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Current Trends in Biotechnology and PharmacyVol. 5 (2) 1110-1122 April 2011. ISSN 0973-8916 (Print), 2230-7303 (Online)1111blocking agent and widely used in the treatmentof mild to moderate hypertension and anginapectoris. It has antioxidant and anti proliferativeproperties which makes it suitable to combat thedeleterious effects of sympathetic nervous systemactivation in heart failure. It undergoes extensivefirst pass metabolism and its systemic bioavailability is only 25 to 35% (7). As perBiopharmaceutical classification it belongs toclass II compound and therefore it is insoluble inaqueous medium (8). Certain strategies such asfast dissolving tablets (9), muco adhesive drugdelivery systems (10), self emulsifying drugdelivery systems (11) and other controlled releasesystems (12, 13) were reported to improve theaqueous solubility, to overcome first passmetabolism and thereby increase the systemicbioavailability. But these technologies requireunique production processes and also have certaindisadvantages like limited formulation flexibilityand complexity in manufacturing, high productioncosts, low stability, low drug loading and fewchoices of dosage forms.The objectives of present study are toinvestigate the feasibility of development of o/wNEs loaded with carvedilol using sesame oil orolive oil by high energy homogenization technique,to study the effect of oil phase volume on thedrug loading efficiency, particle size and zetapotential, to study the effect of concentration andtype of surfactants on the globule size, zetapotential and in-vitro drug release characteristicsand to carry out the comparative pharmacokineticstudy of optimized nano emulsion with marketedtablet dosage-form in rats.Materials and MethodsMaterials: Carvedilol was a gift sample fromOrchid Pharmaceuticals, India. Brij-97, Tween-80, dialysis tubing cellulose membrane (size: 43mm × 27 mm) were purchased from SigmaAldrich, USA. Sesame oil was purchased fromThiagarajan Agro Products Pvt Ltd., Chennai,India. Olive oil was purchased from Figaro, SriRoda Foods Pvt Ltd., New Delhi India. All otherchemicals, water and solvents are of HPLCgrade and purchased from S.D. Fine Chemicals,India.Preparation of carvedilol nano emulsion :Various Carvedilol NEs were prepared by usinghigh energy emulsification technique. Prior toemulsification the oil phase and aqueous phasewere prepared separately.A specified quantity of oil was taken in abeaker and 6.3 mg of drug was added and thetotal weight of the oil phase was determined. Tothis 200 µl of chloroform was added to dissolvethe drug in oil. Then nitrogen gas was purged toevaporate the chloroform. This was confirmedby reweighing oil phase.Aqueous phase was prepared by dissolvingthe non-ionic surfactant in HPLC grade waterpH- 6.8±0.2. A volume of this surfactant solutionwas added and a coarse emulsion was preparedby using a high shear stirrer (RQ-127A, RemiMotors, India) for 25 min at 6000 rpm. Then thecoarse emulsion was subjected to high energyemulsification using a probe sonicator (BandelinSonoplus, Heinrichstrab 3-4 D-12207, Berlin,Germany) in a continuous mode at 37 to 40 HZ.NEs were prepared using 100 µl of sesameoil and non-ionic surfactants Brij-97 or tween-80.Then various formulation parameters such asoil phase volume (100, 150 and 200 µl) andconcentration of each surfactant (1.25, 1.5 and1.75) were optimized for particle size, zetapotential and drug loading efficiency. Theprocedure was repeated for the preparation andoptimization of carvedilol loaded olive oilnanoemulsions.Koteswari Poluri et al
Current Trends in Biotechnology and PharmacyVol. 5 (2) 1110-1122 April 2011. ISSN 0973-8916 (Print), 2230-7303 (Online)1112Preparation of Carvedilol tablet suspension :The various pharmaco kinetic parameters ofcarvedilol NE formulation were compared withcarvedilol extended release oral tablet (Cardivas,Sun Pharma, India) suspension in order to comparethe oral bioavailability of carvedilol by NEformulation with tablet suspension. One tabletcontaining 10mg of carvedilol was taken andcrushed into powder in a mortar and pestle. Tothis 19.2 ml of 1 % tween-80 solution was addedand triturated to prepare a fine suspension withstrength of about 0.52mg/ml.Characterization of NanoemulsionsMeasurement of particle size and zetapotential: The average particle size, polydispersity index (PDI), and Zeta potential weremeasured by photon correlation spectroscopy(PCI) using a Malvern zeta sizer (Nano ZSMalvern Instruments Ltd., UK). The PDIrepresents the uniformity of the globule size andsize distribution of the NE. The preparedformulations were diluted with HPLC gradewater pH-6.8±0.2.The diluted NEs were kept inthe cuvette with an attached dip cell. The cuvettewas placed inside the instrument and theobservations were recorded at 90° light scatteringangle and temperature was maintained at 25 °C.During the measurement, average particle countrate was maintained between 50 to 500kcps. Thezeta potential was also measured by using thesame instrument with inbuilt software based onthe electrophoretic mobility of globules and theHelmholtz-Smoluchowski equation (14, 15, and16).Helmholtz-Smoluchowski equation (Zetapotential (Zp) = 6πυη/εχ) Where Zp is in volts,υ = migration velocity cm/sec, η = viscosity ofthe medium in poise, ε = dielectric constant ofthe external medium, and χ = potential gradientin volts. Average size, poly dispersity index (PDI)and zeta potential were measured for all samplesusing particle sizer Nano ZS (MalvernInstruments, UK).HPLC analysis: A simple HPLC method wasdeveloped in the laboratory with a PhenomenexP/N0-00G-4274-EO C-18, Luna 5µ , Size columnon liquid chromatograph (Shimadzu-10ATVP) anda UV/visible detector (SPD-10ATVP).The mobilephase was Acetonitrile:0.01M phsosphatebuffer(pH-5.2±0.02) in the ratio of 69:31, at aflow rate of 1ml/min and the effluent wasmonitored at 242nm.Solubility studies: Solubility studies of carvedilolwere carried out in water, phosphate buffer salinepH 7.4 and Phosphate buffer saline containing1% tween 80 in order to select the diffusionmedium to perform in-vitro release studies. Avolume of water or phosphate buffer saline pH7.4 or Phosphate buffer saline containing 1%tween 80 was taken in to a conical flask. Excessquantity of carvedilol was added and shaken for2 hrs on a mechanical shaker and kept aside forovernight. Then the solution was centrifuged. Thesupernatant liquid was taken, filtered, sonicatedand appropriate dilutions were made and 20µlquantities were injected into HPLC.Determination of carvedilol content in theformulations: A volume of formulation was takenfrom the bulk and made up to 5ml with methanol.From this appropriate dilutions were made withphosphate buffer saline pH 7.4. Then filtered,degassed and 20 µl was injected in to HPLC.The analysis was carried out by the abovedescribed HPLC method. The total drug contentwas calculated from the calibration curve y =83.106+0.9715(R 2 = 0.9993).In vitro drug release studies: The in vitro drugrelease studies of carvedilol were carried outusing dialysis bag diffusion technique (43mm x27mm size, mol. wt. cutoff 12000 or greater,Sigma-Aldrich, USA). The bag containing 2ml ofFormulation, characterization and Pharmacokinetic studies
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(December 7-9, 2011)Venue: Karunya
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