at least one of the following parameters: t (time still a need for developing a flexible formulation technique to reach maximal plasma concentration), ca (maximal that enables preparation of a variety of dosage forms. plasma concentration), AUC (area under the curve from Accordingly, the requirement to such improved and/or more time 0 to time t), AUConni (area under the curve from flexible compositions may be to obtain the same or better time 0 to time infinity), Wisc (time period where the plasma bioavailability than already seen from the commercially concentration is 50% or more of C), Was ((time period available products. where the plasma concentration is 75% or more of cmax) and/or MRT (mean residence time). 0.052 Accordingly, in further embodiments of the inven tion, the AUC/AUC value obtained by administering 0058. A major problem with treatment with a fibrate is the Solid dosage form or pharmaceutical composition of the the large intra- or inter-individual variation. Thus, in a invention is at least about 1.1 such as, e.g., at least about 1.2, further aspect the invention relates to a pharmaceutical at least about 1.3, at least about 1.4, at least about 1.5, about composition in particulate form comprising one or more 1.75 or more, about 1.8 or more, about 1.9 or more, about 2.0 fibrates, wherein the composition upon oral administration or more, about 2.5 or more, about 2.75 or more, about 3.0 or to a mammal in need thereof reduces inter- and/or intra more, about 3.25 or more, about 3.5 or more, about 3.75 or individual variations compared to those of a commercially more, about 4.0 or more, about 4.25 or more, about 4.5 or available product containing the same fibrate under the same more, about 4.75 or more or about 5.0 or more, the AUC conditions and in a dose that provides an equivalent thera values being determined under similar conditions. peutic effect. 0053 Likewise, the c value obtained by administering 0059. In the comparison tests mentioned above, the com the Solid dosage form or pharmaceutical composition of the mercially available product is Tricor R in the form of tablets invention relative to the c value of commercially avail or, alternatively, Tricor(R) in the form of capsules, when the able Tricor R tablets is at least about 1.1, or at least about 1.2, fibrate is fenofibrate. When the fibrate is gemfibrozil then a or at least about 1.3, or at least about 1.4, or at least about suitable commercially available product is LopidR; when 1.5, or at least about 1.6 or more, or at least about 2.0, or at the fibrate is bezafibrate a suitable commercially available least about 2.5, or at least about 3.0, the c values being product is Bezalip(R); when the fibrate is clofibrate then a determined under similar conditions. suitable commercially available product is AtromidR); and when the fibrate is ciprofibrate then a suitable commercially 0054 Another object of the invention is to reduce or available product is Lipanon(R). eliminate the food effect. Thus, in another aspect, the invention relates to a pharmaceutical composition in par 0060 A convenient method for determining whether a ticulate form or Solid dosage form comprising one or more suitable amount of a fibrate has been absorbed may be to US 2006/01 10444 A1 May 25, 2006

determine the content of unchanged fibrate excreted via the 0065 However, the composition and dosage forms of the feces. Thus, in one embodiment the invention relates to a invention are preferably manufactured by a method com Solid pharmaceutical composition or Solid dosage form, prising the steps of wherein at most about 25% w/w Such as, e.g., at the most i) bringing the vehicle in liquid form, i.e. melting the vehicle about 20% w/w, at the most about 15% w/w, at the most if solid at room temperature, about 10% w/w, at the most about 5% w/w of the fibrate contained in the composition is excreted in the feces after ii) maintaining the liquid vehicle at a temperature below the oral administration. melting point of the fibrate, Method of Manufacture iii) dissolving the desired amount of fibrate in the vehicle, 0061 The particulate composition of the invention may iv) spraying the resulting solution onto a solid carrier having be prepared by any method which is suitable for incorpo a temperature below the melting point of the vehicle, ration of poorly water-soluble active substances. The phar V) mechanically working the resulting composition to obtain maceutical compositions may be prepared by any conve particles, i.e. a particulate material, and nient method Such as, e.g. granulation, mixing, spray drying etc. A particularly useful method is the method disclosed in vi) optionally Subjecting the particulate material to conven the international application published as WO 03/004001, tional methods for preparing Solid dosage forms. which describes a process for preparation of particulate 0066. The pharmaceutical compositions comprising the material by a controlled agglomeration method, i.e. a active Substance at least partly in form of a solid dispersion method, which enables a controlled growth in particle size. or solution may in principle be prepared using any Suitable The method involves spraying a first composition compris procedure for preparing pharmaceutical compositions ing the active substance and a vehicle in liquid form onto a known within the art. A solid dispersion may be obtained in solid carrier. Normally, the vehicle has a melting point of at different ways e.g. by employing organic solvents or by least 5° C., but the melting point must indeed be below the dispersing or dissolving the active Substance in another melting point of the active substance. In the present inven Suitable medium (e.g. an oily material that is in liquid form tion, the melting point of the vehicle and should not exceed at room temperature or at elevated temperatures). Solid 2500 C. dispersions (solvent method) are prepared by dissolving a physical mixture of the active substance (e.g. a drug sub 0062. It is within the skills of the average practioner to stance) and the carrier in a common organic Solvent, fol select a Suitable vehicle being pharmaceutical acceptable, lowed by evaporation of the solvent. The carrier is often a capable of dispersing or fully or at least partly dissolving the hydrophilic polymer. Suitable organic solvents include phar active Substance and having a melting point in the desired maceutical acceptable solvent in which the active Substance range using general knowledge and routine experimentation. is soluble Such as methanol, ethanol, methylene chloride, Suitable candidate for carriers are described in WO chloroform, ethylacetate, acetone or mixtures thereof. 03/004001, which is herein incorporated by reference. 0067 Suitable water-soluble carriers include polymers 0063. In the present context, suitable vehicles are e.g. Such as polyethylene glycol, poloxamers, polyoxyethylene those mentioned as vehicles or as oily materials as well as Stearates, poly-epsilon-caprolactone, polyvinylpyrrolidone those disclosed in WO 03/004001. An advantage of using (PVP), polyvinylpyrrolidone-polyvinylacetate copolymer the controlled agglomeration method described in WO PVP-PVA (Kollidon VA64), polymethacrylic polymers 03/004001 is that it is possible to apply a relatively large (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E) and amount of a liquid system to a particulate material without polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), having an undesirable growth in particle size. Accordingly, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, in one embodiment of the invention, the particulate material and poly(ethylene oxide) (PEO). of a pharmaceutical composition has a geometric weight mean diameter d of e10 um such as, e.g. 220 Lum, from 0068 Polymers containing acidic functional groups may about 20 to about 2000, from about 30 to about 2000, from be suitable for solid dispersions, which release the active about 50 to about 2000, from about 60 to about 2000, from Substance in a preferred pH range providing acceptable about 75 to about 2000 such as, e.g. from about 100 to about absorption in the intestines. Such polymers may be one ore 1500 um, from about 100 to about 1000 um or from about more selected from the group comprising hydroxypropyl 100 to about 700 um, or at the most about 400 um or at the methylcellulose phtalate (HMPCP), polyvinyl acetate phta most 300 um such as, e.g., from about 50 to about 400 um late (PVAP), hydroxypropylmethylcellulose acetate succi such as, e.g., from about 50 to about 350 lum, from about 50 nate (HPMCAS), alginate, carbomer, carboxymethylcellu to about 300 um, from about 50 to about 250 um or from lose, methacrylic acid copolymer (Eudragit L., Eudragit S), about 100 to about 300 um. shellac, cellulose acetate phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate phtalate, hydroxypro 0064. The compositions and dosage forms of the inven pyulcellulose acetate phthalate, cellulose acetate terephtaha tion are preferably formed by spray drying techniques, late, cellulose acetate isophthalate and cellulose acetate controlled agglomeration, freeze-drying or coating on car trimellitate. rier particles or any other solvent removal process. The dried product contains the active Substance present preferably in 0069. The weight ratio of active substance to polymer dissolved form either fully dissolved as a solid solution or may be in a range of from about 3:1 to about 1:20. However, partly dissolved as a solid dispersion including a molecular narrower ranges of from about 3:1 to about 1:5. Such as, e.g., dispersion and a solid solution. from about 1:1 to about 1:3 or about may also be used. US 2006/01 10444 A1 May 25, 2006

0070 Apart from using the organic solvent based Sodium, crospovidone, polacrillin potassium, sodium starch method, Solid dispersion or Solid solutions of one or more glycolate, starch, pregelatinized starch, carboxymethyl fibrates may be also obtained by dispersing and/or dissolv starch (e.g. Primogel(R) and Explotabo(R) etc. Specific ing the active compound in the carrier composition used in examples of binders are e.g. acacia, alginic acid, agar, the controlled agglomeration method. Stabilizing agents etc. calcium carrageenan, Sodium carboxymethylcellulose, may be added in order to ensure the stability of the solid microcrystalline cellulose, dextrin, ethylcellulose, gelatin, dispersion/solution. liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized Pharmaceutical Excipients and Additives starch etc. 0071. In the present context the terms “pharmaceutically 0076 Glidants and lubricants may also be included in the acceptable excipient are intended to denote any material, second composition. Examples include Stearic acid, magne which is inert in the sense that it substantially does not have sium Stearate, calcium Stearate or other metallic Stearate, any therapeutic and/or prophylactic effect per se. Such talc, waxes and glycerides, light mineral oil, PEG, glyceryl excipient(s) may be added with the purpose of making it behenate, colloidal silica, hydrogenated vegetable oils, corn possible to obtain a pharmaceutical, cosmetic and/or food starch, Sodium Stearyl fumarate, polyethylene glycols, alkyl stuff composition, which have acceptable technical proper Sulfates, sodium benzoate, Sodium acetate etc. ties. 0077. Other excipients which may be included in a com 0072 Examples of suitable excipients for use in a com position or Solid dosage form of the invention are e.g. position or Solid dosage form according to the invention flavoring agents, coloring agents, taste-masking agents, pH include fillers, diluents, glidants, disintegrants, binders, adjusting agents, buffering agents, preservatives, stabilizing lubricants etc. or mixture thereof. As the composition or agents, anti-oxidants, wetting agents, humidity-adjusting Solid dosage form according to the invention may be used agents, Surface-active agents, Suspending agents, absorption for different purposes, the choice of excipients is normally enhancing agents, agents for modified release etc. made taken such different uses into considerations. Other pharmaceutically acceptable excipients for Suitable use are 0078. Other additives in a composition or a solid dosage e.g. acidifying agents, alkalizing agents, preservatives, anti form according to the invention may be antioxidants like e.g. oxidants, buffering agents, chelating agents, coloring agents, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, complexing agents, emulsifying and/or solubilizing agents, butylated hydroxytoluene, hypophosphorous acid, mono flavors and perfumes, humectants, Sweetening agents, wet thioglycerol, potassium metabisulfite, propyl gallate, ting agents etc. sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol 0073. Examples of suitable fillers, diluents and/or binders acetate, tocopherol hemisuccinate, TPGS or other toco include lactose (e.g. spray-dried lactose, C.-lactose, B-lac pherol derivatives, etc. The carrier composition may also tose, Tabletose(R), various grades of Pharmatose(R), Micro contain e.g. stabilising agents. The concentration of an tose R or Fast-FlocR), microcrystalline cellulose (various antioxidant and/or a stabilizing agent in the carrier compo grades of Avicel(R), Elcema(R), Vivacel(R), Ming Tai(R) or sition is normally from about 0.1% w/w to about 5% w/w. Solka-FlocR), hydroxypropylcellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropyl methylcellulose 0079 A composition or solid dosage form according to (HPMC) (e.g. Methocel E, F and K, Metolose SH of the invention may also include one or more surfactants or Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Metho Substances having Surface-active properties. It is contem cel E and Metolose 60 SH, the 4,000 cps grades of Methocel plated that such substances are involved in the wetting of the F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps slightly soluble active Substance and thus, contributes to grades of Methocel K; and the 4,000, 15,000, 39,000 and improved solubility characteristics of the active substance. 100,000 grades of Metolose 90 SH), methylcellulose poly Suitable Surfactans for use in a composition or a Solid dosage mers (such as, e.g., Methocel A. Methocel A4C, Methocel form according to the invention are surfactants such as, e.g., A15C, Methocel A4M), hydroxyethylcellulose, sodium car hydrophobic and/or hydrophilic Surfactants such as those boxymethylcellulose, carboxymethylene, carboxymethylhy disclosed in WO 00/50007 in the name of Lipocine, Inc. droxyethylcellulose and other cellulose derivatives, sucrose, 0080 Specific examples of suitable surfactants are poly agarose, Sorbitol, mannitol, dextrins, maltodextrins, starches ethoxylated fatty acids Such as, e.g. fatty acid mono- or or modified starches (including potato starch, maize starch diesters of polyethylene glycol or mixtures thereof Such as, and rice starch), calcium phosphate (e.g. basic calcium e.g. mono—or diesters of polyethylene glycol with lauric phosphate, calcium hydrogen phosphate, dicalcium phos acid, oleic acid, Stearic acid, myristic acid, ricinoleic acid, phate hydrate), calcium Sulfate, calcium carbonate, sodium and the polyethylene glycol may be selected from PEG 4, alginate, collagen etc. PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, 0074 Specific examples of diluents are e.g. calcium PEG 15, PEG 20, PEG 25, PEG 30, PEG 32, PEG 40, PEG carbonate, dibasic calcium phosphate, tribasic calcium phos 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG phate, calcium Sulfate, microcrystalline cellulose, powdered 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lac PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG tose, mannitol, Sorbitol, starch, pregelatinized starch, 35,000, polyethylene glycol glycerol fatty acid esters, i.e. Sucrose, Sugar etc. esters like the above-mentioned but in the form of glyceryl 0075 Specific examples of disintegrants are e.g. alginic esters of the individual fatty acids; glycerol, propylene acid or alginates, microcrystalline cellulose, hydroxypropyl glycol, ethylene glycol, PEG or sorbitol esters with e.g. cellulose and other cellulose derivatives, croscarmellose vegetable oils like e.g. hydrogenated castor oil, almond oil, US 2006/01 10444 A1 May 25, 2006

palm kernel oil, castor oil, apricot kernel oil, olive oil, 0085. A sorption material suitable for use according to peanut oil, hydrogenated palm kernel oil and the like, the present invention is a Solid pharmaceutically acceptable polyglycerized fatty acids like e.g. polyglycerol Stearate, material, which when tested as described herein— polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linoleate, propylene glycol fatty acid esters such as, e.g. i) has an oil threshold value of 10% or more, when tested propylene glycol monolaurate, propylene glycol ricinoleate according to the Threshold Test disclosed herein, and which and the like, mono- and diglycerides like e.g. glyceryl material is used in a composition of the invention further monooleate, glyceryl dioleae, glyceryl mono- and/or fulfilling one or both of i) and ii): dioleate, glyceryl caprylate, glyceryl caprate etc.; Sterol and i) the composition releases at least 30% of the hydrophobic sterol derivatives; polyethylene glycol sorbitan fatty acid or a hydrophilic or water-miscible vehicle, when tested esters (PEG-sorbitan fatty acid esters) such as esters of PEG according to the Release Test; with the various molecular weights indicated above, and the various Tween(R) series; polyethylene glycol alkyl ethers ii) the composition, in the form of a tablet, contains at least such as, e.g. PEG oleyl ether and PEG lauryl ether; sugar about 90% w/w of the oil-sorption material, and exhibits a esters like e.g. Sucrose monopalmitate and Sucrose mono disintegration time of at the most 60 minutes when tested laurate; polyethylene glycol alkyl phenols like e.g. the according to the Ph. Eur. Disintegration Test. Triton R. X or N series; polyoxyethylene-polyoxypropylene 0086) The material is especially useful as a sorption block copolymers such as, e.g., the Pluronic(R) series, the material for oily materials in pharmaceuticals, cosmetics SynperonicR) series, Emkalyx(R), Lutrol(R), SupronicR) etc. and/or foodstuff, especially in pharmaceuticals. The generic term for these polymers is “poloxamers' and relevant examples in the present context are Poloxamer 105, 0087. It is important that the oil sorption material fulfills 108, 122, 123, 124, 181, 182, 183, 184, 185, 188,212, 215, at least two tests. One of the tests is mandatory, i.e. the 217, 231, 234, 235, 237,238,282, 284, 288,331, 333,334, Threshold Test must be met. This test gives a measure for 335, 338, 401, 402, 403 and 407; sorbitan fatty acid esters how much oily material the oil sorption material is able to like the SpanR series or Ariacel(R) series Such as, e.g. absorb while retaining suitable flowability properties. It is Sorbinan monolaurate, Sorbitan monopalmitate, Sorbitan important that an oil sorption material for use according to monooleate, Sorbitan monostearate etc.; lower alcohol fatty the invention (with or without oil absorbed) has a suitable acid esters like e.g. oleate, isopropyl myristate, isopropyl flowability so that it easily can be admixed with other palmitate etc.; ionic Surfactants including cationic, anionic excipients and/or further processed into compositions with and Zwitterionic Surfactants such as, e.g. fatty acid salts, bile out significant problems relating to e.g. adherence to the salts, phospholipids, phosphoric acid esters, carboxylates, apparatus involved. The test is described below in Materials Sulfates and Sulfonates etc. and Methods and guidance is given for how the test is carried out. The Threshold Test involves the determination 0081. When a surfactant or a mixture of surfactants is of the flowability of the solid material loaded with different present in a composition or a solid dosage form of the amounts of oil. invention, the concentration of the Surfactant(s) is normally in a range of from about 0.1-80% w/w such as, e.g., from 0088. From above it is seen that the oil threshold value about 0.1 to about 20% w/w, from about 0.1 to about 15% normally must exceed 10% and often the oil sorption w/w, from about 0.5 to about 10% w/w, or alternatively, material has an oil threshold value of at least about 15%, from about 0.10 to about 80% w/w such as, e.g. from about Such as, e.g., at least about 20%, at least about 25%, at least 10 to about 70% w/w, from about 20 to about 60% w/w or about 30%, at least about 35%, at least about 40%, or at least from about 30 to about 50% w/w. about 45%. 0082 In a specific aspect of the invention, the at least one 0089 An especially suitable material for use according to of the one or more pharmaceutically acceptable excipients is the invention, Aeropearl 300, has a very high oil threshold selected from the group consisting of silica acid or a value of about 60%. Accordingly, materials that have an oil derivative or salt thereof including silicates, silicon dioxide threshold value of at least about 50%, such as, e.g., at least and polymers thereof magnesium aluminosilicate and/or about 55% or at least about 60% are used in specific magnesium aluminometasilicate, bentonite, kaolin, magne embodiments of the present invention. sium trisilicate, montmorillonite and/or Saponite, Nue SellinTM. 0090. Furthermore, an oil sorption material for use according to the invention must fulfill at least one further Sorption Materials test, namely a release test and/or a disintegration test. 0083. Materials such as those mentioned immediately above are especially useful as a sorption material for oily 0091. The release test gives a measure of the ability of an materials in pharmaceuticals, cosmetics and/or foodstuff. In oil sorption material to release the oil that is absorbed to the a specific embodiment, the material is used as a sorption material when contacted with water. This ability is very material for oily materials in pharmaceuticals. The material important especially in those situations where an active that has the ability to function as a sorption material for oily Substance is contained in the oily material. If the oil sorption materials is also denoted “oil sorption material'. material is not capable of releasing the oil from the material then there is a major risk that the active substance will only 0084. Furthermore, in the present context the term “sorp to a minor degree be released from the material. Accord tion' is used to denote “absorption” as well as "adsorption'. ingly, it is envisaged that bioavailability problems relating to It should be understood that whenever one of the terms is used it is intended to cover the phenomenon absorption as e.g. poor absorption etc. will occur in Such situations. well as adsorption. The terms “sorption material” and “oil 0092. The requirements for the release test are that the Sorption material” is intended to have the same meaning. Solid pharmaceutical acceptable material, when tested as US 2006/01 10444 A1 May 25, 2006

described herein, releases at least about 30% such as, e.g., at 0099 iii) in the form of a tablet has a disintegration time least about 35%, at least about 40%, at least about 45%, at of at the most 1 hour such as at the most about 50 min, at least about 50%, at least about 55% or at least about 60% of the most about 40 min, at the most about 30 min, at the most an oil. As it appears from the examples herein a suitable oil about 20 min, at the most about 10 minor at the most about sorption material like Aeroperl 300 has a much higher 5 min, when tested according to Ph. Eur. Disintegration test, release. Therefore, in a specific embodiment of the inven the tablet containing about 90% w/w or more, Such as, e.g., tion, the solid pharmaceutical acceptable material, when about 92.5% w/w or more, about 95% w/w or more, about tested as described herein, releases at least about 65% such 97.5% w/w or more or about 100% of the pharmaceutically as, e.g., at least about 70%, at least about 75% or at least acceptable material. about 80% of an oil. 0.100 Other specific embodiments of the invention are 0093. The disintegration test is not performed on the solid those, wherein material in particulate form but on a tablet made of the solid material. A requirement with respect to disintegration is the solid pharmaceutical material used as a sorption material important in order to ensure that the solid material, when in a composition according of the invention, when tested as included in Solid dosage forms, does not impart unwanted described herein, properties to the dosage form e.g. leading to unwanted i) has an oil threshold value of at least about 55%; properties with respect to dissolution and bioavailability of the active Substance contained in the dosage form. For some the solid pharmaceutical material, when tested as described of the materials suitable for use according to the invention herein, it is possible to press tablets containing 100% w/w of the ii) releases at least about 75% of an oil; and/or solid material itself. If this is the case, the test is carried out on such tablets. However, it is envisaged that there may be the solid pharmaceutical material, when tested as described situations where it is rather difficult to prepare tablets from herein, the Solid material alone. In Such cases it is possible to add iii) in the form of a tablet has disintegration time of at the pharmaceutically acceptable excipients normally used in the most about 10 min, when tested according to Ph. Eur. preparation of compressed tablets up to a concentration of Disintegration test, the tablet containing about 97.5% w/w of 10% wtw or less. Examples of suitable pharmaceutically the pharmaceutically acceptable material. acceptable excipients include fillers, diluents, binders and lubricants. However, excipients, normally classified as dis 0101 The solid pharmaceutically acceptable material integrants, should be avoided. used as a sorption material in a composition according to the invention is normally a particulate material in the form of 0094. Accordingly, the solid pharmaceutical acceptable e.g. powders, particles, granules, granulates etc. material for use according to invention, when tested as described herein, in the form of a tablet should have a 0102) Such particulate material suitable for use as an oil disintegration time of at the most 1 hour, when tested sorption material has normally a bulk density of about 0.15 according to Ph. Eur. Disintegration test, the tablet contain g/cm or more such as, e.g., at least about 0.20 g/cm or at ing about 90% w/w or more, such as, e.g., about 92.5% w/w least about 0.25 g/cm. or more, about 95% w/w or more, about 97.5% w/w or more or about 100% of the pharmaceutically acceptable material. 0103). Furthermore, the oil sorption material normally has an oil absorption value of at least about 100 g oil/100 g such 0.095. In a further embodiment, the solid pharmaceutical as, e.g., at least about 150 g oil/100 g, at least about 200 g acceptable material, when tested as described herein, in the oil/100 g, at least about 250 g oil/100 g, at least about 300 form of a tablet has a disintegration time of at the most about g oil/100g or at least about 400 g oil/100g pharmaceutically 50 min, Such as, e.g., at the most about 40 min, at the most acceptable material. The oil absorption value is determined about 30 min, at the most about 20 min, at the most about as described in the experimental section herein. 10 minor at the most about 5 min, when tested according to Ph. Eur. Disintegration test, the tablet containing about 90% 0.104) The present inventors have found that a common w/w or more, such as, e.g., about 92.5% w/w or more, about feature of some of the materials suitable for use as oil 95% w/w or more, about 97.5% w/w or more or about 100% Sorption material is that they have a relatively large Surface of the pharmaceutically acceptable material. area. Accordingly, pharmaceutically acceptable material for use as an oil sorption material according to the invention 0096. In a specific embodiment, the solid material used as may have a BET surface area of at least 5 m/g such as, e.g., a sorption material fulfils all three tests. Thus, the solid at least about 25 m?g, at least about 50 m?g, at least about pharmaceutical acceptable material, when tested as 100 m/g, at least about 150 m/g, at least about 200 m/g, described herein, at least about 250 m/g or at least about 275 m/g. 0097 i) has an oil threshold value of at least about 10%, 0105. As mentioned above one of the characteristic fea Such as, e.g., at least about 15%, at least about 20%, at least tures of a pharmaceutically acceptable material for use as an about 25%, at least about 30%, at least about 35%, at least oil sorption material according to the invention is that it about 40%, at least about 45%, at least about 50%, at least retains a good flowability even if it has been loaded with oily about 55% or at least about 60%, material. Thus, the flowability of the pharmaceutically 0.098 ii) releases at least about 30% such as, e.g., at least acceptable material loaded with 25% w/w or more such as, about 35%, at least about 40%, at least about 45%, at least e.g. 30% w/w or more, 40% wow or more, 45% w/w or about 50%, at least about 55%, at least about 60%, at least more, 50% w/w or more, 55% w/w or more, 60% w/w or about 65%, at least about 70%, at least about 75% or at least more, 65% w/w or more or about 70% w/w viscoleo will about 80% of an oil, and normally meet the Ph. Eur, requirements. US 2006/01 10444 A1 May 25, 2006

0106 Notably, the oil sorption material may comprise a 0.112. The oily materials that are suitable for use in the silica acid or a derivative or salt thereof such as, e.g., silicon present context are substances or materials, which have a dioxide or a polymer thereof as a pharmaceutically accept melting point of at least about 10° C. and at the most about able excipient. However, dependent on the quality employed 2500 C. a silicon dioxide may be a lubricant or it may be an oil 0113. In specific embodiments of the invention, the oily sorption material. Qualities fulfilling the latter function seem material has a melting point of about 5° C. or more such as, to be most important. e.g., about 10° C. or more, about 15° C. or more, about 20° 0107. In a specific embodiment, a composition or solid C. or more or about 25° C. or more. dosage form according to invention comprises a pharma 0114. In further embodiments of the invention, the oily ceutically acceptable excipient that is a silicon dioxide material has a melting point of at least about 25°C. Such as, product that has properties corresponding to AeroperlR 300 e.g., at least about 30° C. at least about 35° C. or at least about 40° C. For practical reasons, the melting point may 0108 Use of an oil sorption material in compositions or normally not be too high, thus, the oily material normally dosage forms according to the invention is very advanta has a melting point of at the most about 300° C. Such as, e.g., geous for the preparation of pharmaceutical, cosmetic, nutri at the most about 250° C., at the most about 200° C., at the tional and/or food compositions, wherein the composition most about 150° C. or at the most about 100° C. If the comprises oily material. One of the advantages is that is it melting point is higher a relatively high temperature may possible to incorporate a relatively large amount of and oily promote e.g. oxidation or other kind of degradation of an material and still have a material that is solid. Thus, it is possible to prepare solid compositions with a relatively high active Substance in those cases where e.g. a therapeutically load of oily materials by use of an oil sorption material and/or prophylactically active Substance is included. according to the invention. Within the pharmaceutical field 0.115. In the present context, melting points are deter it is an advantage to be able to incorporate a relatively large mined by DSC (Differential Scanning Calorimetry). The amount of an oily material in a solid composition especially melting point is determined as the temperature at which the in those situation where the active Substance does not have linear increase of the DSC curve intersects the temperature Suitable properties with respect to water solubility (e.g. poor axis (see FIG. 1 for further details). water Solubility), Stability in aqueous medium (i.e. degra dation occurs in aqueous medium), oral bioavailability (e.g. 0116 Interesting oily materials are in general Substances, low bioavailability) etc., or in those situations where it is which are used in the manufacture of pharmaceuticals as desired to modify the release of an active substance from a so-called melt binders or solid solvents (in the form of solid composition in order to obtain a controlled, delayed, Sus dosage form), or as co-solvents or ingredients in pharma tained and/or pulsed delivery of the active substance. Thus, ceuticals for topical use. It may be hydrophilic, hydrophobic in a specific embodiment it is used in the preparation of and/or have Surface-active properties. In general hydrophilic pharmaceutical compositions. and/or hydrophobic oily materials are suitable for use in the manufacture of a pharmaceutical composition comprising a 0109 The oil sorption material for use in the processing therapeutically and/or prophylactically active Substance that into solid compositions normally absorbs about 5% w/w or has a relatively low aqueous solubility and/or when the more, such as, e.g., about 10% w/w or more, about 15% w/w release of the active substance from the pharmaceutical or more, about 20% w/w or more, about 25% w/w or more, composition is designed to be immediate or non-modified. about 30% w/w or more, about 35% w/w or more, about Hydrophobic oily materials, on the other hand, are normally 40% w/w or more, about 45% w/w or more, about 50 w/w used in the manufacture of a modified release pharmaceu or more, about 55% w/w or more, about 60% w/w or more, tical composition. The above-given considerations are sim about 65% w/w or more, about 70% w/w or more, about plified to illustrate general principles, but there are many 75% w/w or more, about 80% w/w or more, about 85% w/w cases where other combinations of oily materials and other or more, about 90% w/w or more or about 95% wow or more purposes are relevant and, therefore, the examples above of an oil or an oily material and is still a solid material. should not in any way limit the invention. Oily Materials 0.117) Typically, a suitable hydrophilic oily material is selected from the group consisting of polyether glycols such 0110. An important aspect of the invention is composi as, e.g., polyethylene glycols, polypropylene glycols; poly tions or Solid dosage forms comprising an oily material. oxyethylenes; polyoxypropylenes; poloxamers and mixtures thereof, or it may be selected from the group consisting of 0111. In the present context the term “oily materials” is Xylitol, Sorbitol, potassium sodium tartrate. Sucrose tribe used in a very broad sense including oils, waxes, semi-solid henate, glucose, rhamnose, lactitol, behenic acid, hydro materials and materials that normally are used as solvents quinon monomethyl ether, Sodium acetate, ethyl fumarate, (such as organic solvents) or cosolvents within the pharma ceutical industry, and the term also includes therapeutically myristic acid, citric acid, Gelucire 50/13, other Gelucire and/or prophylactically active Substances that are in liquid types such as, e.g., Gelucire 44/14 etc., Gelucire 50/10, form at ambient temperature; furthermore the term includes Gelucire 62/05, Sucro-ester 7, Sucro-ester 11, Sucro-ester emulsions like e.g. microemulsions and nanoemulsions and 15: maltose, mannitol and mixtures thereof. Suspensions. The oils and oily-like materials that can be 0118. A suitable hydrophobic oily material may be absorbed will normally be liquid at ambient or elevated selected from the group consisting of Straight chain Satu temperature (for practical reasons the max. temperature is rated hydrocarbons, Sorbitan esters, paraffins; fats and oils about 250° C.). They may be hydrophilic, lipophilic, hydro Such as e.g., cacao butter, beef tallow, lard, polyether glycol phobic and/or amphiphilic materials. esters; higher fatty acid Such as, e.g. Stearic acid, myristic US 2006/01 10444 A1 May 25, 2006 acid, palmitic acid, higher alcohols such as, e.g., cetanol, 0.124. Other suitable oily materials may be solvents or Stearyl alcohol, low melting point waxes such as, e.g., semi-solid excipients like, e.g. propylene glycol, polyglyc glyceryl monostearate, glyceryl monooleate, hydrogenated olised glycerides including Gelucire 44/14, complex fatty tallow, myristyl alcohol, stearyl alcohol, substituted and/or materials of plant origin including theobroma oil, carnauba unsubstituted monoglycerides, Substituted and/or unsubsti wax, vegetable oils like e.g. almond oil, coconut oil, corn oil, tuted diglycerides, Substituted and/or unsubstituted triglyc cottonseed oil, Sesame oil, soya oil, olive oil, castor oil, palm erides, yellow beeswax, white beeswax, carnauba wax, kernels oil, peanut oil, rape oil, grape seed oil etc., hydro castor wax, japan wax, acetylate monoglycerides; NVP genated vegetable oils such as, e.g. hydrogenated peanut oil, polymers, PVP polymers, acrylic polymers, or a mixture hydrogenated palm kernels oil, hydrogenated cottonseed oil, thereof. hydrogenated Soya oil, hydrogenated castor oil, hydroge 0119). In an interesting embodiment, the oily material is a nated coconut oil; natural fatty materials of animal origin polyethylene glycol having an average molecular weight in including beeswax, lanolin, fatty alcohols including cetyl, a range of from about 400 to about 35,000 such as, e.g., from Stearyl, lauric, myristic, palmitic, Stearic fatty alcohols; about 800 to about 35,000, from about 1,000 to about 35,000 esters including glycerol Stearate, glycol Stearate, ethyl Such as, e.g., polyethylene glycol 1,000, polyethylene glycol oleate, isopropyl myristate; liquid interesterified semi-syn 2,000, polyethylene glycol 3,000, polyethylene glycol thetic glycerides including Miglycol 810/812; amide or fatty 4,000, polyethylene glycol 5,000, polyethylene glycol 6000, acid alcolamides including Stearamide ethanol, diethanola polyethylene glycol 7,000, polyethylene glycol 8,000, poly mide of fatty coconut acids, acetic acid esters of mono and ethylene glycol 9,000 polyethylene glycol 10,000, polyeth diglycerides, citric acid esters of mono and diglycerides, ylene glycol 15,000, polyethylene glycol 20,000, or poly lactic acid esters of mono and diglycerides, mono and ethylene glycol 35,000. In certain situations polyethylene di-glycerides, poly-glycerol esters of fatty acids, poly-glyc glycol may be employed with a molecular weight from erol poly-ricinoleate, propylene glycol esters of fatty acids, Sorbitan monostearates, Sorbitan tristearates, sodium about 35,000 to about 100,000. Stearoyl lactylates, calcium Stearoyl lactylates, diacetyl tar 0120 In another interesting embodiment, the oily mate taric acid esters of mono and diglycerides etc. rial is polyethylene oxide having a molecular weight of from about 2,000 to about 7,000,000 such as, e.g. from about 0.125 The pharmaceutical composition or a solid dosage 2,000 to about 100,000, from about 5,000 to about 75,000, form according to the invention may have a concentration of from about 10,000 to about 60,000, from about 15,000 to the oily material in the composition or the dosage form of about 50,000, from about 20,000 to about 40,000, from about 5% w/w or more such as, e.g., about 10% w/w or about 100,000 to about 7,000,000 such as, e.g., from about more, about 15% w/w or more, about 20% w/w or more, 100,000 to about 1,000,000, from about 100,000 to about about 25% w/w or more, about 30% w/w or more, about 600,000, from about 100,000 to about 400,000 or from about 35% w/w or more, about 40% w/w or more, about 45% w/w 100,000 to about 300,000. or more, about 50 w/w or more, about 55% w/w or more, 0121. In another embodiment, the oily material is a about 60% w/w or more, about 65% w/w or more, about poloxamer such as, e.g. Poloxamer 188, Poloxamer 237, 70% w/w or more, about 75% w/w or more, about 80% w/w Poloxamer 338 or Poloxamer 407 or other block copolymers or more, about 85% w/w or more, about 90% w/w or more of ethylene oxide and propylene oxide such as the Pluronic R. or about 95% w/w or more. and/or Tetronic R series. Suitable block copolymers of the 0.126 In specific embodiments the concentration of the Pluronic R series include polymers having a molecular oily material in a composition or Solid dosage form of the weight of about 3,000 or more such as, e.g. from about 4,000 invention is in a range from about 20% to about 80% w/w to about 20,000 and/or a viscosity (Brookfield) from about such as, e.g., from about 25% to about 75% w/w. 200 to about 4,000 cps such as, e.g., from about 250 to about 3,000 cps. Suitable examples include Pluronic(R) F38, P65, 0127. One of the advantages is that is it possible to P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, incorporate a relatively large amount of oily material and P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 still have a solid material. Thus, it is possible to prepare solid etc. Suitable block copolymers of the Tetronic R series compositions with a relatively high load of oily materials by include polymers having a molecular weight of about 8,000 use of an oil sorption material according to the invention. or more such as, e.g., from about 9,000 to about 35,000 Within the pharmaceutical field it is an advantage to be able and/or a viscosity (Brookfield) of from about 500 to about to incorporate a relatively large amount of an oily material 45,000 cps such as, e.g., from about 600 to about 40,000. in a solid composition especially in those situation where the The viscosities given above are determined at 60° C. for active substance does not have suitable properties with substances that are pastes at room temperature and at 77°C. respect to water Solubility (e.g. poor water solubility), sta for Substances that are solids at room temperature. bility in aqueous medium (i.e. degradation occurs in aqueous 0122) The oily material may also be a sorbitan ester such medium), oral bioavailability (e.g. low bioavailability) etc., as, e.g., Sorbitan diisostearate, Sorbitan dioleate, Sorbitan or in those situations where it is desired to modify the release monolaurate, sorbitan monoisoStearate, sorbitan of an active Substance from a composition in order to obtain monooleate, Sorbitan monopalmitate, Sorbitan monostearate, a controlled, delayed, sustained and/or pulsed delivery of the Sorbitan sesqui-isostearate, Sorbitan sesquioleate, Sorbitan active Substance. sesquistearate, Sorbitan tri-isostearate, Sorbitan trioleate, Sor 0128. A further advantage is that the particulate material bitan tristearate or mixtures thereof. obtained is a free-flowing powder and therefore readily 0123 The oily material may of course comprise a mix processable into e.g. solid dosage forms such as tablets, ture of different oily materials such as, e.g., a mixture of capsules or Sachets. Normally, the particulate material has hydrophilic and/or hydrophobic materials. properties that are suitable in order to manufacture tablets by US 2006/01 10444 A1 May 25, 2006 direct compression without addition of large amounts of storage at a temperature of about 40° C. and a relative further additives. A suitable test for test the flowability of the humidity of about 75%. Also, the physical stability is very particulate material is the method described in Ph.Eur. and high as can be seen from the Examples below. measuring the flow rate of the material out of a funnel with 0.137 The solid dosage form according to the invention is a nozzle (orifice) diameter of 10.0 mm. obtained by processing the particulate material according to 0129. In an embodiment of the invention, at least a part the invention by means of techniques well-known to a of the fibrate may be present in the composition in the form person skilled in the art. Usually, this involves further of a solid dispersion including a molecular dispersion and a addition of one or more of the pharmaceutically acceptable solid solution. Normally, 10% or more such as, e.g., 20% or excipients mentioned herein. more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more such as, e.g., 0.138. The composition or solid dosage form according to 95% or more or about 100% w/w of the active substance the invention may be designed to release one or more thereof is present in the composition in dissolved form. fibrates in any suitable manner provided that the increase in bioavailability is maintained. Thus, the active Substance may Solid Dosage Forms be released relatively fast in order to obtain an enhanced 0130. The pharmaceutical composition according to the on-set of action, it may be released so as to follow zero or invention is in particulate form and may be employed as first order kinetics or it may be released in a controlled or Such. However, in many cases it is more convenient to modified manner in order to obtain a predetermined pattern present the composition in the form of granules, pellets, of release. Plain formulations are also within the scope of the microspheres, nanoparticles and the like or in the form of present invention. Solid dosage forms including tablets, tablets, beads, cap 0.139. The composition or solid dosage form according to Sules, grains, pills, granulates, granules, powder, pellets, the invention may also be coated with a film coating, an Sachets, lozenges, troches and the like. enteric coating, a modified release coating, a protective 0131) A solid dosage form according to the invention coating, an anti-adhesive coating etc. may be a single unit dosage form or it may in the form of a 0140. A solid dosage form according to the invention polydepot dosage form contain a multiplicity of individual may also be coated in order to obtain Suitable properties e.g. units such as, e.g., pellets, beads and/or granules. with respect to release of the active Substance. The coating 0.132. Usually, a pharmaceutical composition or a solid may be applied on single unit dosage forms (e.g. tablets, dosage form of the invention is intended for administration capsules) or it may be applied on a polydepot dosage form via the oral, buccal or Sublingual administration route. or on its individual units. 0133. The invention also relates to the above-mentioned 0.141 Suitable coating materials are e.g. methylcellulose, presentation form. Within the scope of the invention are hydroxypropylmethylcellulose, hydroxypropylcellulose, compositions/solid dosage forms that are intended to release acrylic polymers, ethylcellulose, cellulose acetate phthalate, the active Substance in a fast release, a delayed release or polyvinyl acetate phthalate, hydroxypropyl methylcellulose modified release manner. phthalate, polyvinylalcohol, Sodium carboxymethylcellu 0134) A solid dosage form according to the present lose, cellulose acetate, cellulose acetate phthalate, gelatin, invention comprises a pharmaceutical composition in par methacrylic acid copolymer, polyethylene glycol, shellac, ticulate form as described above. The details and particulars Sucrose, titanium dioxide, carnauba wax, microcrystalline disclosed under this main aspect of the invention apply wax, Zein. mutatis mutandis to the other aspects of the invention. 0.142 Plasticizers and other ingredients may be added in Accordingly, the properties with respect to increase in the coating material. The same or different active Substance bioavailability, changes in bioavailability parameters, reduc may also be added in the coating material. tion in adverse food effect as well as release of one or more fibrates etc. described and/or claimed herein for pharmaceu 0.143. The pharmaceutical composition or a solid dosage tical compositions in particulate form are analogues for a form according to the invention is designed to release the Solid dosage form according to the present invention. fibrate in a suitable manner. Specific release patterns are disclosed in the appended claims to which reference is made. 0135 Usually, the concentration of the pharmaceutical Herein is also given specific relevant absorption patterns. composition in particulate form is in a range of from about 5 to 100% w/w such as, e.g., from about 10% to about 90% Other Embodiments of the Invention w/w, from about 15% to about 85% w/w, from about 20% to about 80% w/w, from about 25% to about 80% w/w, from 0144. In yet another aspect, the invention relates to a about 30% to about 80% w/w, from about 35% to about 80% Solid pharmaceutical composition in particulate form com w/w, from about 40% to about 75% w/w, from about 45% to prising one or more fibrates and one or more oily materials, about 75% w/w or from about 50% to about 70% w/w of the the composition having a suitable flowability as determined dosage form. In an embodiment of the invention, the con according to the method described in Ph.Eur. measuring the centration of the pharmaceutical composition in particulate flow rate of the composition out of a funnel with a nozzle diameter of 10.0 mm. In order to avoid any adherence to the form is 50% w/w or more of the dosage form. manufacturing and/or filling equipment it is important that 0136. The solid dosage forms of the invention are very the particulate material is freely flowing. This characteristic stable. For example, the fibrate is present in an amount of at is also important in those cases where it is desired to process least 90%, or at least 95%, or at least 100%, relative to the the particulate material further into other kinds of formula amount prior to storage, when assayed after 3 months of tions such as, e.g., Solid dosage forms. US 2006/01 10444 A1 May 25, 2006

0145 Yet another aspect of the invention relates to a solid Tricor Tablet Formulation pharmaceutical composition in particulate form comprising 0150 TRICORR tablets are fenofibrate-containing tab one or more fibrates, one or more oily materials and one or lets available for oral administration, either containing 54 more oil-sorption materials, which mg or 160 mg of micronized fenofibrate per tablet. i) has an oil threshold value of 10% or more, when tested 0151. The tablets contain the following inactive ingredi according to the Threshold Test herein, and fulfills at least ents: colloidal silicon dioxide, crospovidone, lactose mono one of hydrate, lecithin, microcrystalline cellulose, polyvinyl alco ii) releases at least 30% of an oil, when tested according to hol, povidone, Sodium lauryl Sulfate, Sodium Stearyl the Release Test herein, and fumarate, talc, titanium dioxide, Xanthan gum, colorant. Tricor R is indicated as a lipid regulating agent. The recom 0146 iii) in the form of a tablet has a disintegration time mended dosage of Tricor R is 54-160 mg/day taken with of at the most 1 hour, when tested according to Ph. Eur. food. Tricor(R) tablets are provided in strengths of 54 and 160 Disintegration test, the tablet containing about 90% w/w or mg, whereas Tricor R capsules are provided in strengths of more of the oil-sorption material. In certain situations, it has 67 and 200 mg. The tablets have a higher bioavailability than been found that it is an advantage to incorporate a sorption the capsules. Other trade names are Lipanthyl(R), Lipantil(R) material in the composition in order e.g. to enable a high or Catalip(R). concentration of an oily material. In those cases where the oily material has a melting point of at the most about 250° Lipanthyl Formulation C., it may be especially Suitable to incorporate a sorption 0152 Lipanthyl(R)67M results from a process in which material. Suitable examples of oily materials as well as fenofibrate is co-micronized with a solid surface-active Sorption materials are given herein. component to give an intimate and finely divided mixture of the two ingredients. 0147 In a further specific embodiment, the fibrate is present at least partly in the form of a solid dispersion Equipment including a solid solution. 0.153 Laboratory scale fluid bed equipment: Strea-1. 0148. In a further embodiment, the present invention 0154) The melt feed unit is a prototype composed of relates to a solid pharmaceutical composition in particulate separate units for heating of air Supplies for the atomizer, form or a solid dosage form comprising one or more fibrates pressure tank and feeding tube. Granulate was sieved manu dissolved in one or more oily materials. In this aspect, the ally and mixed with extragranular excipients in a Turbula fibrate is present in the form of a solid solution in the mixer. particulate composition and the presence of a solid Solution can be tested by the DSC test mentioned herein. In this 0.155 Tablet compression was performed on a single aspect, the particulate composition is prepared by dissolving punch press, Diaf TM20. the fibrate in an oily material optionally at elevated tem 0156 Methods perature and (optionally after addition of further active Substances and/or one or more pharmaceutically acceptable 0157 According to the method of the invention, the excipients) the mixture is sprayed on a carrier as described fenofibrate drug was dissolved into the melted vehicle(s) and herein. Preferably, the concentration of the oily material is at applied on the particulate carrier(s) as follows: least about 10% w/w. 0158. The vehicle(s) was melted in a beaker placed in a microwave oven. The beaker was transferred to a tempera Materials and Methods ture controlled heating plate Supplied with magnetic stirring. Materials Fenofibrate was dissolved slowly in the melt at a tempera ture of 75° C. under magnetic stirring. The hot solution was Fenofibrate (supplied by Sigma) transferred to the pressure tank for melt spray application Lactose monohydrate 200 mesh (from DMV) onto the carrier in the fluid bed. The granulate product was discharged from the fluid bed and sieved through sieve 0.7 Granulated silicium oxide, AeroperlR 300, (Degussa) mm or 1.0 mm manually. The sieved product was blended with magnesium stearate for 0.5 min in a Turbula mixer. If Polyethylene glycol 6000, Pluracol R. E6000 (from BASF) an extragranular phase has to be incorporated, the extra granular phase was premixed with the granulate in 3 minutes Poloxamer 188, PluronicR) F-68 (from BASF) in a Turbula mixer. Glyceryl monostearate, Rylo(R, MD50, (from Danisco Cul 0159. The tablet compression was performed on a single tor), Ph.Eur. punch machine Diaf TM20. Avicel PH200 (microcrystalline cellulose) (from FMC) Threshold Test Magnesium Stearate 0.160 The test involves determination of flowability 0149 Tablets, capsules or granules might be enteric according to the method described in Ph.Eur. by measuring coated with different types of polymers such as hydroxypro the flow rate of the material out of a funnel with a nozzle pylmethylcellulose acetate Succinate (Aqoat), cellulose diameter of 10.0 mm. acetate phthalate CAP hydroxypropylmethylcellulose phta 0.161 Viscoleo (medium chain triglycerides MCT; Mig late HPMCP or methacrylic acid copolymers such as lyol 812 N from Condea) was added to 100 g of the solid Eudragit L30D, Eudragit 100/S, Eudragit 100/L. pharmaceutically acceptable material to be tested for use US 2006/01 10444 A1 May 25, 2006 according to the invention and mixed manually. The mixture to be tested. The oil absorption value (expressed as g obtained was sieved through sieve 0.3 mm to assure a viscoleo/100 g material) is reached when a further addition homogenous mixture. The oil was added successively until of 10 g oil results in a material that does not have suitable a flow of 100 g of the mixture could not flow through the properties with respect to flowability, i.e. the material does nozzle. If the material to be tested has a high bulk volume (e.g. like that of Aeroperl 300) only 50 g of the mixture is not meet the meet the requirements when tested according to used when testing these blends. The maximal concentration Ph.Eur. (flowability test; see above under Threshold Test of oil where flow of material could be obtained is called the herein). Threshold Value (given as % w/w). Determination of BET Surface Area Release Test 0169. The apparatus applied was a Micromertics Gemini 0162. A fat-soluble colorant Sudan II (BDH GurR) 2375. The method applied was according to USP volumetric obtained from BDH VWR International 14.3 mg was dis methods based on multiple point determination. solved in 50.0 g viscoleo (fractionated medium chain trig lycerides). Determination of Flowability 0170 The flowability was determined according to the 0163 10 g of the oil was added to 10.0 g of the solid method described in Ph.Eur. measuring the flow rate of the pharmaceutically acceptable material to be tested for use material out of a funnel with a nozzle diameter of 10.0 mm. according to the present invention and mixed until the oil was fully absorbed in the solid material. The mixture was Determination of Weight Variation Subsequently sieved through sieve 0.3 mm to achieve a 0171 The tablets prepared in the Examples herein were homogeneous mixture. Subject to a test for weight variation performed in accor 0164 1.00 g of the mixture was transferred to a centrifu dance with Ph. Eur. gal tube and 3.00 ml of water was added. The suspension Determination of Average Tablet Hardness was mixed in a blood sample turner for 1 hour and subse quently centrifuged for 10 minutes at 5000 rpm. The upper 0.172. The tablets prepared in the Examples herein were phase of oil and water was transferred carefully to a beaker Subject to at test for tablet hardness employing Schleuniger and the water was evaporated in an oven at 80° C. until Model 6D apparatus and performed in accordance with the constant weight. The amount of oil released from the solid general instructions for the apparatus. material was calculated on basis of the weight of the Determination of Solid Solution remaining after evaporation of the water phase. 0173 According to the present invention, the fibrate is Disintegration Test dissolved in a vehicle. In order to substantiate this, a test 0165. The disintegration time was determined according involving differential scanning calometry is performed. to the method described in to Ph. Eur. 0.174 The test is performed on the particulate composi Dissolution Test tion, solid dosage form or mixture of vehicle and fibrate 0166 The test was performed in accordance with Ph. Eur (after the solid solution is supposed to form). Standard DSC 2.9.3 using the paddle apparatus. The quantification was equipment connected to a PC is used. performed using HPLC with UV-detection. Sample size: 10 mg in alu pans Heating rate: 5° C./min from 27° C. to 110° C. Medium: 900 ml water with 0.75% sodium lauryl sulfate Evaluation: The fibrate is considered to be in dissolved state or non (SLS) crystalline if no fibrate endoterm peak is observed and if the Rotation speed: 50 rpm melting interval does not significantly shift compared with Temperature: 37o C. the vehicle alone. Sampling time: 10, 20, 30, 45 and 60 minutes Acceptance criteria: >75% at 45 minutes Determination of Geometric Weight Mean Diameter d. Determination of Bulk Density 0.175. The geometric weight mean diameter was deter 0167 The bulk density was measured by pouring 100 g mined by employment of a method of laser diffraction of the powder in question in a 250 ml graduated cylinder. dispersing the particulate material obtained (or the starting The bulk density is given as the tapped bulk density in g/ml. material) in air. The measurements were performed at 1 bar The determination was performed according to Ph. Eur. dispersive pressure in Sympatec Helos equipment, which (apparent Volume). records the distribution of the equivalent spherical diameter. This distribution is fitted to a log normal volume-size Determination of Oil Absorption Value distribution. 0168 The oil absorption value is determined by adding When used herein, “geometric weight mean diameter' well-defined amounts (a 10 g) of viscoleo to a well-defined means the mean diameter of the log normal volume-size amount of the pharmaceutically acceptable material (100 g) distribution. US 2006/01 10444 A1 May 25, 2006

In Vivo Studies in Beagle Dogs -continued 0176). In vivo studies with the purpose of determining the bioavailability of the compositions of the present invention Substance % ng relative to the bioavailability of the commercially available fenofibrate tablet formulation, i.e. Tricor R, was performed PEG 6OOO 31.80 170.88 using Beagle dogs. Poloxamer 188 13.63 73.24 Magnesium Stearate O.SO 2.69 0177. The experimental work was performed in Denmark using four male Beagle dogs each having a body weight of Total 100.00 53745 12-18 kg (starting weight). The studies were conducted as open, non-randomised, cross-over Studies. Each animal was its own control. Oral doses of fenofibrate was administered Mean disintegration time: 26 min, Hardness: 45 N according to the data below. The dogs were fasted overnight prior to dosing (water ad libitum) and were fed 5 hours after EXAMPLE 2 dosing (water ad libitum). Each dog was dosed with the specified dose offenofibrate without taking the weight of the Immediate Release Tablet with Improved Bioavailability dog into consideration. 0181 10 mm tablets of 50 mg strength (540 mg tablet 0178 Blood samples were collected at vena jugularis with compound cup shaped) and having the following extema at the following points of time: Pre-dose, 1, 1.5, 2. composition were prepared as described in Example 1: 3, 4, 6, 8, 12 and 24 hours after dosing. 4 ml of blood were collected, mixed with EDTA, and the samples were frozen (-80° C.). The blood samples were analyzed using on-line Substance % ng extraction LC/MS and results were given in mg/mL. The Fenofibrate 9.30 SO.OO determined full blood concentration profiles of fenofibrate Lactose 44.78 240.64 were treated using the Pharmacokinetic softwear WinNon PEG 6000 45.43 244.12 lin R), (Pharsight, California; USA) to calculate the pharma Magnesium Stearate O.SO 2.69 cokinetic parameters. All data are dose adjusted, when Total 100.00 53745 necessary. 0179 The following examples serve the purpose of illus tration of the invention and are not intended to limiting the Mean disintegration time: 21 min, Hardness: 55 N Scope of the present invention. Pharmaceutical compositions and dosage forms of the invention are exemplified in EXAMPLE 3 examples 1-7. Results of in vitro dissolution tests of dosage Immediate Release Tablet with Improved Bioavailability forms of the invention are found in example 8. Results of stability tests of dosage forms of the invention are found in 0182 10 mm tablets of 50 mg strength (540 mg tablet example 9. Results of in vivo comparison studies in Beagle with compound cup shaped) and having the following dogs (blood plasma concentration) are found in example composition were prepared as described in Example 1: 10-12.

EXAMPLE 1. Substance % ng Immediate Release Tablet with Improved Bioavailability Fenofibrate 9.30 SO.OO Lactose 44.78 240.64 0180 Fenofibrate was dissolved at a concentration of PEG 4OOO 31.80 170.88 17% in polyethylene glycol 6000 and Poloxamer 188 (70:30 Poloxamer 188 13.63 73.24 w/w ratio) at 75°C. 244 g of the melted solution was sprayed Magnesium Stearate O.SO 2.69 on 200 glactose in a fluid bed Strea-1 at 75°C. The granular Total 100.00 53745 product was sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer. The mixture was compressed into 10 mm tablets with a strength Mean disintegration time: 22 min, Hardness: 48 N of 50 mg (540 mg tablet with compound cup shaped). EXAMPLE 4 Immediate Release Tablet with Improved Bioavailability Substance % ng 0183 Fenofibrate was dissolved in polyethylene glycol Fenofibrate 9.30 SO.OO Lactose 44.78 240.64 4000 in a concentration of 17% at 75° C. 244 g of the melted solution was sprayed on 200 glactose in a fluid bed Strea-1 US 2006/01 10444 A1 May 25, 2006 16 at 75°C. The granular product was sieved through sieve 0.7 mm and blended with magnesium Stearate for 0.5 min in a -continued Turbula mixer. The mixture was compressed into 10 mm Substance % ng tablets of 50 mg strength (540 mg tablet with compound cup SDS 2.23 12.03 shaped). PEG 4OOO 45.43 244.12 Magnesium Stearate O.SO 2.69

Total 100.00 53745 Substance % ng

Fenofibrate 9.30 SO.OO Mean disintegration time: 18 min, Hardness: 65 N Lactose 44.78 240.64 EXAMPLE 6 PEG 4OOO 45.43 244.12 Magnesium Stearate O.SO 2.69 Immediate Release Tablet with Improved Bioavailability 0185. Fenofibrate was dissolved in a concentration of Total 100.00 537.45 30% in polyethylene glycol 4000 and Poloxamer 188 (70:30 w/w ratio) at 75° C. 466 g of the melted solution was sprayed on 200 g Aeroperl300 in a fluid bed Strea-1 at 75° C. The Mean disintegration time: 21 min, Hardness: 55 N granular product was sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer. The mixture was compressed into 13.5 mm tablets of EXAMPLE 5 150 mg strength (720 mg tablet with compound cup shaped). Immediate Release Tablet with Improved Bioavailability

0184 Fenofibrate was dissolved in polyethylene glycol Substance % ng 4000 in a concentration of 17% at 75° C. 244 g of the melted Fenofibrate 20.90 1SO.OO solution was sprayed on 190 glactose in mixture with 10 g Aeroperl300 29.85 214.29 sodium lauryl sulfate (SDS) in a fluid bed Strea-1 at 75° C. PEG 6OOO 34.13 245.00 Poloxamer 188 14.63 1OS.OO The granular product was sieved through sieve 0.7 mm and Mg-Stearat O.SO 3.59 blended with magnesium stearate for 0.5 min in a Turbula mixer. The mixture was compressed into 10 mm tablets of 50 Total 100.00 717.88 mg strength (540 mg tablet with compound cup shaped). Mean disintegration time: 35 min, Hardness: 35 N EXAMPLE 7 Substance % ng Formulations of the Invention Fenofibrate 9.30 SO.OO 0186 Tablets of 50 mg and 160 mg strength, respectively Lactose 42.54 228.61 and having the following compositions were prepared as described in Examples 1, 4 and 6:

A. B C D E Substance Ingredient ng ng ng ng ng

Drug Fenofibrate 160.09 50.05 SO.08 SO.09 159.99 Vehicle 1 PEG6OOO 2O8.12 171.09 12429 PEG4OOO 244.57 GMS (Rylo) 86.15 Vehicle 2 Poloxamer188 89.19 73.33 53.27 Carrier Lactose 356.51 231.87 232.02 163.O1 Aeropearl 300 63.89 Excipients Mg stearate 4.09 2.65 1.47 5.32 8.35 Avice 417. SO

Total Hardness Disintegration Minutes 25 14 30 48 >SS time Diameter Mm Oblong 12 12 10 Oblong US 2006/01 10444 A1 May 25, 2006

EXAMPLE 8 Dissolution Tests Total Degradation Product, % WW, impurity 0187. The inventive tablet formulation A of example 7 was subjected to a dissolution test as described in Methods Months 25° C. and 60% RH 30° C. and 65% RH 40° C. and 75% RH with the following results: O O.OS 1 O.OS O.OS O.OS 3 O.OS O.OS O.OS

Time (min) % dissolved EXAMPLE 10

O O In Vivo Study in Dogs 10 28 0191 An in vivo study of formulation A of example 2O 56 7,160 mg in Beagle dogs, performed as described above 30 74 under Methods, relative to Tricor(R), 160 mg (Batch no.: 45 88 098212E21), gave the following results: 60 97 0.192 Blood concentrations (mg/mL) (average of 4 dogs) after administration of formulation:

EXAMPLE 9 Formulation Stability Tests Time Invention, A 0188 Samples of the inventive tablet formulation A of (hr) Tricor (R) (160 mg) (160 mg) example 7 was stored under the following conditions, O Ila. Ila. O.S 367.5 995.8 respectively, and subjected to a dissolution (stability) test as 1.0 612.5 2209.3 described in Methods after 1 month and 3 months of storage; 1.5 722.0 2627.8 2.O 725.8 2097.3 % dissolved is the percentage offenofibrate dissolved after 3.0 443.8 1219.5 45 minutes: 4.0 295.3 93O.S 6.0 16O.S 642.O 8.0 250.3 869.5 12.0 211.8 615.3 % dissolved 24.0 133.3 394.O 48.0 Ila. 164.5 Months 25° C. and 60% RH 30° C. and 65% RH 40° C. and 75% RH

O 88 1 99 88 90 Relative bioavailability based on AUC (invention, A/Tri 3 90 97 90 corr): 306%. Relative c(invention, A/Tricor R): 356%. 0189 Samples of the inventive tablet formulation A of EXAMPLE 11 example 7 was stored under the following conditions, respectively, and subjected to a fibrate assay with the fol In Vivo Study in Dogs lowing results: 0193 A second in vivo study of formulation A of example 7, 160 mg in Beagle dogs, performed as described above under Methods, relative to Tricor R, 160 mg (Batch no.: 09821 2E21), gave the following results: Ing renofibrate 0194 Blood concentrations (mg/mL) (average of 4 dogs) Months 25° C. and 60% RH 30° C. and 65% RH 40° C. and 75% RH after administration of formulation: O 163.8 1 1619 160.1 160.8 3 162.6 164.9 1644 Formulation Time Invention, A 0190. Samples of the inventive tablet formulation A of (hr) Tricor (R) (160 mg) (160 mg) example 7 was stored under the following conditions, O O O respectively, and Subjected to a degradation product test O.S 339.3 3616.O 1.O 1318.8 3724.8 according to Ph. Eur. (Degradation products A, B, G and 1.5 1313.3 2982.O Unknown accumulated into Total Degradation Product; 2.0 1390.0 2355.8 HPLC method) with the following results: US 2006/01 10444 A1 May 25, 2006

2. The Solid dosage form according to claim 1 in the form -continued of tablets, beads, capsules, grains, pills, granulates, granules, powder, pellets, Sachets or troches. Formulation 3. The Solid dosage form according to claim 1, which is Time Invention, A a tablet. (hr) Tricor (R) (160 mg) (160 mg) 4. The solid dosage form according to claim 1, wherein 3.0 1361.3 1359.5 the fibrate is selected from the group consisting of gemfi 4.0 1019.3 1309.5 brozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate and 6.O 969.3 973.8 active metabolites and analogues thereof. 8.O 667.O 1113.0 12.O 390.3 768.5 5. The solid dosage form according to claim 1, wherein 24.O 183.3 295.0 the fibrate is fenofibrate or an analogue thereof. 48.0 85.0 302.0 6. The Solid dosage form according to claim 1, wherein the vehicle has a melting point of at the most about 250° C. 7. The solid dosage form according to claim 1, wherein Relative bioavailability based on AUC (invention, A/Tri the vehicle is hydrophobic and is selected from the group corr): 198%. consisting of Straight chain Saturated hydrocarbons, paraf Relative c(invention, A/Tricor R): 238%. fins; fats and oils; higher fatty acid; hydrogenated tallow, substituted and/or unsubstituted triglycerides, yellow bees EXAMPLE 12 wax, white beeswax, carnauba wax, castor wax, Japan wax, In Vivo Study in Dogs and mixtures thereof. 8. The solid dosage form according to claim 7, wherein 0.195 An in vivo study of the formulations B, C and D of the vehicle is a water-miscible polar lipid; higher alcohols example 7, 2x50 mg in Beagle dogs, performed as described Such as cetanol, Stearyl alcohol; glyceryl monooleate, Sub above under Methods, relative to Lipanthyl(R67M, 2x67 mg stituted and/or unsubstituted monoglycerides, Substituted (Batch no. 75641), gave the following results: and/or unsubstituted diglycerides, and mixtures thereof. 0.196 Blood concentrations (mg/mL) (average of 4 dogs) 9. The solid dosage form according to claim 1, wherein after administration of formulation: the vehicle is hydrophilic or water-miscible. 10. The solid dosage form according to claim 9, wherein the hydrophilic or water-miscible vehicle is selected from the group consisting of polyethylene glycols, polyoxyethyl Formulation ene oxides, poloxamers, polyoxyethylene Stearates, poly Time Lipanthyl (R) 67M Invention, B Invention, C Invention, D epsilon caprolactone and mixtures thereof. (hr) (2 x 67 mg) (2 x 50 mg) (2 x 50 mg) (2 x 50 mg) 11. The solid dosage form according to claim 9, wherein O O O O O the hydrophilic or water-miscible vehicle is a polyglycolized O.S 1873 2769.5 227.3 546.0 glyceride. 1.O 669.5 3526.8 521.5 1381.5 12. The Solid dosage form according to claim 9, wherein 1.5 96.O.3 3106.3 858.3 161S.S 2.0 895.3 2938.0 989.3 1566.8 the hydrophilic or water-miscible vehicle is selected from 3.0 433.O 246S.S 902.5 1SO3.3 the group consisting of polyvinylpyrrolidones, polyvinyl 4.0 24O.O 1492.3 783.8 1719.0 polyvinylacetate copolymers-(PVP-PVA), polyvinyl alcohol 6.O 77.8 809.5 655.8 1034.5 (PVA). PVP polymers, acrylic polymers, polymethacrylic 8.0 79.3 12O2.8 409.0 1056.0 12.0 291.3 848.0 269.8 597.3 polymers, myristyl alcohol, cellulose derivatives including 24.0 82.5 378.O 163.8 282.8 hydroxypropyl methylcellulose (HPMC), hydroxypropyl 48.0 19.3 18.8 51.5 36.5 cellulose (HPC), methylcellulose, sodium carboxymethyl 72.0 O O O O cellulose, hydroxyethyl cellulose, pectins, cyclodextrins, galactomannans, alginates, carragenates, Xanthan gums and mixtures thereof. Relative bioavailability based on AUC (invention, 13. The solid dosage form according to claim 10, wherein B/Lipanthyl(R67M): 532%. the vehicle is a polyethylene glycol (PEG). Relative c(invention, BA/Lipanthyl(R)67M): 548%. 14. The solid dosage form according to claim 13, wherein Relative bioavailability based on AUC (invention, the polyethylene glycol has an average molecular weight of C/Lipanthyl(R67M): 228%. at least 3000. 15. The solid dosage form according to claim 9 compris Relative c(invention, C/Lipanthyl(R67M): 161%. ing a mixture of two or more hydrophilic or water-miscible Relative bioavailability based on AUC (invention, vehicles. D/Lipanthyl(R67M): 424%. 16. The solid dosage form according to claim 15, wherein the mixture comprises a polyethylene glycol and a poloX Relative c(invention, D/Lipanthyl(R)67M): 329%. amer in a weight proportion of between 1:3 and 10:1, preferably between 1:1 and 5:1, more preferably between and 3:2 4:1, especially between 2:1 and 3:1, in particular 1. A solid oral dosage form comprising a fibrate dissolved about 7:3. in a vehicle, which is hydrophobic, hydrophilic or water 17. The solid dosage form according to claim 16, wherein miscible. the poloxamer is poloxamer 188. US 2006/01 10444 A1 May 25, 2006

18. The solid dosage form according to claim 16, wherein 34. The Solid dosage form according to claim 1, which the polyethylene glycol has an average molecular weight of further comprises a pharmaceutically acceptable additive about 6000. selected from the group consisting of flavoring agents, 19. The solid dosage form according to claim 1, wherein coloring agents, taste-masking agents, pH-adjusting agents, the vehicle is non-aqueous. buffering agents, preservatives, stabilizing agents, anti-oxi 20. The Solid dosage form according to claim 1, wherein dants, wetting agents, humidity-adjusting agents, Surface the concentration of fibrate in the vehicle is at least 10% active agents, Suspending agents and absorption enhancing w/w, based on the total weight of the fibrate and the vehicle. agents. 21. The Solid dosage form according to claim 1, wherein 35. The solid dosage form according to claim 1, which the concentration of fibrate in the vehicle is at least 15% further comprises at a pharmaceutically acceptable oil wfw, or at least 16% w/w, or at least 17% w/w, or at least Sorption material. 20% w/w, preferably at least 25% w/w, more preferably at 36. The solid dosage form according to claim 1, which is least 30% w/w, especially at least 35% w/w, based on the a unit dosage form. total weight of the fibrate and the vehicle. 37. The solid dosage form according to claim 1, wherein 22. The Solid dosage form according to claim 1, wherein the individual units of the solid dosage form are coated with the concentration of fibrate in the vehicle is at the most 90% a coating selected from the group consisting offilm coatings, w/w, based on the total weight of the fibrate and the vehicle. modified release coatings, enteric coatings, protective coat 23. The Solid dosage form according to claim 1, wherein ings and anti-adhesive coatings. the concentration of fibrate in the vehicle is at the most 80% 38. The solid dosage form according to claim 1, wherein wfw, or at the most 75% w/w, or at the most 70% w/w, or at the fibrate is embedded in a matrix that releases the fibrate the most 60% w/w, preferably at the most 50% w/w, more by diffusion. preferably at the most 40% w/w, especially at the most 35% 39. The solid dosage form according to claim 38, wherein w/w, based on the total weight of the fibrate and the vehicle. the matrix remains substantially intact during the period of 24. The Solid dosage form according to claim 1, wherein drug release. at least 90% w/w of the fenofibrate is dissolved in the 40. The Solid dosage form according to claim 1, wherein vehicle. the fibrate is embedded in a matrix that releases the fibrate 25. The solid dosage form according to claim 1, wherein by eroding. at least 93% w/w, or at least 95% w/w, or at least 97% w/w, 41. The Solid dosage form according to claim 1, wherein or at least 98% w/w, or at least 99% w/w, or at least 99.5% the fibrate is released from the dosage form by diffusion wfw, or at least 99.9% w/w, of the fenofibrate is dissolved in through a Substantially water-insoluble coating. the vehicle. 42. The Solid dosage form according to claim 1, which 26. The Solid dosage form according to claim 1, wherein results in an increased bioavailability of fibrate relative to at least 75% of the fibrate is released within about 45 min existing commercial fibrate dosage forms when adminis when tested in an in vitro dissolution test according to Ph. tered to a mammal in need thereof. Eur. dissolution test (paddle) employing water with 0.75% 43. The Solid dosage form according to claim 42, which Sodium lauryl Sulfate as dissolution medium, 50 rpm and a provides an AUC value relative to that of commercially temperature of about 37° C. available Tricor R tablets of at least about 1.1, or at least 27. The solid dosage form according to claim 26, wherein about 1.2, or at least about 1.3, or at least about 1.4, or at the dissolution test is carried out after 3 months of storage least about 1.5, or at least about 1.75 or more, or at least at a temperature of about 40° C. and a relative humidity of about 2.0, or at least about 2.5, or at least about 3.0, the AUC about 75%. values being determined under similar conditions. 28. The solid dosage form according to claim 1 which 44. The Solid dosage form according to claim 42, which further comprises one or more pharmaceutically acceptable provides a c, value relative to that of commercially excipients. available Tricor R tablets of at least about 1.1, or at least 29. The solid dosage form according to claim 28, wherein about 1.2, or at least about 1.3, or at least about 1.4, or at the pharmaceutically acceptable excipients are selected from least about 1.5, or at least about 1.6 or more, or at least about the group consisting of fillers, diluents, disintegrants, bind 2.0, or at least about 2.5, or at least about 3.0, the c values ers, glidants and lubricants. being determined under similar conditions. 30. The solid dosage form according to claim 28, wherein 45. The Solid dosage form according to claim 1, wherein at least one pharmaceutically acceptable excipient is a silica the fibrate is stable. acid or a derivative or salt thereof. 46. The solid dosage form according to claim 45, wherein 31. The solid dosage form according to claim 28, wherein the fibrate is present in an amount of at least 90%, or at least at least one pharmaceutically acceptable excipient is a silica 95%, or at least 100%, relative to the amount prior to acid or a derivative or salt thereof selected from the group storage, when assayed after 3 months of storage at a tem consisting of silicates, silicon dioxide and polymers thereof, perature of about 40° C. and a relative humidity of about magnesium aluminosilicase, magnesium aluminometasili 75%. cate, bentonite, kaolin, magnesium trisilicate, montmorillo 47. A composition comprising a fibrate dissolved in a nite and/or Saponite. vehicle, which is hydrophobic, hydrophilic or water-mis 32. The solid dosage form according to claim 28, wherein cible. at least one pharmaceutically acceptable excipient is silicon 48. The composition according to claim 47, wherein the dioxide or a polymer thereof. vehicle has a melting point of at the most about 250° C. 33. The solid dosage form according to claim 28, wherein 49. The composition according to claim 47, wherein the the silicon dioxide product has properties corresponding to vehicle is selected from the group consisting of straight AeroperlR 300. chain Saturated hydrocarbons, Sorbitan esters, paraffins; fats US 2006/01 10444 A1 May 25, 2006 20 and oils such as cacao butter, beef tallow, lard, polyether about 1.5, or at least about 1.75 or more, or at least about 2.0, glycol esters; higher fatty acid such as Stearic acid, myristic or at least about 2.5, or at least about 3.0, the AUC values acid, palmitic acid, higher alcohols such as cetanol, Stearyl being determined under similar conditions. alcohol; low melting point waxes such as glyceryl 56. The composition according to claim 47, which pro monostearate, glyceryl monooleate, hydrogenated tallow, vides a c, value relative to that of commercially available myristyl alcohol, Stearyl alcohol, Substituted and/or unsub Tricor R tablets of at least about 1.1, or at least about 1.2, or stituted monoglycerides, Substituted and/or unsubstituted at least about 1.3, or at least about 1.4, or at least about 1.5, diglycerides, Substituted and/or unsubstituted triglycerides, or at least about 1.6 or more, or at least about 2.0, or at least yellow beeswax, white beeswax, carnauba wax, castor wax, about 2.5, or at least about 3.0, the c values being japan wax, acetylate monoglycerides; PVP polymers, acrylic determined under similar conditions. polymers; polyethylene glycols, polyoxyethylene oxides, 57. The composition according to claim 47 in the form of poloxamers, polyoxyethylene Stearates, poly-epsilon capro particles, i.e. in particulate form. lactone, polyglycolized glycerides such as Gelucire R, poly 58. The composition according to claim 47, which exhib vinylpyrrolidones, polyvinyl-polyvinylacetate copolymers its a suitable flowability when determined according to the (PVP-PVA), polyvinyl alcohol (PVA), polymethacrylic method described in Ph.Eur., measuring the flow rate of the polymers (Eudragit RS: Eudragit RL, Eudragit NE, Eudragit composition out of a funnel with a nozzle diameter of 10.0 E), cellulose derivatives including hydroxypropyl methyl . cellulose (HPMC), hydroxypropyl cellulose (HPC), meth 59. A solid composition in particulate form comprising a ylcellulose, sodium carboxymethylcellulose, hydroxyethyl fibrate, a hydrophobic or a hydrophilic or water-miscible cellulose, pectins, cyclodextrins, galactomannans, alginates, vehicle and an oil-sorption material, which composition carragenates, Xanthan gums, and mixtures thereof. exhibits an oil threshold value of at least 10%, and which 50. The composition according to claim 47, wherein the composition further fulfills one or both of i) and ii): mixture comprises a polyethylene glycol and a poloxamer in a weight proportion of between 1:3 and 10:1, preferably i) the composition releases at least 30% of the hydropho between 1:1 and 5:1, more preferably between and 3:24:1, bic or a hydrophilic or water-miscible vehicle: especially between 2:1 and 3:1, in particular about 7:3. ii) the composition, in the form of a tablet, contains at 51. The composition according to claim 47, wherein the least about 90% w/w of the oil-sorption material, and concentration of fibrate in the vehicle is at least 10% w/w, exhibits a disintegration time of at the most 60 minutes. or at least 15% w/w, or at least 16% w/w, or at least 17% 60. A method of manufacturing the solid oral dosage form w/w, or at least 20% w/w, preferably at least 25% w/w, more of claim 1 comprising the steps of: preferably at least 30% w/w, especially at least 35% w/w, based on the total weight of the fibrate and the vehicle. i) Bringing the vehicle in liquid form, if applicable, 52. The composition according to claim 47, wherein at ii) Maintaining the liquid vehicle at a temperature below least 90% w/w, or at least 93% w/w, or at least 95% w/w, or the melting point of the fibrate, at least 97% w/w, or at least 98% w/w, or at least 99% w/w, of the fenofibrate is dissolved in the vehicle. iii) Dissolving the desired amount of fibrate in the vehicle, 53. The composition according to claim 47, which further iv) Spraying the resulting solution onto a solid carrier comprises one or more pharmaceutically acceptable excipi having a temperature below the melting point of the ents selected from the group consisting of fillers, diluents, vehicle, disintegrants, binders, glidants and lubricants. 54. The composition according to claim 47, which further V) Mechanically working the resulting composition to comprises at a pharmaceutically acceptable oil-sorption obtain particles, i.e. a particulate material, and material. vi) Optionally Subjecting the particulate material to con 55. The composition according to claim 47, which pro ventional methods for preparing Solid dosage forms. vides an AUC value relative to that of commercially avail 61-62. (canceled) able Tricor R tablets of at least about 1.1, or at least about 1.2, or at least about 1.3, or at least about 1.4, or at least