Nanosuspension for enhancement of oral bioavailabi

Authors: Bhanu P Sahu Malay K Das

Publish Date: 2013/01/11

Volume: 4, Issue: 2, Pages: 189-197

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Abstract

The oral bioavailability of poorly water soluble drug can be improved using nanosuspension Nanosuspensions are fine dispersion of uniformsized solid particles in an aqueous vehicle The present work is aimed at the formulation and evaluation of nanosuspension of felodipine a poorly water soluble antihypertensive drug The nanosuspension of felodipine may increase the dissolution rate of drug to improve its oral bioavailability The nanosuspensions were prepared by nanoprecipitation alone and in combination with ultrasonnication method using ethanol as solvent and water as antisolvent The prepared nanosuspensions were characterised for particle size zeta potential polydispersity index Scanning electron microscopy SEM Differential scanning calorimetry DSC Xray diffraction XRD pattern and release behaviour The effect of variable concentration of drug and stabiliser ultrasonnication and solvent to antisolvent ratio on the physical morphological and dissolution properties of felodipine were studied The average particle size of felodipine nanoparticles was found to be in the range of 60–330 nm It was further confirmed by SEM photograph The particle size varies with increase in concentration of drug and stabiliser The preparations showed negative zeta potential and polydispersity index in the range of 03–08 DSC and XRD studies indicated that the crystallinity of precipitated felodipine nanoparticles was markedly lowered than the pure drug The dissolution of prepared felodipine nanoparticles markedly increased as compared to the original drug The dissolution profiles of nanosuspension formulation showed up to 7967  release in 4 h It may be concluded that the nanoprecipitation with ultrasonnication have potential to formulate homogenous nanosuspensions with uniformsized stable nanoparticles of felodipine The prepared nanosuspension showed enhanced dissolution which may lead to enhanced oral bioavailability of felodipineThe enhancement of the bioavailability of poorly water soluble drugs is one of the main targets of drug development during the last decades Several techniques have been developed concerning the optimization of the dissolution rate of these drugs Such methods include particle size reduction solubilization salt formation and preparation of solid dispersion systems Nevertheless there are several disadvantages and limitations in the use of these techniques Specifically the particle size reduction technique is practically limited regarding the minimum size which could be achieved while the production of very fine powders deteriorates their flow properties and wettability while it advances the development of electrostatic forces leading to problematic formulations The solubilization techniques correspond to liquid preparations which usually do not assure the patient’s acceptability and normally appear to have poor stability Salt formation is a complicated process while it is not feasible for neutral compounds In addition the dissolution enhancement is not always predictable due to the high correlation of the salt’s solubility with the pH value which appears to be a high variability in the gastrointestinal tract Kakrana et al 2010In fact for biopharmaceutic class II drugs the bioabsorption process is ratelimited by dissolution in gastrointestinal fluids According to the Noyes–Whitney equation the dissolution rate of poorly watersoluble drugs could be increased by reducing the particle size to the micro or nanoscale thus increasing the interfacial surface area Müller and Peters 1998 Douroumis and Fahr 2006 The conventional approaches to produce untrafine drug particles can be divided into topdown and bottomup techniques Keck and Müller 2006 Rabinow 2004 In the case of topdown techniques which include jetmilling pear/ball milling and high pressure homogenising the bulk drugs are comminuted into micro or nanosized range using mechanical force Rasenack et al 2004 However these techniques need high energy input and exhibit some disadvantages in practice such as contamination of drugs variation of crystal structures uncontrolled particle morphology and broad particle size distribution Keck and Müller 2006 Kharb et al 2006 In the last decade bottomup techniques that rely on dissolving the drug in a solvent and precipitating it by the addition of a nonsolvent like supercritical fluid SCF technique and liquid precipitation have been widely investigated to obtain ultrafine drug particles such as cephradine Zhong et al 2005 cefuroxime axetil Zhang et al 2006 danazol Rogers et al 2002 Zhao et al 2007 ibuprofen Rasenack et al 2004 etcThe nanoprecipitation technique or solvent displacement method for nanoparticle manufacture was first developed and patented by Fessi and coworkers Fessi et al 1988 1992 This technique presents numerous advantages in that it is a straight forward technique rapid and easy to perform The nanoparticle formation is instantaneous and the entire procedure is carried out in only one step Briefly it requires two solvents that are miscible Ideally both the polymer and the drug must dissolve in the first one the solvent but not in the second system the nonsolvent Nanoprecipitation occurs by a rapid desolvation of the polymer when the polymer solution is added to the nonsolvent Indeed as soon as the polymercontaining solvent has diffused into the dispersing medium the polymer precipitates involving immediate drug entrapment The rapid nanoparticle formation is governed by the socalled Marangoni effect which is due to interfacial turbulences that take place at the interface of the solvent and the nonsolvent and result from complex and cumulated phenomena such as flow diffusion and surface tension variations QuintanarGuerrero et al 1998 Nanoprecipitation often enables the production of small nanoparticles 100–300 nm with narrow unimodal distribution This technique is mostly suitable for compounds having a hydrophobic nature such as indomethacin which is soluble in ethanol or acetone but has very limited solubility in water Consequently reduced or even zero drug leakage toward the outer medium led to nanoparticles with entrapment efficiency values reaching 100  Fessi et al 1988 Barichello et al 1999Felodipine is a dihydropyridine calcium antagonist widely used as a potent antihypertensive drug Saltiel et al 1988 However the oral bioavailability of felodipine extensively metabolised in the gut and the liver and is excreted almost entirely as metabolites About 70  of each dose is excreted in the urine the remainder appears in the faeces Dunselman and Edgar 1991 Edgar et al 1987 Felodipine is a compound with a strong lipophilic character whilst it appears as a crystalline powder practically insoluble in aqueous solutions solubility 05 mg/l Karavas et al 2005 Abrahamsson et al 1994 On the contrary Felodipine is rapidly absorbed by the gastrointestinal tract after dissolution However even though it is highly permeable through biological membranes Diez et al 1991 the physicochemical characteristics of felodipine indicate that its dissolution profile is the limiting factor of its bioavailability Wingstrand et al 1990 In order to increase its dissolution rate several attempts were carried out in the past Kerc et al 1991 Kim et al 2005 Lee et al 2003 Other methods of solubility enhancement like solid dispersions have also been explored for enhancement of solubility of felodipine DongHan et al 2005The aim of this study is to investigate the possibility of producing a nanosuspension of felodipine by controlled precipitation using ultrasonnication technique to enhance the dissolution and thereby oral bioavailability of the drug The impact of experimental parameters for particle formation including solvent–antisolvent flow rate drug concentrations type and concentration of stabiliser and stirring time was studied Characterization and physical stability of the obtained nanosuspension were also carried outFelodipine nanoparticles were produced by precipitation–ultrasonnication technique The required amount of drug was completely dissolved in watermiscible solvent Different concentrations of drug in solvent 20 40 60 80 100 mg/ml were used The obtained drug solution was then injected into the water containing the stabiliser under stirring at 1000 rpm Precipitation of solid drug particles occurred immediately upon mixing The suspension was then ultrasonicated for 15 min under cold conditionThe particle size and the polydispersity Index PI of the formed drug particles was measured immediately after precipitation by dynamic laser light scattering Zetasizer Ver 611 Malvern The measurement was done in triplicate and size ZAverage dnm and the polydispersity Index PI was reported Yuancai et al 2010 The zeta potential of the preparations was also measured using Zetasizer Malvern

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