Garhwal University, Srinagar (UA) - 246 174, India 2 Department of Pharmacy, S.R.I.S.Dehradun - 248 001, India Date of Submission 10-Oct-2006 Date of Decision 15-Nov-2007 Date of Acceptance 15-Jan-2008 CORRESPONDENCE ADDRESS: Semalty Mona Department of Pharmaceutical Sciences, H.B.University, Srinagar (UA) - 246 174 India SOURCE OF SUPPORT: None, CONFLICT OF INTEREST: None Abstract Mucoadhesive buccal films of glipizide were prepared by solvent casting technique using hydroxypropylmethylcellulose, sodium carboxymethylcellulose, carbopol-934P and Eudragit RL-100.Were evaluated for weight, thickness, surface pH, swelling index, _ in vitro_ residence time, folding endurance, _ in vitro_ release, permeation studies and drug content uniformity.Films exhibited controlled release over more than 6 h.The study it was concluded that the films containing 5 mg glipizide in 4.And 1.Sodium carboxymethylcellulose exhibited satisfactory swelling, an optimum residence time and promising drug release.Formulation was found to be suitable candidate for the development of buccal films for therapeutic use.Buccal film, glipizide, _ in vitro_ studies HOW TO CITE THIS ARTICLE: Semalty M, Semalty A, Kumar G.And characterization of mucoadhesive buccal films of glipizide.J Pharm Sci 2008;70:43-8 HOW TO CITE THIS URL: Semalty M, Semalty A, Kumar G.And characterization of mucoadhesive buccal films of glipizide.J Pharm Sci ;70:43-8.Amongst the various routes of administration tried so far for novel drug delivery systems, localized delivery to tissues of the oral cavity has been investigated for a number of applications including the treatment of toothaches , periodontal disease , , bacterial and fungal infections , aphthous and dental stomatitis and in facilitating tooth movement with prostaglandins .The last two decades mucoadhesion has be of interest for its potential to optimize localized drug delivery, by retaining a dosage form at the site of action (e.Within gastrointestinal tract) or systemic delivery, by retaining a formulation in intimate contact with the absorption site (e.The buccal cavity).Maybe defined as a state in which two materials, one of which is mucus or a mucous membrane, is held together for extended period of time .Jasti _ et al.Et al.Semalty _ et al.Reviewed the use of mucoadhesive polymers in buccal drug delivery and highlighted the use of novel mucoadhesive polymers ,, .Studies have been conducted on buccal delivery of drugs using mucoadhesive polymers.Been made to formulate various mucoadhesive devices including tablets , films , patches , , disks , , strips , ointments and gels .Film may be preferred over adhesive tablet in terms of flexibility andfort.Addition, they can circumvent the relatively short residence time of oral gels on the mucosa, which are easily washed away and removed by saliva.Buccal films are able to protect the wound surface, thus reducing pain and treating oral diseases more effectively .A second generation sulfonylurea used as an antidiabetic agent.Is one of the most potent of the sulfonylurea antidiabetic agents.Is 100 times more potent than tolbutamide in evoking pancreatic secretion of insulin .Differs from other oral hypoglycemic drugs in that tolerance to its action apparently does not occur.Also upregulates insulin receptors in the periphery, which seems to be the primary action.Short biological half-life (3.0.Necessitates its administration in 2 or 3 doses of 2.10 mg per day.About 90% of the drug is metabolized in the liver forming several inactive metabolites .An attempt has been made to develop a buccal mucoadhesive dosage form of glipizide for improving and enhancing bioavailability in a controlled release fashion.May also be possible to circumvent the hepatic first pass effect by administering the drug through buccal mucosa.Work deals with the formulation and characterization of mucoadhesive buccal films of glipizide using mucoadhesive polymers like hydroxy propylmethylcellulose, Carbopol-934P, Eudragit RL-100 and sodium carboxymethylcellulose.And Methods Glipizide was obtained as a gift sample from USV Ltd (Daman, India).Carbopol-934P (CP-934P), Eudragit RL-100 and sodium carboxymethylcellulose, 1500-400cps (SCMC) were procured from Central Drug House, Mumbai.Glycol was procured from E.(P) Ltd, Mumbai.Other reagents used were of analytical grade.Films were prepared by solvent casting method.Of mucoadhesive buccal films: Buccal films of glipizide were prepared by solvent casting technique employing aluminum foil cups (placed on glass surface) as substrate .A single circular cast film of various formulations is mentioned in .Were prepared by using HPMC-E15 alone and inbination with CP-934P, Eudragit RL-100 and sodium CMC (high viscosity grade).Glycol, a plasticizer is used in the concentration of 30% w/w.Was used as a solvent.Amounts of polymers were dispersed in ethanol.Hundred milligrams of glipizide was incorporated in the polymeric solutions after levigation with 30% w/w propylene glycol which served the purpose of plasticizer as well as penetration enhancer.Medicated gels were left overnight at room temperature to obtain clear, bubble-free gels.Prevent the evaporation of alcohol, medicated gels were filled into the vials and closed tightly by the rubber closures.Gels were caste into aluminum foil cups (4.Diameter), placed on a glass surface and allowed to dry overnight at room temperature (25°) to form a flexible film.Dried films were cut into size of 20 mm diameter, packed in aluminum foil and stored in a desiccator until further use.Weight and thickness: For evaluation of film weight three films of every formulation were taken and weighed individually on a digital balance (Fisher Brand PS-200).Average weights were calculated.Films of each formulation were taken and the film thickness was measured using micrometer screw gauge (Mitutoyo MMO-25DS) at three different places and the mean value was calculated.PH of films: For determination of surface pH three films of each formulation were allowed to swell for 2 h on the surface of an agar plate.PH was measured by using a pH paper placed on the surface of the swollen patch.Mean of three readings was recorded .After determination of the original film weight and diameter, the samples were allowed to swell on the surface of agar plate kept in an incubator maintained at 37±0.Increase in the weight of the films (_ n_ = 3) was determined at preset time intervals (1-5 h).Percent swelling, %S, was calculated using the following equation: Percent Swelling (%S) = (X t - X o /X o ) x 100, where X t is the weight of the swollen film after time t, X o is the initial film weight at zero time .Endurance: Three films of each formulation of size (2 x 2 cm) were cut by using sharp blade.Was determined by repeatedly folding a small strip of film at the same place till it broke.Number of times, the film could be folded at the same place without breaking gave the value of folding endurance.Mean value of three readings and standard deviation were shown in .VITRO_ RESIDENCE TIME: The _ in vitro_ residence time was determined using IP disintegration apparatus.Disintegration medium was 800 ml of pH 6.Buffer (PB) maintained at 37±2°.Of rat intestinal mucosa, each of 3 cm length, were glued to the surface of a glass slab, which was then vertically attached to the apparatus.Mucoadhesive films of each formulation were hydrated on one surface using pH 6.And the hydrated surface was brought into contact with the mucosal membrane.Glass slab was vertically fixed to the apparatus and allowed to move up and down.Film waspletely immersed in the buffer solution at the lowest point and was out at the highest point.Time required forplete erosion or detachment of the film from the mucosal surface was recorded (_ n_ = 3) as given in .Content uniformity: Three film units (each of 20 mm diameter) of each formulation were taken in separate 100 ml volumetric flasks, 100 ml of pH 6.Buffer was added and continuously stirred for 24 h.Solutions were filtered, diluted suitably and analyzed at 274 nm in a UV spectrophotometer (Thermospectronic UV-1).Average of drug contents of three films was taken as final reading.VITRO_ RELEASE STUDY: The USP XXIV six station dissolution apparatus type 1 (V Scientific Model No.Was used throughout the study.Film of each formulation was fixed to the central shaft at just above the basket, using a cyanoacrylate adhesive.Dissolution medium consisted of 900 ml pH 6.Buffer (PB).Release study was performed at 37 ± 0.A rotation speed of 50 rpm.Release study was carried out for 6 h.Every hour, 1 ml sample was withdrawn from each station and the same volume was replaced (with the dissolution medium) back to the stations.Withdrawn sample was filtered, diluted suitably and then analyzed spectrophotometrically at 274 nm.Presented were the mean of three determinations.VIVO_ PERMEATION STUDIES: In this study, porcine buccal mucosa was used as a barrier membrane.Pouch of freshly sacrificed animal was procured from local slaughter house.Buccal mucosa was excised and trimmed evenly from the sides.Was then washed in isotonic phosphate buffer (pH 6.Immediately .Ex vivo_ permeation studies of mucoadhesive buccal films of glipizide through an excised layer of porcine buccal mucosa were carried out using the modified Franz diffusion cell .2.Diameter film of each formulation under study was placed in intimate contact with the excised porcine buccal mucosa and the topside was covered with aluminum foil as a backing membrane.Bead was placed in the receptorpartment filled with 100 ml of pH 7.Buffer.Cell contents were stirred with a magnetic stirrer and temperature of 37±1° was maintained throughout the experiment.Samples were withdrawn at every hour, filtered, diluted suitably and then analyzed using UV- spectrophotometer at 276 nm.Results and Discussion Mucoadhesive buccal films of glipizide were prepared using mucoadhesive polymers HPMC-E15, CP-934P, Eudragit RL-100 and sodium CMC.Glycol was used as the plasticizer as well as penetration enhancer.Drug delivery system was formulated as a matrix.Films were characterized for their physical characteristics, bioadhesive performance, release characteristics, surface pH, thickness, folding endurance, drug content uniformity and percent swelling .Film thicknesses were observed to be in the range of 0.Mm to 0.Mm and weight was found to be in the range of 56±1.To 84±0.The fact that acidic or alkaline pH may cause irritation to the buccal mucosa and influence the degree of hydration of polymers, the surface pH of the buccal films was determined to optimize both drug permeation and mucoadhesion , .Were made to keep the surface pH as close to buccal/salivary pH as possible, by the proper selection of the polymers for developing the buccal films.PH of all the films was within the range of salivary pH.Difference was found in surface pH of different films.Required for a mucoadhesive polymer to expand and create a proper macromolecular mesh of sufficient size, and also to induce mobility in the polymer chains in order to enhance the interpenetration process between polymer and mucin.Swelling permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucous network .A critical degree of hydration of the mucoadhesive polymer exists where optimum swelling and bioadhesion occurs .Effect of glipizide on the swelling behaviour and the residence time of various mucoadhesive polymers, was also observed .Medicated films showed high swelling index inparison to plain films.Addition of the water-insoluble drug increased the water uptake of the film.Is possibly due to micronized drug particles which exist between the polymer chains allowing each chain to hydrate freely, resulting in weak hydrogen bonding areas around the glipizide molecules.Areas may increase the strength of the swollen layer followed by an obvious increase in the amount of penetrated water .A practically water-insoluble drug, was found to increase the swelling behaviour of HPMC matrices , while lower swelling indices were observed when the same drug was added to Gantrez-169pressed matrix .Influence of drug on the swelling properties of polymer matrices is primarily dependent on the substituted groups of the polymer.Hydroxyl group in the molecules plays an important role in the matrix integrity of the swollen hydrophilic cellulose matrices.Amount and properties of the incorporated drug determine matrix integrity.For various formulations was in order of F2 > F1 > F4 > F3.Percentage swelling of HPMC-E15 films was reduced by the addition of Carbopol 934P and Eudragit-RL100 and increased by the addition of SCMC.Containing films showed higher percent swelling due to presence of more hydroxyl group in the SCMC molecules.Hydrophilic additive dissolves rapidly resulting in high porosity.Void volume is thus expected to be occupied by the external solvent diffusing into the film and thereby accelerating the dissolution of the gel .Of the drug induced significant reduction of the residence time of various formulations.Enhanced erosion rate was observed with the non-ionic polymers (HPMC with Eudragit RL100).The particle swells, the matrix experiences intra-matrix swelling force which promotes disintegration and leaching of the drug leaving behind a highly porous matrix.Influx weakens the network integrity of the polymer, thus influencing structural resistance of the swollen matrices, which in turn results in pronounced erosion of the lose gel layer .Water-soluble hydrophilic polymers like SCMC dissolve rapidly and introduce porosity.Void volume is thus expected to be occupied by the external solvent which diffuses into the film and thereby accelerate the dissolution of the gel .In vitro_ residence time of the film was in the order of F4 > F2 > F1 > F3.Folding endurance was measured manually, by folding the film repeatedly at a point till they broke.Breaking time was considered as the end point.Was found to be highest for F4 (290±4.Lowest for F1 (164.It was found that folding endurance of HPMC films was increased by the addition of polymers in the order; Eudragit-RL100 SCMC > Carbopol 934P.Folding endurance values of the films were found to be optimum and therefore the films exhibited good physical and mechanical properties.In formulations was uniform with a range of 4.Mg/20 mm diameter of the film (F1) to 4.Mg/20 mm diameter of the film (F3).This basis, it was found that the drug was dispersed uniformly throughout the film.Vitro_ release studies of various formulations were performed using pH 6.Buffer as dissolution medium and measuring drug concentration spectrophotometrically at 274 nm.Difference was observed in the release of glipizide films containing eudragit, carbopol and SCMC in the graph plotted between the cumulative per cent drug released from the formulations and the time .Carbopol polymers exhibited high swelling, the film weight of these polymers was noted to be increased to the extent of 25 to 60% from the initial weight within 2 h .The marked increase in surface area during swelling can promote drug release but the increase in diffusion path length of the drug may paradoxically delay the release.Addition, the thick gel layer formed on the swollen film surface is capable of preventing matrix disintegration and controlling additional water penetration .Films showed high dissolution rate aspared to Eudragit RL100 films.Was found that the drug release from the films varied with respect to the proportion of polymers.Studies done with the groups of formulations, from which these four formulations were selected, showed that increase in the polymer concentration reduced the diffusion of drug from the matrix.Formulations, formulation F2 showed the good release pattern aspared to others.Drug release whether diffusion, swelling or erosion was confirmed by Higuchi's plots.Shows the graphical representation of cumulative percentage drug release versus square root of time.Higuchi's Plots were found to be linear with correlation coefficient values of 0.0.0.F1, F2, F3 and F4, respectively.Was concluded that the release of drug from the films followed the diffusion controlled mechanism in all the formulations.Also concluded that formulation F1 (containing HPMC alone) and F2 (containing HPMC with SCMC) showed good swelling, a convenient residence time as well as promising drug release pattern.Basis of release pattern, swelling and residence time, F1 and F2 formulations were selected for _ ex vivo_ study._ ex vivo_ study, drug permeation through the porcine buccal mucosa was determined for formulation F1 and F2 .Drug permeation was found to be 78.In F1 and F2 after 10 h.Study indicates a good potential of erodible mucoadhesive buccal films containing glipizide for systemic delivery with an added advantage of circumventing the hepatic first pass metabolism.Results of the study show that therapeutic levels of glipizide can be delivered buccally.May be concluded that the films containing 5 mg glipizide in 4.HPMC with 1.SCMC (F2), show good swelling, a convenient residence time and promising controlled drug release, thus seems to be a potential candidate for the development of buccal film for effective therapeutic use.In vivo_ studies need to be designed and executed to substantiate further _ in vitro - in vivo_ correlation.References Ishida M, Nambu N, Nagai T.Mucosal dosage form of insulin.Bull 1982;30:980.Collins AE, Deasy PB, MacCarthy DJ, Shanley DB.Of a controlled releasepact containing tetracycline hydrochloride bonded to tooth for the treatment of periodontal disease.J Pharm 1989;51:103.Elkayam R, Friedman M, Stabholz A, Soskolne AW, Sela MN, Golub L.Containing minocycline for local treatment of periodontal disease.Control Release 1988;7:231.Samaranayake L, Ferguson 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