(12) Patent Application Publication (10) Pub. No.: US 2006/0110444 A1 Holm Et Al
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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