Novel fenofibric acid-loaded controlled release pellet bioequivalent to choline fenofibrate-loaded commercial product in beagle dogs.

The objective of this study was to develop a novel fenofibric acid-loaded controlled release pellet showing enhanced, or equivalent to, bioavailability compared with two commercially available products containing fenofibrate or choline fenofibrate. The effect of solubilizing agents on drug solubility and the impact of fillers on core properties were investigated. Among them, magnesium carbonate most improved drug solubility, and κ-carrageenan provided the best spherical cores. The fenofibric acid-loaded pellet was prepared with magnesium carbonate and κ-carrageenan employing the extrusion/spheronizing technique followed by coating with ethylcellulose. Furthermore, dissolution and pharmacokinetic study in beagle dogs were performed compared to the fenofibrate-loaded commercial tablet (FCT) and choline fenofibrate-loaded commercial mini-tablet (CFCM). This fenofibric acid-loaded pellet showed controlled release of the drug in phosphate buffer (pH 6.8) and 0.025 M sodium laurylsulfate within 4h. Furthermore, this pellet and CFCM exhibited similar dissolution profiles. Plasma concentrations greater than 1,000 ng/ml were maintained from 30 min to 8h, suggesting a sustained release pattern. Also, the fenofibric acid-loaded pellet gave significantly higher AUC and Cmax values than FCT, indicating that it improved the bioavailability of fenofibrate due to enhanced solubility and sustained release. In addition, this pellet and CFCM were not significantly different in terms of pharmacokinetic parameters including AUC, Cmax and Tmax. Thus, this pellet was bioequivalent to CFCM in beagle dogs. In conclusion, this fenofibric acid-loaded controlled release pellet would be a potential alternative to the choline fenofibrate-loaded commercial product.

[1]  R. Rosenson.  Fenofibrate: treatment of hyperlipidemia and beyond , 2008, Expert review of cardiovascular therapy.

[2]  K. Pintye-Hódi,et al.  Study of the influence of alkalizing components on matrix pellets prepared by extrusion/spheronization , 2012, Pharmaceutical development and technology.

[3]  P. Alagona.  Fenofibric acid: a new fibrate approved for use in combination with statin for the treatment of mixed dyslipidemia , 2010, Vascular health and risk management.

[4]  J. Idle,et al.  Fenofibrate Metabolism in the Cynomolgus Monkey using Ultraperformance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based Metabolomics , 2009, Drug Metabolism and Disposition.

[5]  M. Minaiyan,et al.  Preparation and evaluation of a controlled drug release of repaglinide through matrix pellets: in vitro and in vivo studies , 2014, Journal of microencapsulation.

[6]  R. Simó,et al.  Prevention and treatment of diabetic retinopathy: evidence from large, randomized trials. The emerging role of fenofibrate. , 2012, Reviews on recent clinical trials.

[7]  D. McTavish,et al.  Fenofibrate , 2012, Drugs.

[8]  P. Kleinebudde.  Use of a power-consumption-controlled extruder in the development of pellet formulations. , 1995, Journal of pharmaceutical sciences.

[9]  A Ward,et al.  Pentoxifylline , 1987, Drugs.

[10]  S. Daskalopoulou,et al.  Fenofibrate: metabolic and pleiotropic effects. , 2005, Current vascular pharmacology.

[11]  P. Kleinebudde,et al.  Preparing of pellets by extrusion/spheronization using different types of equipment and process conditions , 2014, Drug development and industrial pharmacy.

[12]  G. Malhotra,et al.  Comparison of pharmacokinetics of two fenofibrate tablet formulations in healthy human subjects. , 2014, Clinical therapeutics.

[13]  R. R. Panda,et al.  Hot melt granulation: a facile approach for monolithic osmotic release tablets , 2012, Drug development and industrial pharmacy.

[14]  Baojian Wu,et al.  Effects of PEGylated lipid nanoparticles on the oral absorption of one BCS II drug: a mechanistic investigation , 2014, International journal of nanomedicine.

[15]  Han‐Gon Choi,et al.  Development of novel bepotastine salicylate salt bioequivalent to the commercial bepotastine besilate in beagle dogs , 2013, Drug development and industrial pharmacy.

[16]  A. Nokhodchi,et al.  Preparation and characterization and release properties of Eudragit RS based ibuprofen pellets prepared by extrusion spheronization: effect of binder type and concentration , 2013, Drug development and industrial pharmacy.

[17]  A Review of Currently Available Fenofibrate and Fenofibric Acid Formulations , 2013 .

[18]  Han‐Gon Choi,et al.  Development of novel sibutramine base-loaded solid dispersion with gelatin and HPMC: physicochemical characterization and pharmacokinetics in beagle dogs. , 2010, International journal of pharmaceutics.

[19]  W. Brown.  Treatment of hypercholesterolaemia with fenofibrate: a review. , 1989, Current medical research and opinion.

[20]  Sunil B Jaiswal,et al.  A flexible technology for modified-release drugs: multiple-unit pellet system (MUPS). , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[21]  Jm Newton,et al.  Comparative gastrointestinal transit of pellet systems of varying density , 1995 .

[22]  M. Thommes,et al.  Multiple batch manufacturing of theophylline pellets using the wet-extrusion/spheronization process with κ-carrageenan as pelletisation aid , 2013, Pharmaceutical development and technology.

[23]  M. Elisaf,et al.  Fenofibrate plus simvastatin (fixed-dose combination) for the treatment of dyslipidaemia , 2011, Expert opinion on pharmacotherapy.

[24]  P. Kleinebudde,et al.  Influence of the Granulation Step on Pellets Prepared by Extrusion/Spheronization , 1999 .

[25]  Dong-Jin Kim,et al.  Comparison of Release-Controlling Efficiency of Polymeric Coating Materials Using Matrix-type Casted Films and Diffusion-Controlled Coated Tablet , 2010, AAPS PharmSciTech.

[26]  C. Ballantyne,et al.  Study Design, Rationale, and Baseline Characteristics: Evaluation of Fenofibric Acid on Carotid Intima-Media Thickness in Patients with Type IIb Dyslipidemia with Residual Risk in Addition to Atorvastatin Therapy (FIRST) Trial , 2012, Cardiovascular Drugs and Therapy.

[27]  J. Ansquer,et al.  Comparison of the Gastrointestinal Absorption and Bioavailability of Fenofibrate and Fenofibric Acid in Humans , 2010, Journal of clinical pharmacology.

[28]  D. Bhavesh,et al.  Determination of fenofibric acid in human plasma by ultra performance liquid chromatography-electrospray ionization mass spectrometry: application to a bioequivalence study. , 2009, Biomedical chromatography : BMC.

[29]  P. Kleinebudde,et al.  Preliminary assessment of carrageenan as excipient for extrusion/spheronisation. , 2005, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[30]  Clive G. Wilson,et al.  Statistical investigation of simulated intestinal fluid composition on the equilibrium solubility of biopharmaceutics classification system class II drugs. , 2015, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[31]  A. Keech,et al.  An Update on the Molecular Actions of Fenofibrate and Its Clinical Effects on Diabetic Retinopathy and Other Microvascular End Points in Patients With Diabetes , 2013, Diabetes.

[32]  P. Kleinebudde,et al.  Use of kappa-carrageenan as alternative pelletisation aid to microcrystalline cellulose in extrusion/spheronisation. I. Influence of type and fraction of filler. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[33]  In-kyu Lee,et al.  Fenofibrate differentially regulates plasminogen activator inhibitor‐1 gene expression via adenosine monophosphate–activated protein kinase–dependent induction of orphan nuclear receptor small heterodimer partner , 2009, Hepatology.

[34]  Neeraj Kumar,et al.  Dual coating of swellable and rupturable polymers on glipizide loaded MCC pellets for pulsatile delivery: formulation design and in vitro evaluation. , 2011, International journal of pharmaceutics.

[35]  G Vergnault,et al.  Pharmacokinetic evaluation of oral fenofibrate nanosuspensions and SLN in comparison to conventional suspensions of micronized drug. , 2007, Advanced drug delivery reviews.

[36]  A. Basit,et al.  Oral modified-release formulations in motion: the relationship between gastrointestinal transit and drug absorption. , 2010, International journal of pharmaceutics.

[37]  M. Thommes,et al.  Systematic evaluations regarding interparticular mass transfer in spheronization. , 2012, International journal of pharmaceutics.

[38]  G. Steiner.  Fenofibrate for cardiovascular disease prevention in metabolic syndrome and type 2 diabetes mellitus. , 2008, The American journal of cardiology.

[39]  G. Keating,et al.  Fenofibrate , 2012, Drugs.

[40]  P. Mitchell,et al.  Fenofibrate - a potential systemic treatment for diabetic retinopathy? , 2012, American journal of ophthalmology.

[41]  P. Dodson,et al.  Medical management of diabetic retinopathy: fenofibrate and ACCORD Eye studies , 2011, Eye.

[42]  M. Thommes,et al.  New Insights into the Pelletization Mechanism by Extrusion/Spheronization , 2010, AAPS PharmSciTech.

[43]  C. Liew,et al.  Importance of Wet Packability of Component Particles in Pellet Formation , 2013, AAPS PharmSciTech.

[44]  L. Delattre,et al.  A new enteric tablet of acetylsalicylic acid. II. Biopharmaceutical aspects , 1987 .

[45]  C. A. Kingsmill,et al.  The development and stability assessment of extemporaneous pediatric formulations of Accupril. , 2005, International journal of pharmaceutics.

[46]  Han‐Gon Choi,et al.  Development of a novel combination tablet containing trimebutine maleate and mosapride citrate for the treatment of functional dyspepsia. , 2010, International journal of pharmaceutics.

[47]  M. Bogataj,et al.  Gastric emptying of non-disintegrating solid drug delivery systems in fasted state: relevance to drug dissolution , 2010, Expert opinion on drug delivery.