Polymers Used For Fast Disintegrating Oral Films: A Review

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Int. J. Pharm. Sci. Rev. Res., 21(1), Jul – Aug 2013; n 29, 169-178ISSN 0976 – 044XReview ArticlePolymers used for Fast Disintegrating Oral Films: A ReviewYogyata S. Pathare*, Vishakha S. Hastak, Amruta N. Bajaj*Department of Pharmaceutics, Shree Chanakya Education Society's, Indira college of Pharmacy, Tathawade, Pune, Maharashtra, India.*Corresponding author’s E-mail: yogyataspathare@gmail.comAccepted on: 16-04-2013; Finalized on: 30-06-2013.ABSTRACTCurrent developments in the technology have presented viable dosage alternatives from oral route for pediatrics, geriatric,bedridden, nauseous or noncompliant patients. Oral thin film, a new drug delivery system for the oral delivery of the drugs, wasdeveloped based on the technology of the transdermal patch. Fast-dissolving oral thin film is a solid dosage form, which disintegrateor dissolve within 1 min when placed in the mouth without drinking of water or chewing. Oral film includes various ingredients forits formulation which includes polymers, active pharmaceutical ingredient, film stabilizing agents, sweeteners, flavours, colors, salivastimulating agents, preservatives, surfactants etc but the first and far most a very essential ingredient which helps in film formationis a Polymer. Fast dissolving Film is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity,delivering the drug to the systemic circulation via dissolution when contact with liquid is made. Water-soluble polymers are used asfilm formers for fast dissolving films. The water-soluble polymers achieve rapid disintegration, good mouth feel and mechanicalproperties to the films. Fast-dissolving oral thin film offer fast, accurate dosing in a safe, efficacious format that is convenient andportable, without the need for water or measuring devices. In this review article the different polymers used for preparation of fastdissolving oral thin film like Pullulan, Gelatin, Sodium Alginate, Pectin, Rosin, Starch, Chitosan are discussed together with theirphysicochemical properties and film forming properties.Keywords: Fast dissolving films, Oral thin films, plasticizers, polymers.INTRODUCTIONRecent developments in the technology havepresented viable dosage alternatives from oralroute for pediatrics, geriatric, bedridden, nauseousor noncompliant patients. Buccal drug delivery has latelybecome an important route of drug administration.Various bioadhesive mucosal dosage forms have beendeveloped, which includes adhesive tablets, gels,ointments, patches and more recently the use ofpolymeric films for buccal delivery, also known as oralthin films1,2 which is also known as, fast dissolving film,oral strip, mouth dissolving film etc. Oral thin film, a newdrug delivery system for the oral delivery of the drugs,was developed based on the technology of thetransdermal patch. The delivery system consists of a verythin oral strip, which is simply placed on the patient’stongue or any oral mucosal tissue, instantly wet by salivathe film rapidly hydrates and adheres onto the site ofapplication. It then rapidly disintegrates and dissolves torelease the medication for oromucosal absorption or withformula modifications, will maintain the quick-dissolvingaspects allow for gastrointestinal absorption to be1, 3achieved when swallowed.Pharmaceutical companies and consumers alike haveembraced OTFs as a practical and accepted alternative totraditional OTC medicine forms such as liquids, tablets,and capsules. OTFs offer fast, accurate dosing in a safe,efficacious format that is convenient and portable,without the need for water or measuring devices. OTFsare typically the size of a postage stamp and disintegrateon a patient's tongue in a matter of seconds for the rapidrelease of one or more APIs.3Fast-dissolving oral thin film is a solid dosage form, whichdisintegrate or dissolve within 1 min when placed in themouth without drinking of water or chewing. Afterdisintegrating in mouth, enhanced the clinical effect ofdrug through pre-gastric absorption from mouth pharynxand oesophagus as the saliva passes down into thestomach. In such cases, bioavailability of drug issignificantly greater than those observed fromconventional tablet dosage form. Fast dissolving filmsmay be preferred over adhesive tablets in terms offlexibility and comfort.4 In addition, they can circumventthe relatively short residence time of oral gels on themucosa, which are easily washed away and removed bysaliva.Oral thin film has main four types: Flash release film, flashdispersible film, Nondisintegrating mucoadhesive film,medium disintegrating mucoadhesive film.5 An ideal filmshould be flexible, elastic, and soft, yet adequately strongto withstand breakage due to stress from mouthmovements. It must also possess good bioadhesivestrength in order to be retained in the mouth for thedesired duration of action.6Oral film includes various ingredients for its formulationwhich includes polymers, active pharmaceuticalingredient, film stabilizing agents, sweeteners, flavours,colors, saliva stimulating agents, preservatives,surfactants etc but the first and far most a very essentialingredient which helps in film formation is a Polymer.7 Avariety of polymers are available for preparation of FDF.As the strip forming polymer (which forms the platformfor the FDF) is the most essential and major componentof the FDF at least 45%w/w of polymer should generallyInternational Journal of Pharmaceutical Sciences Review and ResearchAvailable online at www.globalresearchonline.net169

Int. J. Pharm. Sci. Rev. Res., 21(1), Jul – Aug 2013; n 29, 169-178be present based on the total weight of dry film buttypically 60 to 65%w/w of polymer is preferred to obtaindesired properties.8 The polymers can be used alone or in9combination to obtain the desired strip properties. Thefilm obtained should be tough enough so that there won'tbe any damage while handling or during transportation.The robustness of the strip depends on the type ofpolymer and the amount in the formulation.10, 11Ideal properties of the film forming polymers12, 13 The polymer employed should be non-toxic, nonirritant and devoid of leachable impurities It should have good wetting and spreadabilityproperty The polymer should exhibit sufficient peel, shear andtensile strengths The polymer should be readily available and shouldnot be very expensive It should have good shelf life It should not aid in cause secondary infections in theoral mucosa/ dental region It should have a good mouth feel property The polymers employed should have good shelf life It should not aid in causing secondary infections inthe oral mucosa or dental regions It would be ideal to have a polymer that would havelocal enzyme inhibition action along with penetrationenhancing propertyFast dissolving Film is prepared using hydrophilicpolymers that rapidly dissolves on the tongue or buccalcavity, delivering the drug to the systemic circulation viadissolution when contact with liquid is made. Watersoluble polymers are used as film formers for fastdissolving films. The water-soluble polymers achieve rapiddisintegration, good mouth feel and mechanicalproperties to the films. The disintegration rate of thepolymers is decreased by increasing the molecular weightof polymer film bases.13Some of the water soluble polymers used as film formerare HPMC E3, E5 and E15 and K-3, Methyl cellulose A-3,A-6 and A-15, Pullulan, carboxmethylcellulose cekol 30,Polyvinylpyrollidone PVP K-90, Pectin, Gelatin, SodiumAlginate, Hdroxypropylcellulose, Polyvinyl alcohol,Maltodextrins and Eudragit RD108, 9, 10, 11, 12 EudragitRL100. Polymerized rosin is a novel film forming14-16polymer.Various polymers can be employed to modulate thedisintegration property of the FDF. This is especially usedin case of slowly disintegrable oral bioadhesive strips orpatches that need to be retained in intact form for longerduration in the oral cavity. The bioadhesive polymer usedin such formulations imparts the adhesive property to thestrip such that it adheres to buccal mucosa to deliver theISSN 0976 – 044Xdrug for prolonged period. Bioadhesive polymer shouldideally adhere quickly to the buccal mucosa and shouldhave sufficient mechanical strength.17, 18Plasticizer is a vital ingredient of the OS formulation. Ithelps to improve the flexibility of the strip and reducesthe brittleness of the strip. Plasticizer significantlyimproves the strip properties by reducing the glasstransition temperature of the polymer. The selection ofplasticizer will depend upon its compatibility with thepolymer and also the type of solvent employed in thecasting of strip. The flow of polymer will get better withthe use of plasticizer and enhances the strength of the19, 20polymer.Glycerol, Propylene glycol, low molecularweight polyethylene glycols, phthalate derivatives likedimethyl, diethyl and dibutyl phthalate, Citratederivatives such as tributyl, triethyl, acetyl citrate,triacetin and castor oil are some of the commonly usedplasticizer excipients. However inappropriate use ofplasticizer may lead to film cracking, splitting and peelingof the strip. It is also reported that the use of certainplasticizers may also affect the absorption rate of thedrug. The Plasticizer employed should impart thepermanent flexibility to the strip and it depends on thevolatile nature plasticizer and the type of interaction withthe polymer. It should be noted that the properties ofplasticizer are important to decrease the glass transitiontemperature of polymer in the range of 40.60 C for nonaqueous solvent system and below 75 C for aqueoussystems. Cellulosic hydrophilic polymers were easilyplasticized with hydroxyl containing plasticizers like PEG,propylene glycol, glycerol and polyols. In contrast, lesshydrophilic cellulosic polymers were plasticized withesters of citric acid and phthalic acid. Glycerol acts as abetter plasticizer for polyvinyl alcohol while diethyleneglycol can be used for both Hypromellose as well aspolyvinyl alcohol films. Typically the plasticizers are usedin the concentration of 0–20%w/w of dry polymerweight.21Various polymers are used for preparation of fastdissolving oral films. Some of them are discussed belowtogether with their physichochemical properties and filmforming abilities.PullulanPullulan is a natural and extracellular microbialpolysaccharide produced by the fungus-like yeast,Aureobasidium pullulans. It is a neutral glucan (likeamylose, dextran, cellulose), with a chemical structuresomewhat depending on carbon source, producingmicroorganism, fermentation conditions. The basicstructure is a linear α- glucan one, made from threeglucose units linked α-(1,4) in maltotriose units which are22linked in a α-(1,6) way. The three glucose units inmaltotriose are connected by an α- (1,4) glycosidic bond,whereas consecutive maltotriose units are connected toeach other by an α-(1,6) glycosidic bond. The regularalternation of (1 4) and (1 6) bonds results in twodistinctive properties of structural flexibility andInternational Journal of Pharmaceutical Sciences Review and ResearchAvailable online at www.globalresearchonline.net170

Int. J. Pharm. Sci. Rev. Res., 21(1), Jul – Aug 2013; n 29, 169-178enhanced solubility. The unique linkage pattern alsoendows pullulan with distinctive physical traits along withadhesive properties and its capacity to form fibers,compression moldings and strong, oxygen impermeablefilms. The α-(1,6) linkages that interconnect the repeatedmaltotriose units along the chain are responsible for theflexible conformation and the ensued amorphouscharacter of this polysaccharide in the solid state.23, 24It has film-forming properties and can be used as asubstitute for gelatin or other film-forming polymers incertain foods. A white to off-white tasteless, odourlesspowder that forms a viscous non-hygroscopic solutionwhen dissolved in water at 5-10%. Pullulan starts todecompose at 250 C and chars at 280 C. It is moldableand spinnable, being a good adhesive and binder. It is alsonontoxic, edible and biodegradable. Highly soluble inwater, dilute alkali, insoluble in alcohol and other organicsolvents except dimethylsulphoxide and formamide.Solubility of pullulan can be controlled or provided withreactive groups by chemical derivatization.25 Its aqueoussolutions are stable and show a relatively low viscosity ascompared to other polysaccharides.10% w/w solution ofPI-20 has a pH between 5.25Pullulan can be made into very thin films (down to 0.01mm) these have a high tensile strength and are stableover a range of temperatures. Pullulan can be made intofilms of high tensile strength and low oxygenpermeability, are oil and grease resistant. Pullulan filmsare usually prepared by rapid evaporation of a 5-10%aqueous pullulan solution applied to a smooth surfaceand dried; it may also involve the use of high temperatureand pressure. Pullulan can also be made into shapedbodies (This process usually involves rapid evaporation ofwater, compression moulding or extrusion at hightemperature) commonly pullulan may be mixed withgelatin, amylose and polyvinyl alcohol. Pullulan films orshaped bodies may also contain polyhydric alcohols asplasticizers; e.g. maltitol, sorbitol, glycerol and water25-27soluble polyvinyl alcohol.Due to its excellent properties, pullulan is used as a lowcalorie ingredient in foods, gelling agent, coating andpackaging material for food and drugs, binder forfertilizers and as an oxidation-prevention agent fortablets. Other applications include contact lensesmanufacturing, biodegradable foil, plywood, watersolubility enhancer and for enhanced oil recovery.28-30About 50 to 80 %w/w of pullulan can be replaced byISSN 0976 – 044Xstarch in the production of OS without loss of requiredproperties of Pullulan.GelatinGelatin is prepared by the thermal denaturation ofcollagen, isolated from animal skin, bones and fish skins.Gelatin is a generic term for a mixture of purified proteinfractions obtained either by partial acid hydrolysis (type Agelatin) or by partial alkaline hydrolysis (type B gelatin) ofanimal collagen and/ or may also be a mixture of both.31It is readily soluble in water at temperatures above 40 C,forming a viscous solution of random-coiled linearpolypeptide chains. The physical properties of gelatins arerelated not only to the molecular weight distribution butalso to the amino acid composition.32 Mammalian gelatinscommonly have better physical properties andthermostability than most fish gelatins, and this has beenrelated mainly to their higher amino acid content. The useof mammalian gelatin in the elaboration of edible film orcoatings was very well studied until the sixties, whichresulted in many patents, mainly in the pharmaceuticalarea. The properties and film forming ability of gelatinsare directly related to the molecular weight, i.e., thehigher the average molecular weight, the better thequality of the film. Gelatin films were found to dissolverapidly, excellent carriers for flavors and produce asmooth mouth feel.33Sodium AlginateAlginate is an indigestible biomaterial produced by brownseaweeds (Phaeophyceae, mainly Laminaria) therefore itmay also be viewed as a source of dietary fibre. Chieflysodium alginate consists of sodium salt of alginic acid,which is a mixture of polyuronic acids composed ofresidues of D-mannuronic acid and L-guluronic acid.34Alginate has a potential to form biopolymer film orcoating component because of its unique colloidalproperties, which include thickening, stabilizing,suspending, film forming, gel producing, and emulsionstabilizing. An attractive feature of alginate solutions isthe gelling capacity in presence of Calcium. Edible filmsprepared from alginate form strong films and exhibit poorInternational Journal of Pharmaceutical Sciences Review and ResearchAvailable online at www.globalresearchonline.net171

Int. J. Pharm. Sci. Rev. Res., 21(1), Jul – Aug 2013; n 29, 169-178ISSN 0976 – 044Xwater resistance because of their hydrophilic nature. Thewater permeability and mechanical attributes can beconsidered as moderate compared to synthetic films.Alginate edible-films are appropriated to load additivesand antibacterial compounds. A mixture of starch andalginate to form edible film improve the mechanicalproperties of film.34PectinPectin is a heterogeneous grouping of acidic structuralpolysaccharides, found in fruit and vegetables and mainlyprepared from citrus peel and apple pomace. Thiscomplex anionicpolysaccharide is composed of β-1,4linked d-galacturonic acid residues, wherein the uronicacidcarboxyls are either fully (HMP, high methoxy pectin)or partially (LMP, low methoxy pectin) methyl esterified.Rosin is brittle and friable, with a faint piney odor. It istypically a glassy solid, though some rosin will formcrystals, especially when brought into solution. Thepractical melting point varies with different specimens,some being semi-fluid at the temperature of boilingwater, others melting at 100 C to 120 C. It is soluble inalcohol, ether, benzene and chloroform.Films produced from the plasticizer-free solutions weresmooth and transparent but brittle. Improvement in themechanical properties was attempted by addition ofplasticizers such as dibutyl sebacate (DBS). The additionof plasticizers plays a critical role in the performance offilm coating, which results in decreased tensile strength,lowered Tg, and increased elongation and flexibility of thefilms.35With Chitosan, HMP or LMP forms excellent films. Indeed,the cationic nature of chitosan offers the possibility totake advantage of the electrostatic interactions withanionic polyelectrolytes, such as pectin. It is alsointeresting to point out the application of LMP basededible coatings as a pre-treatment in osmotic dehydrationfor obtaining a better dehydration efficiency. Finallyrecently, an investigations demonstrated the preventionof crumb ageing of dietetic sucrose-free sponge cakewhen a pectin-containing edible film was used. Thissponge cake had better preserved freshness, especiallyup to the fifth day of storage.31RosinRosin is a thermoplastic acidic product isolated fromexudates of living pine trees &from freshly cut and stumpwood of various species of pine. It is a hydrophobicbiomaterial which is biodegradable. It is principally a resinacid and investigated as a film forming polymer and alsouseful as a coating material in pharmaceuticals. Free filmof rosin is prepared by casting or solvent evaporationmethod. Rosin is also known as colophony or colophoniaresina from its origin in Colophon, an ancient Ionic city.StarchStarch is the major carbohydrate reserve in plant tubersand seed endosperm. Biopolymer starch is composed ofglucose units and having two main constituents are,amylose and amylopectin. Amylose constituent is a linearone, having long chain of α-D glucose units linkedtogether by α-1,4 glycoside linkages (Figure 1) and onlyslightly branced. The amylopectin constitutes α-1,4linkages of glucose units, interlinked by α- 1,6 linkagesand having a branched structure. The starch obtainedfrom different sources has varying quantity of amyloseand amylopectin usually 16-28% of amylose content instarch granules, whereas waxy starch solely containedamylopectin. Starch occur in nature in three maincrystalline allomorphs designated as A, B and V-type. Btype crystalline is rapidly formed by amylose rich starchfilms and slowly by the aging of amylopectin rich starch36films. Amylose is responsible for the film-formingcapacity of starch. The largest source of starch is corn(maize) with other commonly used sources being wheat,potato, tapioca and rice.International Journal of Pharmaceutical Sciences Review and ResearchAvailable online at www.globalresearchonline.net172

Int. J. Pharm. Sci. Rev. Res., 21(1), Jul – Aug 2013; n 29, 169-178Starch is used to produce biodegradable films to partiallyor entirely replace plastic polymer. The films aretransparent or translucent, flavourless, t

polymers that rapidly dissolves on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made. Water-soluble polymers are used as film formers for fast dissolving films. The water-soluble polymers achieve rapid disintegration, good mouth feel and mechanical

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