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Ondansetron Transdermal


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Ondansetron Transdermal

  1. 1. Research J. Pharm. and Tech. 4(5): May 2011ISSN 0974-3618 www.rjptonline.orgRESEARCH ARTICLEFormulation and Evaluation of Matrix-Type Transdermal Delivery System of Ondansetron Hydrochloride Using Solvent Casting Technique Farsiya Fathima1, Vijaya Kumar B1*, Shashi Ravi Suman Rudrangi2, Satish Kumar Vemula1, Prasad Garrepally1, Swathi Chilukula1 and Samatha Rudrangi3 1 Department of Pharmaceutics, Jangaon Institute of Pharmaceutical Sciences, Kakatiya University, Yeshwanthapur, Jangaon-506167, Andhra Pradesh, India2 Department of Pharmaceutical Sciences, School of Science, University of Greenwich, Chatham Maritime, Kent, United Kingdom ME4 4TB3 Department of Pharmaceutics, Talla Padmavathi College of Pharmacy, Kakatiya University, Urus, Kareemabad- 506002, Andhra Pradesh, India *Corresponding Author E-mail: suman_rudrangijips@yahoo.comABSTRACT:The purpose of this research was to develop a matrix-type Transdermal therapeutic system containing drugOndansetron hydrochloride (OSH) with different ratios of hydrophilic and hydrophobic polymeric systems by thesolvent evaporation technique by using 25 % w/w of di-butyl phthalate to the polymer weight, incorporated asplasticizer. 5% menthol was used to enhance the Transdermal permeation of OSH. Formulated transdermal patcheswere physically evaluated with regard to thickness, weight variation, drug content, flatness, folding endurance,percentage of moisture content and water vapour transmission rate. All prepared formulations indicated good physicalstability. Ex vivo permeation studies of formulations were performed by using Franz diffusion cells. Formulationprepared with combination of hydrophilic polymers containing permeation enhancer showed best ex vivo skinpermeation through rat skin (Wistar albino rat) as compared to all other formulations. The release profile of OSHfollowed zero-order kinetics in all formulations. However, the release profile of the optimized formulation F17 (r2 =0.999 for Higuchi) indicated that the permeation of the drug from the patches was governed by a diffusion mechanism.Formulation F showed highest flux among all the formulations in drug permeation. These results indicate that theformulations containing menthol as the penetration enhancer (5%) giving better penetration of OSH through rat skinwere considered as suitable for large scale manufacturing with a backing layer and a suitable adhesive membrane.KEYWORDS: Transdermal drug delivery, penetration enhancers, hydrophilic and hydrophobic polymers,Ondansetron hydrochloride.INTRODUCTION:Transdermal drug delivery systems are topically Patient satisfaction has been realized through decreased sideadministered medicaments in the form of patches that are effects, reduced dosing frequency, and improved plasmamainly used for non-invasive “intravenous infusion” of profiles as compared with conventional oral dosing ordrugs for systemic effects at a predetermined and controlled painless administration as compared with injection therapy.rate.1 In the last two decades, among the greatest successes in CR drug delivery is the commercialization of transdermalTransdermal systems are designed to deliver the therapeutic dosage forms for the systemic treatment of a variety of 2-7agent at a controlled rate from the device to and through the into the systemic circulation. This route ofadministration avoids unwanted presystemic metabolism To date, nearly 20 drugs alone or in combination have been(first-pass effect) in the GI tract and the liver. launched into transdermal products worldwide. Additional drugs are in the late development phases (phase II to registration). Matrix based transdermal formulations have been developed for a vast number of drugs that include ephedrine, ketoprofen, metoprolol, labetolol hydrochloride,Received on 21.02.2011 Modified on 12.03.2011 triprolidine, nitrendipine, lercanidipine, and propranolol. 8-14Accepted on 24.03.2011 © RJPT All right reservedResearch J. Pharm. and Tech. 4(5): May 2011; Page 806-814 806
  2. 2. Research J. Pharm. and Tech. 4(5): May 2011Ondansetron is a potent antagonist of Serotonin (5 HT3) Preparation of standard solution: Firstly, stock solution-1receptor which has been proved effective in prevention of of OSH was prepared by dissolving 10 mg of drug in 100chemotherapy and radiotherapy-induced nausea and ml of PBS pH 7.4, so as to get a solution of 1 mg/mlvomiting. It can control diarrhoea and nausea in up to 100% concentration. Then stock solution -2 was prepared byof patients and occasionally ameliorate the flushing. In this taking 10 ml from the previous stock solution andwork an attempt was made to formulate and evaluate TDDS dissolving in 100 ml of PBS pH 7.4, so as to get a solutionfor sustained release OSH by solvent casting method. Low of 100 mg/ml concentration. Accurately measured aliquotmolecular weight, good permeability, poor bioavailability portions of standard drug solution, like 0.4 ml, 0.6 ml, 0.8(60%) and shorter half-life (5-6 h) of OSH made it a ml, 1.0 ml, 1.2 ml, 1.4 ml and 1.6 ml were taken from stocksuitable drug candidate for the development of Transdermal solution-2 and were transferred in to 10 ml volumetricpatches. The main objective of formulating the Transdermal flasks and were diluted up to the mark with PBS pH 7.4.system was to prolong the drug release time, reduce the Absorbance of each solution was measured at max of 310frequency of administration and to improve patient nm against PBS pH 7.4 as the blank, by using UV-compliance. spectrophotometer. A graph of concentration of drug vs. absorbance was plotted.MATERIALS AND METHODS:Materials: Ondansetron hydrochloride was obtained as a Formulation of Transdermal Patches16, 17generous gift from Sun Pharmaceuticals (Baroda, India). Preparation of blank patches: Polymers of single or inEudragit RL100 and Eudragit RS100 were procured from combination were accurately weighed and dissolved inAurobindo Pharmaceuticals (Hyderabad, India). Di-butyl respective solvent and then casted in a Petri-dish withphthalate, menthol, hydroxypropyl methylcellulose, ethyl mercury as the plain surface. The films were allowed to drycellulose, cellulose acetate phthalate were purchased from overnight at room temperature.SD Fine Chemicals (Mumbai, India). All the polymersreceived were of pharmaceutical grade and were used as Development of Transdermal Patches: Mercury substratereceived. Other materials and solvents used were of method was employed in preparing transdermal patches ofanalytical grade. OSH.Methodology: Table 1: Formulations of OSH Transdermal Patch Formu EC: RL: PVA: HPMC SOLVENTPreformulation study: lation PVP RS PVP K4M:Solubility study: OSH has very low aqueous solubility and code PVPhas not been reported in any official book, so determination F1 8:2 - - - CHLOROFORMof solubility is important. The solubility was determined in F2 7:3 - - - CHLOROFORMdistilled water and Phosphate Buffered Saline (PBS) pH F3 6:4 - - CHLOROFORM7.4. F4 5:5 - - - CHLOROFORM F5 4:6 - - - CHLOROFORM F6 - 8:2 - - ACETONESaturated solution of OSH was prepared using 10 ml of F7 - 6:4 - - ACETONEdistilled water/ PBS pH 7.4 in 25 ml volumetric flasks in F8 - 5:5 - - ACETONEtriplicate. Precautions were taken so that the drug remained F9 - 4:6 - - ACETONEin medium in excess. Then by employing mechanical F10 - 8:2 - WATER F11 - - 6:4 - WATERshaker, the flasks were shaken for 48 h and the sampling F12 - - 5:5 - WATERwas done on 24th & 48th h. The sample withdrawn (1 ml F13 - - - 8:2 EDCMafter filtration) was diluted with appropriate medium and F14 - - - 6:4 EDCManalyzed by using UV spectrophotometer (Systronic Pc- F15 - - - 5:5 EDCMBased Double-Beam Spectrophotometer 2202, Ahmedabad, F16 4:6 EDCMIndia) at 310 nm and 303.5 nm for PBS and distilled water F17 2:8 EDCM EDCM= Ethanol: Dichloromethanerespectively.15 Mercury Substrate Method: The polymers,Construction of standard graph: Standard graph of OSH hydroxypropyl methylcellulose, ethyl cellulose, cellulosewas plotted in PBS pH 7.4 which was selected from acetate phthalate, Eudragit RL100 and Eudragit RS100,solubility study. OSH was estimated spectrophotometrically poly vinyl Pyrrolidone, poly vinyl alcohol were taken in aat max of 310 nm. weighing bottle. About 10ml of solvent mixture of dichloromethane: methanol (6:4) / chloroform / acetonePreparation of Phosphate Buffer pH 7.4: Accurately were added and shaked to prevent the formation of lumpsmeasured 250 ml of 0.2 M potassium dihydrogen phosphate and kept aside for swelling of polymers. After complete(KDHP) was taken in a 1000 ml of volumetric flask and solubilization of polymers in mixture of solvent, requiredadded 195.5 ml of 0.2 M sodium hydroxide, and then water quantity of dibutyl phthalate was added to the mixture andwas added to make up the volume and adjusted pH 7.4 by stirred. Finally weighed quantity of OSH was dissolved inusing 0.2 M KDHP/sodium hydroxide. 5ml of solvent mixture, added to the polymer solution and mixed well. It was set-aside for some time to exclude any 807
  3. 3. Research J. Pharm. and Tech. 4(5): May 2011entrapped air and was then transferred into a previously membranes (in weight %) was calculated in terms ofcleaned Petri plate (70.00 cm2) and kept aside for solvent percentage increase in weight of membrane over the initialevaporation. The rate of solvent evaporation was controlled weight of the specimen. The experiments were carried outby inverting a glass funnel over the Petri plate. After 12h, in triplicate and the average values were used for thethe dried films were taken out and stored in a desiccator. calculation. The percentage degree of swelling (DS) wasThe composition of the patches is given in Table 1. calculated asEvaluation of Transdermal Patches: DS%= Ws-Wd/Wd * 100Physical Methods: Where Ws and Wd indicate the weight of the swollenWeight Variation: All the transdermal patches were and dry membranes respectivelyvisually inspected for color, clarity, flexibility &smoothness. Drug Content Determination: The patch of area 3.83 cm2 was cut and dissolved in PBS pH 7.4. Then ethanol andThickness: Thickness of the patches was assessed at 3 dichloromethane were added to the mixture to makedifferent points using digital micrometer (Digital Caliper, polymer soluble, and the remaining volume was made upAerospace, India). For each formulation, three randomly with PBS pH 7.4 to 100 ml in 100 ml volumetric flask.1 mlselected patches were used. was withdrawn from the solution and diluted to 10 ml. The absorbance of the solution was found at 310 nm andPhysical Appearance: Three disks of 2x2 cm were cut and concentration was calculated. By correcting dilution factor,weighed on electronic balance (Shimadzu, Aux*220) for the drug content was calculated.21weight variation test. The test was done to check theuniformity of weight and thus check the batch- to- batch Water Vapour Transmission Rate: Glass vials of 5 mlvariation. 16 capacity were washed thoroughly and dried to a constant weight in an oven. About 1 g of fused calcium chloride wasFlatness: Longitudinal strips were cut out from each patch, taken in the vials and the polymer films of 3.83 cm2 wereone the centre and two from either side. The length of each fixed over the brim with the help of an adhesive tape. Thenstrip was measured and the variation in the length was the vials were weighed and stored in a humidity chamber ofmeasured by determining present constriction, considering 80-90 % RH condition for a period of 24 h. The vials were0% constriction equivalent to 100% flatness18. removed and weighed at 24 h time intervals to note down the weight gain. The values are noted in table 4. WaterFolding Endurance: The folding endurance of the vapour transmission rate is expressed as the number ofprepared patch was measured manually. A strip of the film grams of moisture gained/hr/cm2. 22(4x3 cm) was cut evenly and repeatedly folded at the sameplace till it was broken. The thinner the patch more flexible Water Vapour Transmission Rate= Final weight-Initialit is.19 weight/ Time*AreaMoisture Uptake: The patches were placed in the Permeation Studies:desiccators containing 200 ml of saturated potassium In vitro Permeation Studies using Dialysis Membrane: Inchloride to get the humidity inside the desiccators at 84 % vitro permeation of OSH from Transdermal patches throughRH. After 3 days the films were taken and weighed, the dialysis membrane (Hi-Media) with molecular weight cutpercentage moisture absorption of the patch was found.19 off of 12000 was studied. The membrane was mounted over a Franz diffusion cell and a transdermal patch. The receiver % moisture absorbed= Final weight-Initial weight/ Initial compartment of the diffusion cell was filled with 15.0 ml of weight * 100. PBS pH 7.4 and the setup was placed over a magnetic stirrer with temperature maintained at 370C. Samples of 3Moisture Content: The patches were weighed ml were withdrawn and replenished immediately from theindividually and kept in a desiccator containing fused receiver compartment at 1, 2, 3, 4, 6 and 12h. They werecalcium chloride at 40 ºC for 24 h. The patches were stored in refrigerated condition till the analysis wasreweighed until a constant weight was obtained. Moisture performed. The content of drug in the samples wascontent was calculated in percentage based on the analyzed by UV-Visible spectrophotometer at 310 nm.difference between the initial and constant final weights. An .average of three readings was noted20. Ex vivo Rat Skin Permeation Studies: Preparation of skin: A full thickness of skin was excisedSwelling Study: Completely dried membranes with a from dorsal site of dead rat and was washed with water. Thespecified area (3.83 cm2) were weighed and put in fatty tissue layer was removed by using nails of fingers. Thedesiccators for 24 h. They were removed and exposed to outer portion with hairs was applied with depilatory andrelative humidity conditions of 75 % (containing saturated allowed to dry. With the help of wet cotton the hairs weresolution of sodium chloride) in desiccators. Weight was scrubbed and washed with normal saline solution. The skintaken on a single pan balance periodically until a constant was kept in normal saline solution and stored in refrigeratorweight was obtained. The swelling capacity of the 808
  4. 4. Research J. Pharm. and Tech. 4(5): May 2011until further use. The skin was allowed to equilibrate with Table 3: Standard graph of OSH in PBS pH 7.4room temperature prior to use and was mounted between CONCENTRATION(µG/ML) ABSORBANCEdonor and receptor compartment of cell. It was clamped in 0 0.00 2 0.129such a way that the dermal side was in contact with receptor 4 0.231 23medium . 6 0.359 8 0.482Method: PBS pH 7.4 was used as receptor solution. The 10 0.591volume of diffusion cell was 15 ml and stirred with 12 0.697 14 0.837magnetic beads. The temperature was maintained at 37 ± 16 0.9821°C with the help of hot plate. The diffusion was carried out Slope 0.06for 10 h and 3 ml sample was withdrawn at an interval of 1 R2 0.998h. The same volume of PBS pH 7.4 was added to receptorcompartment to maintain sink conditions and the sampleswere analyzed at 310 nm.Analysis of Permeation Data:Determination of Flux: The flux (J) of OSH wascalculated from the slope of the plot of cumulative amountof drug permeated per cm2 of skin at steady state against thetime using linear regression analysis. The steady statepermeability coefficient (Kp) of the drug through ratepidermis was calculated by equation: Kp =J / C Where, J= flux (µg/cm2/hr) and C= concentration of drug in the patch Fig.1: Standard curve of OSHKinetic Modeling of Drug Release: Various models weretested for explaining the kinetics of drug release. To analyzethe mechanism of the drug release rate kinetics of thedosage form, the obtained data were fitted into zero-order,first order, Higuchi, and Korsmeyer-Peppas releasemodel.24-27Stability study of Optimized Formulation: Stabilitystudies were carried out at 45 °C and 75% RH for threemonths (climatic zone IV condition for accelerated testing)to assess their long-term (2 years) stability of Transdermalformulation. The protocols of stability studies were incompliance with the guidelines in the WHO document forstability testing of products intended for the global market.After 3 months samples were withdrawn and evaluated forphysical properties and in vitro diffusion study. 28 Fig2a: In-vitro release profile of F1-F7RESULTS AND DISCUSSION:Preformulation study: Preformulation studies wereprimarily done to investigate the physical properties ofdrug.Solubility Study: Ondansetron was best soluble in the PBSBuffer pH 7.4. The solubility results are shown in Table 2.Table 2: Solubility data for OSH SOLUBILITY TIME DURATION SOLUBILITY MEDIUM ( g/ml) Distilled water 24 hours 62.03±3.35 48 hours 78.63±1.25 Buffer pH 7.4 24 hours 82.14±1.49 48 hours 96.34±1.92 Fig.2b: In-vitro release profile of F8-F12 809
  5. 5. Research J. Pharm. and Tech. 4(5): May 2011Table 4: Physical evaluation data of OSH Transdermal patches. Results are the mean of triplicate observations ± SD Formul Weight Thickness Folding (%)Moistur (%) Moisture WVT Rate Drug Swellability ation variation (mm) endurance e uptake content (g.cm2/day content (%)±SD code (mg) ±SD ±SD ±SD ±SD ±SD X10-4 ±SD (%)±SD F1 65.34±1.6 0.025±1.6 71±0.9 2.96±0.95 3.08±0.97 2.36±0.14 97.24±0.2 12.73±0.43 F2 65.87±1.6 0.025±1.6 72±1 3.27±0.62 3.11±0.83 2.48±0.15 97.36±0.2 13.25±0.36 F3 66.12±1.8 0.024±1.6 71±0.9 3.89±0.86 3.28±0.75 2.62±0.16 97.45±0.2 14.28±0.38 F4 66.45±1.8 0.026±1.6 72±1 4.85±0.91 3.32±.058 2.93±0.16 98.41±0.3 16.34±0.42 F5 65.34±1.6 0.026±1.6 72±0.9 4.55±1.14 3.98±1.17 3.07±0.17 98.58±0.3 18.94±0.48 F6 66.39±1.8 0.025±1.6 71±1 4.75±1.08 4.63±0.67 3.14±0.17 98.34±0.3 20.67±0.46 F7 65.48±1.6 0.025±1.6 71±0.9 4.27±1.17 4.92±1.38 3.35±0.18 101.17±0.3 22.01±0.38 F8 67.28±1.7 0.045±1.8 77±1 4.93±0.6 3.12±0.3 3.66±0.13 99.38±0.4 38.59±0.61 F9 67.91±1.7 0.045±1.7 77±1 4.68±0.6 3.26±0.3 3.82±0.12 96.75±0.4 35.48±0.45 F10 68.08±1.7 0.047±1.9 80±2 4.86±0.8 3.53±0.6 3.91±0.13 96.81±0.4 32.87±0.46 F11 68.36±1.8 0.046±1.8 79±2 4.53±0.8 3.34±0.3 4.15±0.11 96.84±0.5 30.13±.055 F12 68.94±1.8 0.046±1.8 77±1 4.37±0.7 3.47±0.3 4.28±0.13 96.48±0.5 28.63±0.54 F13 64.86±1.8 0.045±1.5 78±2 4.48±0.5 4.39±0.5 4.12±0.26 98.28±0.7 42.15±0.62 F14 64.53±1.5 0.036±1.3 78±2 4.65±0.4 4.62±0.5 4.16±0.28 98.46±0.7 44.86±0.64 F15 64.21±1.4 0.037±1.4 77±2 4.83±0.6 4.92±0.8 4.28±0.24 98.74±0.3 46.38±0.39 F16 64.83±1.5 0.037±1.3 77±1 4.96±0.4 4.87±0.6 4.38±0.21 98.83±0.7 48.34±0.42 F17 64.46±1.4 0.036±1.3 79±2 5.03±0.5 5.01±0.7 4.48±0.21 100.15±0.8 48.92±0.64WVT=Water Vapour Transmission; SD=Standard Deviation.Table 5a: In vitro drug release from F-1 to F-7 Cumulative % drug released Time F1 F2 F3 F4 F5 F6 F7 0 0.00 0.00± 0.00 0.00 0.00 0.00 0.00 1 6.81±0.45 7.06±0.54 7.91±0.71 8.50±0.86 8.94±0.94 9.31±0.96 9.75±1.01 2 13.80±0.46 14.29±0.56 16.33±0.74 16.89±0.89 17.32±0.97 17.77±0.98 18.45±1.07 3 20.98±0.49 22.74±0.58 23.63±0.76 24.30±0.92 24.93±0.99 25.92±1.01 26.34±1.11 4 28.49±0.51 30.61±0.61 32.23±0.77 33.49±1.02 34.37±1.01 35.34±1.05 36.44±1.15 5 34.58±0.53 37.16±0.63 38.19±0.82 41.56±1.05 42.53±1.05 43.85±1.12 45.11±1.18 6 41.73±0.55 44.38±0.66 47.01±0.85 50.68±1.06 53.89±1.08 55.33±1.16 57.16±1.23 12 76.31±0.57 79.76±0.69 84.07±0.87 88.47±1.07 90.38±1.13 92.98±1.18 96.79±1.29Release profile data with mean ±SDTable 5b: In vitro drug release from F-8 to F-12 Time F8 F9 F10 F11 F12 0 0.00 0.00 0.00 0.00 0.00 1 8.94±0.41 8.16±0.48 7.75±0.53 7.22±0.65 6.69±0.77 2 16.63±0.41 15.94±0.51 15.33±0.54 14.82±0.66 13.99±0.79 3 24.82±0.43 24.31±0.52 23.93±0.56 23.03±0.68 21.93±0.81 4 33.89±0.45 32.86±0.54 32.01±0.58 31.31±0.71 29.79±0.83 5 41.95±0.46 40.43±0.56 39.64±0.59 38.74±0.74 37.13±0.86 6 50.27±0.48 49.01±0.58 47.91±0.62 46.81±0.76 44.58±0.89 12 93.19±0.49 88.40±0.61 85.99±0.63 80.30±0.79 76.63±0.91Release profile data with mean ±SDTable 5c: In vitro drug release from F-13 to F-17 Time F13 F14 F15 F16 F17 0 0.00 0.00 0.00 0.00 0.00 1 7.06±0.21 7.94±0.31 8.63±0.42 8.78±0.52 9.09±0.61 2 14.91±0.22 15.93±0.33 16.66±0.46 16.91±0.54 17.23±0.63 3 22.99±0.24 23.86±0.35 24.81±0.49 25.16±0.57 25.78±0.66 4 30.67±0.27 31.74±0.37 33.29±0.51 33.61±0.59 34.11±0.67 5 38.57±0.28 39.61±0.39 41.11±0.52 41.59±0.61 42.61±0.68 6 46.67±0.29 47.93±0.42 49.89±0.55 50.99±0.62 51.76±0.69 12 90.22±0.35 93.79±0.45 94.54±0.56 96.66±0.64 98.43±0.75Release profile data with mean ±SDTable 6a: Ex vivo diffusion release data for F1-F7 Cumulative % drug permeated Time F1 F2 F3 F4 F5 F6 F7 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 4.19±0.45 4.29±0.53 4.36±0.68 4.41±0.77 4.54±0.83 4.43±0.87 4.28±0.93 2 7.32±0.46 7.41±0.57 7.54±0.69 7.67±0.79 7.83±0.86 7.63±0.89 7.50±0.95 3 9.82±0.51 10.12±0.59 10.23±0.72 10.38±0.81 10.91±0.89 10.43±0.92 10.27±0.98 4 12.06±0.49 13.13±0.62 13.99±0.75 15.02±0.84 16.12±0.91 14.96±0.94 14.21±1.01 5 16.18±0.53 17.65±0.66 18.32±0.76 19.38±0.89 21.64±0.93 20.20±0.96 19.16±1.06 6 20.10±0.55 21.78±0.68 23.59±0.79 25.14±0.92 27.09±0.96 25.78±0.99 24.92±1.08 12 50.69±0.57 51.35±0.71 52.26±0.82 54.81±0.94 56.64±0.99 57.42±1.02 58.60±1.13Release profile data with mean ±SD 810
  6. 6. Research J. Pharm. and Tech. 4(5): May 2011Fig.2c: In vitro release profile of F13-F17 Fig.3b: Ex vivo release profile of F8-F12Fig.3a: Ex vivo release profile of F1-F7 Fig.3c: Ex vivo release profile of F13-F17Table 6b: Ex vivo diffusion release data for F8-F12 Cumulative % drug permeated Time F8 F9 F10 F11 F12 0 0.00 0.00 0.00 0.00 0.00 1 4.36±0.61 4.59±0.71 4.85±0.81 4.94±0.85 4.99±0.89 2 7.70±0.63 8.03±0.72 8.57±0.83 8.83±0.87 8.96±0.92 3 10.70±0.67 11.88±0.75 12.61±0.86 13.63±0.89 14.23±0.95 4 15.09±0.69 16.37±0.77 18.01±0.89 19.20±0.93 20.04±0.98 5 20.42±0.72 21.65±0.81 23.42±0.91 24.27±0.96 25.70±1.02 6 25.73±0.74 27.45±0.83 29.00±0.94 31.21±0.99 30.63±1.06 12 54.84±0.75 56.64±0.85 59.25±0.97 61.88±1.03 63.17±1.11Release profile data with mean ±SDTable 6c: Ex vivo diffusion release data for F13-F17 Cumulative % drug permeated Time F13 F14 F15 F16 F17 0 0.00 0.00 0.00 0.00 0.00 1 4.27±0.81 5.02±0.85 6.01±0.91 8.19±0.97 8.27±1.01 2 8.57±0.82 9.03±0.87 9.57±0.93 16.16±0.99 17.3±1.04 3 12.65±0.85 15.04±0.91 17.00±0.96 23.10±1.02 24.28±10.8 4 17.79±0.87 21.28±0.93 22.15±0.97 32.59±1.06 35.36±1.11 5 24.59±0.89 26.90±0.95 28.15±0.98 40.17±1.09 42.84±1.14 6 31.61±0.92 31.78±0.97 35.33±0.99 48.59±1.11 48.76±1.18 12 60.27±0.94 63.64±0.99 68.47±1.02 70.63±1.15 73.15±1.21Release profile data with mean ±SD 811
  7. 7. Research J. Pharm. and Tech. 4(5): May 2011Table 7: Ex vivo skin permeation steady state flux, permeability coefficients of Transdermal patches Formulation code Flux (µgcm-2h-1) Permeability coefficient (Kp) F1 4.266 0.533 F2 4.336 0.542 F3 4.433 0.554 F4 4.676 0.584 F5 4.851 0.606 F6 4.928 0.616 F7 5.041 0.630 F8 4.686 0.585 F9 4.824 0.603 F10 5.035 0.629 F11 5.268 0.658 F12 5.355 0.669 F13 5.203 0.65 F14 5.388 0.673 F15 5.779 0.722 F16 5.683 0.710 F17 5.937 0.742Table 8: Ex vivo skin permeation kinetics followed by formulations of OSH Transdermal patches Formulation code Zero order model First order model R2 Higuchi model Peppas model R2 R2 n R2 F6 0.990 0.847 0.958 0.992 0.989 F8 0.994 0.771 0.971 0.703 0979 F17 0.971 0.970 0.972 0.766 0.991Table 9: Physical evaluation data of OSH Transdermal patches before and after 3 months Formulation Weight Thickness Folding (%)Moisture (%)Moist WVT Drug Swellability code variation (mm) endurance uptake ure Rate(g.cm2/ content (%)±SD (mg) ±SD ±SD ±SD ±SD content day X10-4 (%)±SD ±SD ±SD F6 Before 66.39±1.8 0.025±1.6 71±1.8 4.75±1.08 4.63±0.67 3.14±0.17 98.34±0.3 21.67±0.46 After 66.58±1.6 0.027±1.6 72±2.1 4.97±1.17 4.82±1.38 3.25±0.18 99.17±0.3 22.01±0.38 F8 Before 67.28±1.7 0.045±1.8 77±1 4.93±0.6 3.12±0.3 3.66±0.13 99.38±0.4 38.59±0.61 After 67.91±1.7 0.046±1.7 78±1 4.98±0.6 3.26±0.3 3.82±0.12 99.75±0.4 39.48±0.45 F17 Before 64.46±1.5 0.036±1.3 79±1 5.03±0.4 5.01±0.6 4.38±0.21 98.83±0.7 48.34±0.42 After 64.83±1.4 0.037±1.3 80±2 4.98±0.5 4.99±0.7 4.48±0.21 99.15±0.8 48.92±0.64Table10: In vitro drug release data of optimized formulations before and after 3 months OPTIMIZED Before stability After stability FORMULATION CODE 0 month 1st month 2nd month 3rd month F6 92.98±1.18 93.06±1.19 93.13±1.20 93.21±1.21 F8 93.19±0.49 93.38±0.51 93.45±0.52 93.49±0.54 F17 98.43±0.75 98.56±0.76 98.62±0.77 98.71±0.79 SIMILARITY FACTOR 80.23Table 11: Ex vivo skin permeation steady state flux, permeability coefficient, kinetics followed by optimized formulations of transdermalpatches Formulation Flux (µgcm-2h-1) Permeability Zero order First order Peppas model code coefficient (Kp) model R2 model R2 HiguchimodelR2 n R2 F6 4.968 0.636 0.987 0.849 0.921 0.993 0.991 F8 4.716 0.592 0.999 0.781 0.976 0.711 0981 F17 5.981 0.761 0.999 0.975 0.977 0.774 0.992Standard graph of OSH in PBS pH 7.4: Standard graph The physical evaluation of Transdermal patches for allof drug was plotted as per the procedure in experimental formulations was performed. Weight variation was found inmethod and its linearity was shown in table 3 and graph. the range of 64.21±1.4 to 68.94±1.8 and thickness wasThe standard graph showed good linearity with R2 of 0.998 found to be between 0.024±1.6 to 0.047±1.9. The results ofwhich indicates that it obeys “Beer-Lambert’s” law. flatness study showed that none of the formulations had the difference in the strip lengths before and after longitudinal 812
  8. 8. Research J. Pharm. and Tech. 4(5): May 2011cut, indicating 100% flatness, thus they could maintain a the slope (0.992) indicated that the drug released by zerosmooth surface when applied to the skin. The folding order type as shown in Table 8.endurance was found to be in the range of 71±0.9 to 80±2which indicated that the patches would not break and would Stability: After storage, the formulations were subjected tomaintain their integrity with general skin folding when drug content, physical evaluation and in vitro releaseused. The folding endurance of Eudragit patches was higher studies. The statistical analysis of these parameters afterthan patches containing Ethyl cellulose and PVA-PVP. storage at 45 °C and 75% RH for three months showed noDrug content was found to be in the range of 96.48±0.5 to significant change Table 9-11.101.17±0.3 indicating that the drug was uniformlydistributed throughout the patches and evidenced by the low ACKNOWLEDGEMENTS:values of SD. Hydrophilic polymers showed considerable We would like to express our deepest gratitude towardsswelling, as they increased the surface wettability and Prof. Stephen. R. Wicks, University of Greenwich, U.K.,consequently water penetration within the matrix varied Prof. D. Rambhau and Prof. Shashank Apte, Natcobetween 12.73 to 48.92%. Research Centre, Hyderabad for their noble guidance throughout the project.Patches containing higher amount of PVP showed goodwater vapour transmission (4.48±0.21) than that of Eudragit CONCLUSION:and Ethyl cellulose patches. The enhancement of water Seventeen formulations were prepared using differentvapour permeation with increase of PVP is due to the polymers in different ratios and combinations, along withirregular arrangement of molecules in the amorphous state, plasticizers and penetration enhancer. Mercury was used aswhich causes the molecules to be spaced further apart than a substrate for pouring the polymeric solution. The filmsin crystal. Hence the specific volume is increased and the were evaluated for uniformity of thickness, weightdensity decreased compared to that of crystal, which leads variation, drug content, folding endurance, % elongation, %to the absorption of vapour into their interstices. All the moisture absorption, moisture content, water vapourformulations were permeable to water vapour. transmission study, in vitro release and ex-vivo diffusion studies using Franz diffusion cell. The formulationsDiffusion Studies: followed the Higuchi’s model for the drug diffusion study.In vitro Release: The in vitro release studies were Since the formulations follow Higuchi’s model, thus theyconducted for all the formulations and the data was indicate diffusion mechanism. The Peppa’s plot showed therepresented in tables 5a, b and c. The in-vitro release n value of 0.766 for formulation F17, thus indicating non-profiles for all the formulations were shown in fig.2a, b and fickian diffusion. There is scope for the further study andc. The percentage release was found to be highest (98.43%) development of the Ondansetron Hydrochloridefor formulation carrying PVA: PVP in ratio 2:8 because of Transdermal patches.the hydrophilic nature of the polymer. REFERENCES:Ex vivo Permeation Studies: The cumulative amount 1) Chien YW. Novel Drug Delivery Systems. Drugs and thepermeated was calculated and presented in tables 6a, b and Pharmaceutical Sciences. Marcel Dekker, New York. 1992.c and figures 3a, b and c. It was higher in case of PVA-PVP 2) Kydonieus A and Berner B. Transdermal Delivery of Drugs.polymer containing matrix. CRC Press, Boca Raton, Florida. 1987. 3) Chien Y. Transdermal Controlled System Medications. Marcel Dekker, New York. 1987.The reason for high release from PVA-PVP polymers could 4) Hadgraft J and Guy R. Transdermal Drug Delivery:be explained by the hydrophilic nature of the polymers and Developmental Issues and Research Initiatives. Marcel Dekker,due to leaching of PVP and pore formation. This leads to an New York. 1989.increase in the external film area exposed to the solvent, 5) Gurney R and Teubner A. Dermal and Transdermal Drug Delivery. Stuttgart: Wissenschaftliche Verlagsgesellschaft, 1993.increased internal porosity and decreased tortuosity. The 6) Ghosh T, Pfister W and Yum S. Transdermal and Topical Drugenhancement in solubility of drug increased with Delivery Systems. Interpharm Press, Buffalo Grove, Illinois.thermodynamic activity that facilitated permeation of dug 1997.across the skin. The patch coded F1 (EC: PVP 8:2) showed 7) Brahmankar DM and Jaiswal SB. Biopharmaceutics andthe slowest permeation. This could be attributed to the Pharmacokinetics- A Treatise. Vallabh Prakashan, New Delhi,hydrophobic nature of the polymer which helped to retain India. 1995. 8) Aquil M, Sultana Y and Ali A. 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