Sndeep Krki,Hyeongmin Kim,Seon-Jeong N, Dohyun Shin,c,Knghee Jo,c,Jehwi Lee,b,c,*

aPharmaceutical Formulation Design Laboratory,College of Pharmacy,Chung-Ang University,Seoul 06974, Republic of Korea

bBio-Integration Research Center for Nutra-Pharmaceutical Epigenetics,Chung-Ang University,Seoul 06974, Republic of Korea

cCenter for Metareceptome Research,Chung-Ang University,Seoul 06974,Republic of Korea

Review

Thin flms as an emerging platform for drug delivery

Sandeep Karkia,1,Hyeongmin Kima,b,c,1,Seon-Jeong Naa, Dohyun Shina,c,Kanghee Joa,c,Jaehwi Leea,b,c,*

aPharmaceutical Formulation Design Laboratory,College of Pharmacy,Chung-Ang University,Seoul 06974, Republic of Korea

bBio-Integration Research Center for Nutra-Pharmaceutical Epigenetics,Chung-Ang University,Seoul 06974, Republic of Korea

cCenter for Metareceptome Research,Chung-Ang University,Seoul 06974,Republic of Korea

A R T I C L EI N F O

Article history:

Received 21 April 2016

Accepted 12 May 2016

Available online 6 June 2016

Thin flm

Film-forming polymer

Mechanical properties

Manufacturing

Characterization

Pharmaceutical scientists throughout the world are trying to explore thin flms as a novel drug delivery tool.Thin flms have been identifed as an alternative approach to conventional dosage forms.The thin flms are considered to be convenient to swallow,selfadministrable,and fast dissolving dosage form,all of which make it as a versatile platform for drug delivery.This delivery system has been used for both systemic and local actionviaseveral routes such as oral,buccal,sublingual,ocular,and transdermal routes.The design of effcient thin flms requires a comprehensive knowledge of the pharmacological and pharmaceutical properties of drugs and polymers along with an appropriate selection of manufacturing processes.Therefore,the aim of this review is to provide an overview of the critical factors affecting the formulation of thin flms,including the physico-chemical properties of polymers and drugs,anatomical and physiological constraints,as well as the characterization methods and quality specifcations to circumvent the diffculties associated with formulation design.It also highlights the recent trends and perspectives to develop thin flm products by various companies.

?2016 Shenyang Pharmaceutical University.Production and hosting by Elsevier B.V.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

1.Introduction

Generally,thin flms can be referred as a thin and fexible layer of polymer with or without a plasticizer[1].Since they are thin and fexible by their nature,it can be perceived to be less obtrusive and more acceptable by the patient[2].The thin flm is polymeric matrices that meet many requirements for being used effciently as a drug release platform[3].Fundamentally,thin flms are excellent candidates for targeting sensitive site that may not be possible with tablets or liquid formulations[4].Thin flms have shown the capabilities to improve the onset of drug action,reduce the dose frequency and enhance the drug effcacy[3].Similarly,thin flms may be useful for eliminating side effects of a drug and reducing extensive metabolism caused by proteolytic enzymes[5,6].Ideal thin flms need to exhibit desirable features such as suffcient drug loading capacity,fast dissolution rate or long residence time at the site of administration,and acceptable formulation stability.They should also be non-toxic,biocompatible and biodegradable[7,8].

Compared with the existing traditional dosage forms,it stands out to be superior in terms of enhanced bioavailability, high patient compliance,and patent extension of active pharmaceutical ingredients(API)[9].Furthermore,thin flm formulations offer several advantages,including(a)convenient administration through non-invasive routes,(b)ease of handling during manufacture and transportation,and(c)costeffectiveness in the development of formulations[8,10,11].The availability of a wide array of suitable polymers and the paradigm shift in manufacturing technology have made possible to develop a wide range of thin flms[12].Therefore,a thin flm is gaining popularity and acceptance in the pharmaceutical arena as a novel drug delivery dosage form.

Substantial efforts have been made to formulate polymeric thin flms that are administered generallyviabuccal,sublingual,ocular and skin routes[13,14].Among different routes,the useofthinflmsfordeliveringmedicineintosublingualorbuccal mucosahasdrawnimmenseinterestinrecentyears[15].Meanwhile,ophthalmicflmsarecurrentlydevelopedforovercoming the ocular barriers and preventing loss of drugs through the lacrimal drainage system[16].Controlling compositions of polymers of different grades has facilitated the modifcation of key characteristics of thin flms such as drug release rate, mucoadhesiveproperties,mechanicalstrengthandotherrelated properties.Additionally,variousinactivecomponentscanbeincluded such as fllers,plasticizer,saliva stimulating agent, colorants,and sweeteners for improving aesthetic characteristics.Many pharmaceutical companies are fascinated by the appealingfeaturesofthinflms,andasaresulttheyhavealready patented various technologies for producing thin flms[17].

Currently,a signifcant amount of original works and patents can be found in literature,but still there is a need for extensive studies to optimize the performance of thin flms accurately.The lack of appropriate guidance for the manufacture,characterization and quality control of the thin flms has sought the need of adequate studies in this area from the pharmaceutical viewpoint.Therefore,this paper will contribute to give insights on understanding the critical quality attributes and characterization methods with the aim to enhance the performance of thin flms.

2.Types of thin flms

Thin flm is not a recent formulation,and it was frst introducedinlate1970toovercomeswallowingdiffcultiesexhibited by tablets and capsules[15].Various names of thin flms appeared,such as oral flm(oral thin flm),oral soluble flm,wafer, oral strip,orodispersible flm(ODF),buccal flm,mucoadhesive flm,ophthalmicflm,andtransmucosalflm.Whileseveralflms are designed to be dissolved quickly in the oral cavity for the absorption of a drug in the gastrointestinal cavity(oral and oral soluble,or orodispersible flms),some are prepared to deliver a drug at the site of administration(e.g.,buccal,sublingual and ophthalmic thin flms).Drugs with high mucosal permeability have been known to be suitable for buccal and sublingual delivery with flms[18].Likewise,ophthalmic thin flms are generally applied to treat diseases of the anterior segment such asconjunctivitis,glaucomaandchronicdryeyesyndromes[5,19].

A flm that readily dissolves in the oral cavity is generally termed as orodispersible flm according to European Medicines Agency(EMA)or simply soluble flm according to FDA [3].Usually,fast dissolving oral flms are ultra-thin flm(50–150 μm)having size of postage stamp,which dissolves within a minute in the oral cavity after being in contact with the saliva, resulting in quick absorption and instant bioavailability of the drugs[20,21].Drugs loaded in buccal adhesive flms are absorbed directlyviabuccal mucosa,which delivers the drug to the systemic circulation after their absorption[22].Likewise, wafer is frequently mentioned as paper-thin polymeric flms employed as carriers for pharmaceutical agents.This innovative dosage form is taken orally but does not require water to swallow for the absorption of a drug[23].Orodispersible flms should not be misunderstood with buccal flms designed for staying longer on the cheek mucosa[24].Therefore,different types of flms should be distinguished accurately to prevent possible misinterpretations.

3.Advantages of thin flms as an emerging dosage form

3.1.Advantages over conventional dosage forms

A thin flm dissolves rapidly than other conventional dosage forms[25].Thin flms are less friable and easy to carry dosage form compared to commercialized orally fast disintegrating tablets,which need special packing.Likewise,a single dose of strip can be carried individually without requiring the secondary container[26,27].It is very important to address the poor stability of liquid dosage forms,especially the aqueous formulations.Unlike the thin flms,there is a need for great care during accurate measurement of the amount and shaking the bottle every time before administration may contribute to less acceptance by the patients[3].Conventional ophthalmic drug delivery systems such as eye drops or solutions are commonly used but they are limited in their ability to provide high ocular drug bioavailability and sustained duration of action [28].Ophthalmic thin flms can be used to improve the drug delivery to the eye.In contrast to transdermal patch,the transdermal flm is less associated with skin irritation due to lessocclusive properties that improve the water vapor permeation through the skin and do not leave sticky sensation on the site of application[29,30].

3.2.Clinical advantages

Patients show preference toward thin flm due to its appellative form and ease of administration[17].Furthermore,oral dissolving flm is extensively useful for pediatric,geriatric,and psychiatric patients since it is easy to administer and avoid the risk of choking or suffocation,thus ensuring patient safety [22].Ophthalmic flms have been known to enhance the retention time of a drug,and thereby the absorption of the drug was greatly improved from the anterior segment of the eye[31].Moreover,the polymeric thin flms can also be benefcial for bedridden and non-cooperative patients as they can be administered easily and hardly spit out.A thin flm is useful in cases where a rapid onset of action is required,such as in motion sickness,sudden episodes of allergic attack or coughing,bronchitis or asthma[22].

4.Major limitations of thin flms

Use of thin flms is sometimes limited largely due to low drug loading capacity for a less potent drug given at high dose[10]. Thin flms are usually hygroscopic in nature.Thus,special precaution should be taken for their longer preservation[4]. Combining more than one drug concomitantly is a very challengingtaskinoralflmformulationbecauseboththedissolution rate as well as the disintegration time are hindered by the coadministrationofadruginoralflms[32].Thediffcultytoobtain a high degree of accuracy with respect to the amount of drug inindividualunitdoseoftheflmcanleadtotherapeuticfailure, non-reproducible effects and sometimes toxic effects to the patient[33].Preparing oral flm formulation is concerned with theissuesofrequiringexcessivetimefordrying.Ittakesaround one day for the complete drying at room temperature,which notably decreases the rate of production of flms.Since it is not recommended to use hot air oven for thermolabile drugs, an alternative process of drying should be explored[22].

5.Polymers for the preparation of thin flms

Polymers are the backbone of flm formulations and various polymers are available for the preparation of thin flms[34]. The polymers can be used alone or in combination with other polymers to achieve the desired flm properties.The polymers employed should be non-toxic,non-irritant,and absence of leachable impurities is required.Water-soluble polymers are used as flm formers to produce a thin flm with rapid disintegration,good mechanical strength,and good mouthfeel effects.Both natural and synthetic polymers are used for flm preparation[20,35].The list of polymers commonly used in the manufacture of polymeric flms,with additional descriptions and properties,is depicted in Table 1.

Availabilityofdiversepolymersallowsimpartingspecifcproperties in the thin flms.For instance,gelatins are available in different molecular weights,and thus the appealing and glossy flms could be obtained with the gelatin having a high molecular weight.Pullulan is frequently used for producing a thin flm withgreatsolubility,highmechanicalstrengthandtheyarestable overawiderangeoftemperatures.Theblendingofchitosanand high methoxy pectin(HMP)or low methoxy pectin(LMP)resultedinathinflmexhibitinganexcellentmechanicalstrength. Theflmformingpolymerssuchashydroxypropylcellulose(HPC), methyl cellulose,and carboxymethyl cellulose(CMC)produce athinflmwithlesswatervaporbarrierduetohydrophilicnature which aids in water retention[15].

In one study,a fast-dissolving flm of triclosan was prepared using different grades of hydroxypropyl methylcellulose (HPMC)named as Methocel E3,Methocel E5,and Methocel E15 Premium LV as a primary flm former.The result demonstrated that Methocel E5 Premium LV at the concentration of 2.2%w/v produced flms with excellent flm properties[37].Thein vitroresidence time of the flm made from Carbopol?934P and HPMC E15 was almost double than the flms containing only HPMC E15.Additionally,it was observed that the combined polymers were more resistant to breakage[11].Cilurzo et al.reported the use of maltodextrins(MDX)with low dextrose content as a flm forming polymer for the preparation of oralfast-dissolvingflmsofaninsolubledrug,piroxicam.Despite the decrease in flm ductility due to the loading of the drug as a powder,the produced flm exhibited satisfactory fexibility and resistance to elongation along with rapid dissolution[38]. Similarly,oral dissolving flms of granisetron HCl manufacturedusingHPMCandpullulanillustratedtheeffectofincreasing polymer concentration on mechanical properties and physical properties of flms.Pullulan with 40–45%concentration was notabletoproduceflmswithgoodstrengthwhereastheHPMC used in 40%concentration yielded the flm which was diffcult to peel.Likewise,the flm stickiness increased when the concentration of HPMC was beyond 50%[39].

Mucoadhesive flms are thin and fexible retentive dosage forms,andreleasedrugdirectlyintoabiologicalsubstrate.They facilitate in extending residence time at the application site leadingtoprolongedtherapeuticeffects[40].Majorityofthethin flm having mucoadhesive properties are hydrophilic in nature and undergoes swelling and form a chain interaction with the mucin[11].Amongtheseveralstudiedpolymers,themostcompelling mucoadhesion properties are exhibited by chitosan, hyaluronan,cellulosederivatives,polyacrylates,alginate,gelatin and pectin[41].Compared with non-ionic polymers,the cationic and anionic polymers facilitate strong interaction with mucus[42].Anionic polymers are well characterized due to the existence of carboxyl and sulfate functional groups,which create the negative charge at pH values surpassing the pKa of the polymer.As an example,sodium carboxymethyl cellulose(NaCMC)and polyacrylic acid(PAA)exhibit excellent mucoadhesive properties because of bond formation with the mucin[43].Thiomers,i.e.polymer containing thiol group,stand out to enhance mucoadhesion because they are able to interact with the mucin through the formation of disulfde linkages. The process of‘thiloation’is possible with many polymers, using amide-coupling chemistry,where the aqueous solvent systemsareused[44].Eudragitdisplayedpromisingmucoadhesive properties when used alone or in combination with other hydrophilic polymers.Films,prepared from the propranolol HCl,Eudragit RS100,and triethyl citrate(plasticizer),demonstrated mucoadhesive force three times greater than the flm prepared with chitosan as the mucoadhesive polymer[11].Juliano et al. prepared a buccoadhesive flms consisting of alginate and/or HPMC and/or chitosan either as a single polymer or in a combination of two.Basically,they aimed the flms to release the chlorhexidine diacetate in a controlled manner.HPMC was not able to prolong the chlorhexidine release as more than 80%of thedrugwasreleasedwithinonly30 min.However,chlorhexidine incorporatedinalginateandalginate/chitosan-basedflmsshowed that only 30–35%of the drug was released in 30 min;hence,this polymeric system is benefcial for prolonged drug release[45].

(continued on next page)

In common terms,polymers are understood as excipients,but it has become an essential component while designing and formulating thin flms.Therefore,understanding the properties of polymers such as chemistry,rheology,and physicochemical properties of polymer seems to be imminent for maximizing their uses to develop a thin flm.The selection of appropriate polymer during the development of polymeric thin flms may be critical;thereby,several points should be considered according to the requirements.Therefore,it is imperative to consider the appropriate polymer for producing a thin flm with a better performance that assures high therapeutic success.

Table 1–(continued)

6.Technologies for manufacturing thin flms

The most commonly used techniques for the preparation of thin flms are solvent casting[46,47]and hot melt extrusion [38,48].However,an innovative technique like inkjet printing [49]has evolved in the past few years.Various methods that have been employed for polymeric thin flm manufacturing are described below in detail:

6.1.Solvent casting

Among several techniques of flm manufacturing,solvent casting is feasible,preferable and undoubtedly widely used method mainly due to the straightforward manufacturing process and low cost of processing.The manufacturing procedure of thin flms with the solvent casting method along with the quality control parameters in each step is illustrated in Fig.1. The rheological properties of the polymeric mixture should be taken into account since they affect the drying rate,the flmthickness,the morphology as well as the content uniformity of the flms[26].The mixing process could introduce the air bubbles into the liquid inadvertently;therefore,de-aeration is a pre-requisite to obtain a homogeneous product[17].After casting the solution into a suitable substrate,they are left for drying to allow the solvent to evaporate,which just leaves a polymeric flm with a drug on it[2].

Fig.1–Solvent casting method for flm preparation with quality control parameters in each step.

After the complete drying of the flm,it is cut into suitable shapeandsizedependingupontherequireddosageoftheformed strip.Inthemajorityofthecases,thestripsarerolledandstored for a certain time before cutting,which is known as‘rollstock’in an industry.However,a flm should not be exposed for too longtimesinceitisproneforbeingdamaged.Ifpossible,itshould be cut and packed immediately after the preparation to keep itsstability[17].Severaladvantagessuchasbetterphysicalproperties,easy and low cost processing,and excellent uniformity of thickness are observed with the flm obtained by solventcasting[50].However,thisprocesssuffersfromsomelimitation. For instance,a polymeric thin flm prepared by solvent casting method was brittle upon storage,as marked by decrease in the percent elongation due to evaporation or loss of the residual solvent in the flm over time[51].Another issue under scrutiny associatedwiththismethodistherequirementofusingorganic solvents.The presence of organic solvent system is a serious problem because it causes a hazard to health and environment.As a result,strict regulations have been adopted by many countries regarding the use of an organic solvent[11].

Translating the production of flms from a bench scale to production scale is one of the biggest challenges because many factors such as heating,mixing speed,and temperature could bring variability in quality,and consistent formation of flms in commercial scale may not be possible.Therefore,suffcient endeavor should be invested to optimize the various parameters such as the speed of casting,drying time,and fnal thickness of the dried strip,which may affect the production of flms from commercial scale output[17].Fig.2 depicts the machine that is used for a large-scale production of flm based on solvent casting technique.

Fig.2–Commercial manufacturing of flm based on solvent-casting(reproduced from Ref.[22]).

6.2.Hot-melt extrusion(HME)

HME is a versatile method adopted for the manufacture of granules,tablets,pellets[52],and also thin flms[38].It is a substitute method to solvent casting for the preparation of the flm,especially useful when no organic solvent system is required[10]. However,only few literature has reported the use of hot-melt extrusion for the preparation of polymeric thin flms[11].HME is a process of shaping a mixture of polymers,drug substance,and other excipients into a flm by melting all the components[3].Eventually,the flms are cut into a particular shape and dimensions[6].In this method,a mixture of pharmaceutical ingredients is molten and then charged through an orifce(the die)to obtain homogeneous matrices[11].Since APIs are subjected to operation at high temperature with complete absence of solvents,this method is not suitable for thermos-labile APIs[17].The practical steps of HME are outlined as follows[53]:

(1)Feeding of the components to the extruder through a hopper,

(2)Mixing,grinding,and kneading,

(3)Flowing the molten and blended mass to the die,and

(4)Extruding the mass through the die and further downstream processing.

The equipment for the process of HME is illustrated in Fig.3, which consists of the hopper,extruder,flm die,and roller.The extruder contains one or two rotating screws(co-rotating or counter rotating)inside a static cylindrical barrel.The barrel is often manufactured in sections to shorten the residence time of the molten material.The sectioned part of the barrel is eitherboltedorclampedtogether.Similarly,theendportionofthebarrel is connected to the end-plate die,which is interchangeable depending upon the required shape of the extruded materials[1].

Fig.3–Hot-melt extrusion system for the preparation of flms(reproduced from Ref.[22]).

With regard to the advantages of HME,it produces a drug in the form of solid dispersion or solution,which could improve solubility of poorly soluble drugs[51].However,at elevated temperature,there is a high chance of recrystallization of API in the polymer blend as the temperature drop.Using highly viscous polymeric substance or increasing the amount of plasticizer can prevent this problem.Another issue of HME is the“Die swell phenomenon,”i.e.an increase in the cross-section of the flm after ejection from the die depending on the viscoelastic characteristics of polymers.This is due to the polymer withstanding high energy kneading and high shear force during extrusion. This problem can be prevented by slowing the speed of screw operation or by gently mixing molten mass for a long time instead of high shear kneading for a short duration[54].Unlike solvent casting,this method avoids the need of organic solvent; hence,they are proven to be environment friendly[2].

6.3.Printing technologies

Novel methods such as 3D printing could be used for manufacturing polymeric thin flms.It could potentially be a platform for producing the dosage form benefcial to the individual patient.This possibly will resolve the issue of the pharmaceutical industry and pharmacies to meet the future demand of customized medicine[55].The printing technologies are increasingly gaining popularity because of its fexibility and costeffectiveness.From the viewpoint of pharmaceutical industry, printing technologies are commonly in practice for identifying or labeling of the pharmaceutical dosage forms,particularly to optimize the product to be readily identifed and to prevent counterfeit production.However,this approach has recently been adopted for the drug loading of pharmaceutical dosage forms[3].The examples include the use of off-the-shelf consumer inkjet printers in which drug-loaded inks are deposited to yield accurately dosed units of pharmaceutical ingredients.In addition,a combination of inkjet and fexographic technologies has been practiced as well[55].The inkjet printing was used for printing of API on different substrate,whereas the fexographic printing was employed to coat the drug loadedsubstrate with a polymeric thin flm[56].

Loading of drug substances into transdermal patches is possibleviascreenprintingandpadprinting;however,padprinting is limited by the low speed of production.In recent years,inkjet printing has made inroads for preparation of flm formulation asasafeandaccuratemethodtoproducedosageformofpotent drugadministeredatlowdose[57].Preparationofmultiplelayers can be done by adding a second printing layer on the top of thefrstwithorwithoutanintermediatebaseflmlayer.Further, the printed layer would be shielded by a second base flm layer. This will result in modifed drug release profles and protect theinklayerfromdetachmentormechanicalstressduringprocessing like cutting or packaging area[55].

Regardless of the various types of printing technique used,all of them contribute to producing a flm with more homogeneous distribution and accurate dosage of the drug throughout the flms.The dose accuracy and uniform distribution of the drug substances in the flms are accounted for several reasons,such as coating mass properties,like viscosity or density,which are inherently infuenced by the amount and characteristics of the processed drug substances.With regard to the conventional method of flm preparation,it may be very challenging to ensure the same dosage accuracy in the individual units[3].To summarize,printing a drug on dosage form is the latest intervention for flm preparation and it has become a powerful tool to manufacture dosage form with excellent uniformity,speed-ability,and stability.Representing printing technologies that have been used for preparation of polymeric thin flms are discussed below.

6.3.1.Inkjet printing

Inkjet printing is the recently developed technology,which is characterized by its versatility,accuracy,repeatability and relatively inexpensive method that deposits small volumes of solution in flms.Inkjet printing is extensively applicable for the preparation of low dose medicines and also offers an opportunity to manufacture personalized medicines[58].

Inkjet technology is usually divided into mainly two types: (a)continuous inkjet printing(CIP)and(b)drop on demand (DoD)printing.Both are different in their printing process by which the drops are generated.In the case of CIP,there is a consistent ejection of a liquid through an orifce(nozzle),and it breaks up into a stream of drops under the force of surface tension.For the continuous production of a stream of inkdrops,the individual drop should be‘steered’to a particular landing site to produce a printed pattern.This is possible by applying an electric charge on some of the drops that defect the stream from the main axis under an electrostatic feld.On the other hand,ejection of the liquid from the printhead occurs in drop-on-demand printing only when a drop is needed.The production of individual drop takes place rapidly under the response of trigger signal.A DoD printhead consists of multiple nozzles(ranges from 100 to 1000,even though specialist printhead may have a single nozzle).The drop ejection occurs due to the kinetic energy of drops generated from the source located in the printhead nearby to each nozzle[59].

The uniform distribution and dose accuracy of the drug substance in the flm rely upon the density or viscosity of the ink (drug substance solution or suspension),which determine the printability characteristics[3].Jan?en et al.demonstrated the deposition of low doses of salbutamol sulfate onto commercially available starch-based flm using conventional desktop printers[10].However,inkjet printing is not applicable for highthroughput industrial production,instead using of fexographic printing is regarded more suitable for industrial preparation.

6.3.2.Flexographic printing technology(FPT)

FPT is a process that transfers active pharmaceutical ingredient into thin flms gentlyviacontact printing[10].The fexographic printing is a rotary printing process as depicted in Fig.4,where ink consisting of drug substance solution and suspension is measured by an anilox roller,then are transferred to a printing cylinder that prints the flm after unwinding the daughter roll[3].It is useful for heat sensitive products like proteins and peptides.As the mixing and drying of flm formulation are processed before introducing the drug,the problems such as loss of activity of API can be prevented.The production effciency is also high considering the productionrate of 530 oral flms per minute;hence,this process could be expanded to scale-up production[6].No effect on the mechanical properties of polymeric thin flms upon printing drug solutions was witnessed using fexographic printing[57].In a study,Jan?en et al.found that it was possible to dispense tadalafl and rasagiline mesylate solution onto hydroxypropyl methylcellulose flms using fexographic printing.The introduction of hydroxypropyl cellulose appeared to reduce drug crystallization after printing.However,the main drawbacks of fexography are relatively low resolution,high chances of contamination,and the need to prepare a print roller,which is not suitable for large scale production[10].

Fig.4–Schematic overview of fexography technology for the preparation of flms(reproduced from Ref.[57]).

7.Quality issues of thin flms

For being regarded as an ideal thin flm,a flm should have adequate fexibility,softness,elasticity,and good physicochemical stability.Therefore,all these parameters should be considered carefully while developing flm to ensure its effcient performance.Characterization of a flm is a pre-requisite that may include assessing properties such as mechanical strength,hydration,in vitrorelease and surface morphology. The following section outlines the various critical quality attributes affecting flm properties and commonly usedin vitromethods for flm characterization.

7.1.Thickness and weight variation

The measurement of thickness is necessary as it directly correlates with the amount of drug in the flm.In addition,an appropriate thickness is required for the comfortable administration of flms.For instance,the ideal thickness of buccal flms should be in the range of 50 to 1000 μm[12].Generally, the thickness of the formed thin flms is measured usingVernier caliper,electronic digital micrometer,screw gauge,or scanning electron microscopy(SEM)images[60,61].The amount of plasticizer in the formulation is known to increase the flm thickness slightly[62].By inserting m(Batch)–the mass of the whole batch,m(API/flm)–the drug amount per flm,ρ(Batch)–the density of the formulation,m(API)–the total drug amount in the batch and A(Film)–the area of one flm in Eq.(1),it is possible to calculate the casting thickness(h).A correction factor f is added due to the shift of actual value of flm thickness compared to the set values.A shift behavior is defned beforehand over different coating thicknesses[63].

where API is active pharmaceutical ingredient,m is mass,ρ is density,and A is area expressed in g,g/cm3,and cm2respectively.

The weight variation is generally determined to ensure that each flm contains the consistent amount of a drug without signifcant deviation.It is calculated by weighing the individual flm and the average weights of specifed flms respectively.The average weight of flm is subtracted from the individual weight of patches.The mean±SD values are calculated for all the formulations.A large variation in weight signifes the ineffciency of the method applied and high chances are there for non-uniformity in drug content[12].

7.2.Mechanical and physical properties

Polymeric flms should possess enough tension so that it can be ejected easily from the pouch,rolled up after casting,and peeled from the release liner,but should not be too fexible because greater elongation during cutting and packaging might cause variation in flm amount resulting in non-uniformity of API amount per flm[49,64].Mechanical properties of flms can be defned in terms of Young’s modulus,percent elongations, tensile strength and tear resistance[64,65].It has been known that soft and weak polymers exhibit low tensile strength,low elongation at break and lowYoung’s modulus,whereas the hard and tough polymer have a high tensile strength,high elongation at break and high Young’s modulus[11].Additionally,the mechanical properties of flms are affected by the method of manufacturing and the formulation.Some general behaviors of flms observed from stress–strain curves are shown in Fig.5 [6].The concentration and types of the polymers are largely responsible for producing a flm having good mechanical strength and integrity[66].Likewise,the morphological state of the flm may alter the mechanical strength,e.g.by crystal growth[64].Therefore,different factors such as flm-forming agent,type of manufacturing process,thickness of flm and the type and amount of API in the flm have to be considered carefully for controlling the mechanical strength of the flm.

Blending and cross-linking of two or more polymers are useful methods to improve the mechanical properties of the combined polymeric mix[67].The flm maintains their appearance and integrity after cross-linking,but hardening of the flm surface can occur[68].Consistent with this observation, the mechanical properties of PVA–NaCMC flms were greaterthan flm composed of PVA or NaCMC alone.The tensile strength of PVA–NaCMC flm was found to be 13 to 17 times greater than those of flms made of the synthetic polymer N-vinylpyrrolidone[69,70].Use of plasticizer may overcome the brittleness and soften the rigidity of the flm structure by reducing the intermolecular forces.The most commonly used plasticizer are glycerol,sorbitol,propylene glycol and polyethylene glycol[66,71].However,using too much amount of plasticizer can decrease the adhesive strength of flms by overhydrating the flm formulations[72].For example,glycerin intercalates themselves between every individual strand of polymer,thereby causing disruption of polymer–polymer interaction.The tertiary structure of the polymers is changed into more fexible and porous type.For this reason,the plasticized polymer deforms at lower tensile strength compared with a polymer without plasticizer[73].

Fig.5–Examples of stress–strain curves obtained from polymeric thin flms(reproduced from Ref.[11]).

In most of the works of literature,the most commonly used method for characterizing the mechanical strength of a polymeric flm is carried out by using texture analyzer.The system starts measuring force and displacement of the probe when they are in contact with the sample.There is an individual sample holder to aid measurement of small-sized flm samples (Fig.6).Films are attached by screws between two plates with a cylindrical hole of required diameter.The plate is stabilized to avoid movements using pins,which are placed centrally beneath the punch.The adjustment can be made to move the probe forward according to required working velocity.The measurement starts after the probe is in contact with the sample surface(triggering force).The movement of probe occurs at constant fxed speed until the flm detaches.At last,the applied force and displacement(penetration depth)should be recorded along with the room temperature and relative humidity [64].During the measurement of mechanical strength using texture analyzer,it was found that the contact time,contact force,and the speed of probe withdrawal markedly infuence the experimental outcome[74].The tensile strength is calculated by using several parameters such as folding endurance, percent elongation,elongation at break andYoung’s modulus.

7.2.1.Folding endurance

The fexibility of thin flm is important when considering that the flms can be administered without breakage.The fexibility of the polymeric thin flms can be measured with respect to its folding endurance.The folding endurance is determined by folding the flm repeatedly at 180°angle of the plane at the same place until it breaks.The flm exhibiting folding endurance value of 300 or more is considered to have excellent fexibility[75].

7.2.2.Percent elongation and elongation at break

Fig.6–Experimental setup(left)and sample holder for the flm preparation(right),where rsindicates radius of samples, and rpindicates radius of probe.Geometry of cylindrical probes A and B and spherical probe C is shown on the right bottom (reproduced from Ref.[64]).

Elongation,a kind of deformation,is a simple change in shape that any objects encounter under any applied stress.In otherwords,when the sample is subjected to tensile stress,deformation of the sample takes place resulting in stretching or elongation of sample[17].Measurement of elongation is generally done to predict the ductility of polymers[65].Elastic elongation or elongation at break of a sample can be measured by using a texture analyzer.Elastic elongation is a phenomenon shown by all kinds of elastomers.The percent elongation indicates the stretch ability of material without being broken,whereas elongation at break means the point until which the flm can be stretched when it is torn(or broken)by the applied probe(Fig.7).With the exertion of stress to a sample, strain generates,and the sample elongations will become more predominant as the amount of stress applied increases.After reaching a certain point,the sample breaks;this point of breakage is referred to as percent elongation break[76].The formula for percent elongation is given in Eq.(2)as under:

Fig.7–Determination of percent elongation of thin flms using a texture analyzer,where a=initial length of the flm in the sample holder opening,a’=initial length?radius of probe,b=displacement of the probe,c’+r=length after strain,c’=length of a’after strain,r=radius of the probe [64].

Elongation at break can also be calculated by using following formula as well:

where a is the initial length of the flm in the sample holding opening,a’is the length of the flm not punctured by the probe, b is the penetration depth/vertical displacement by the probe, and r is the radius of the probe(Fig.7)[64].

7.2.3.Young’s modulus

Young’s modulus or elastic modulus refects the stiffness or elasticity of the flms.This indicates resistance to deformation of the flms,which can be calculated by plotting the stress strain curve,where slope indicates the modulus,i.e.the greater the slope,the greater would be the tensile modulus.On the other side,the small slope means lesser tensile modulus and deformation[77].Simply,a flm,exhibiting higher tensile strength and greater Young’s modulus values,is the one that is hard and brittle with small elongation.Texture analyzer can be used for the measurement ofYoung’s modulus,where slope is obtained from the stress strain curve.Young’s modulus is represented as the ratio of applied stress over strain in the region of elastic deformation,which can be determined using the following formula:

A range of crosshead speed can be obtained by changing the speed of the motor of the texture analyzer[15].

7.2.4.Tear resistance

The property of the flm to withstand the rupture is known as tear resistance.The measurement of tear resistance is done by allowing the flm to undergo a constant rate of deformation.The maximum force or stress needed to tear the flm is measured in Newton or pound-force[17].In a stress strain curve, the area of the plot measures the tear resistance.The relation of an area under the stress strain curve is directly proportional to the toughness of the flm,i.e.higher area of the plot means higher toughness of the flm and also greater amount of energy that a material can absorb.Therefore,it measures the strength of the material rather than toughness.In fact,a less strong material can be tougher compared with a strong material and no confusion should be created[12].

7.3.Moisture content

The amount of moisture in the flm could be crucial as it affects the mechanical strength,adhesive properties,and friability of flm[78].Several factors are responsible for elevating water level such as hygroscopic properties of API,polymers,and solvent system used to dissolve the polymeric mixture,and manufacturing techniques.In general,the moisture content of the flm is determined by using several methods like Karl Fischer titration or by weighing method.In weighing method,preweighed flms(initial weight)are heated at a temperature of 100–120°C until they attain constant weight.Finally,the weight of the fnal dried sample is taken.Eq.(5)is used for calculating the amount of moisture content in the flm that is expressed as%moisture and is given below[12]:

7.4.Swelling

Swelling properties of flms are generally observed as the polymers employed for making flms are hydrophilic[79].Swelling of the polymers is known to be the fundamental step required for bioadhesion[80,81].In many cases the degree and rate of swelling play a key role in controlling the release of the drug.Hence,these parameters can be considered as the indicator for bioadhesive or mucoadhesive potential and drug release profles.The testing of swelling is done to measure polymer hydration[82].Hydrophilic polymers with different structures possess a varying degree of swelling based on therelative resistance of matrix network structure to water molecule movement.For example,a polymer chain having the low ability to form hydrogen bond is unable to form a strong network structure,and water penetration is also diffcult to occur.When the number of hydrogen bonds as well as the strength between the polymers increase,the diffusion of water particles into the hydrated matrix occurs at a slow rate[83]. This was demonstrated by Panomsuk et al.,where it was reported that the introduction of mannitol to methylcellulose matrix decreases the swelling index of the membrane.This may be due to the formation of hydrogen bonding between drugs and the polymeric matrix[84].

Measuring swelling or degree of hydration of the polymeric flm plays an important role in providing key information on the mucoadhesive strength.As we know,the hydration of polymersisthereasonforrelaxationandinterpenetrationofpolymeric chain;however,the overhydration results in a decrease of mucoadhesion properties due to formation of slippery mucilage[85].The swelling properties of flms,i.e.water absorption capacities,are measured by evaluating the percentage of hydration.For example,the piece of flms is weighed(W1)and it is subjected to immersion in simulated physiological fuid for a predetermined time.After the predetermined time,the sample istakenout,wipedofftoremoveexcessivewateronthesurface and weighed(W2).The calculation is done by using the following formula,which is expressed in%[83,86].

Furthermore,area swelling ratio(ASR)can be used to determine the swelling property of the prepared flms.As a procedure,the flms are placed in a Petri dish and 100 ml quantity of phosphate buffer(pH=7.4)was poured into it as a swelling fuid.The diameter of a flm is calculated at certain time intervals.The calculation of ASR is based on Eq.(7)[87].

where Atis area of the flm at time t,and A0is area of the flm at time zero.

7.5.Drug release profles

Toagreatextent,thereleasekineticsofdrugsfromthepolymer matrixisprimarilydependentonthephysicochemicalproperties of the materials used as well as the morphology of the system [36].Variation in pH or temperature may cause increase or decrease in the erosion or dissolution rates of polymers[88].Upon contact with biological fuids,the polymeric flm starts to swell following polymer chain relaxes,resulting in drug diffusion. The release of drug holds a direct relationship with polymer structure;for example,linear amorphous polymers dissolve much faster than cross-linked or partially crystalline polymers [89].Accordingtoseveralstudies,thereleaseofthedrugismarkedly infuenced by erosion of the flm.The degradation rate of the flm is also dependent on the types of plasticizer[11].For the drug to penetratethebiologicalmembrane,thedrugshould be released from the delivery systems at an optimum rate. Assessing the drug release from the flm is essential as it is the rate-determining step in the process of absorption.The dissolution of drugs and/or flms is assessed with the apparatus that is approved for other solid dosage forms[90].

In the literature,many authors have done some improvisation on the dissolution apparatus,while others have employed Franz diffusion cells(FDC)for testing the drug release from the polymeric flms[12].A major barrier with respect to flm in dissolution testing is the placing of the samples.Several methods have been practiced,where the flm is attached on the inner side of the glass vessels or the stirring element using an adhesive tape[24].Okamoto et al.conducted a dissolution study of lidocaine flm for buccal administration using a JP XIII dissolution apparatus at 37±0.1°C.A flm was cut into a circle having an area of 1 cm2and adhered to a 3 cm diameter weight using double adhesive tape.Then,the flm with weight was placed in a glass vessel flled with 500 ml of artifcial saliva so that the flm dosage form faces upwards as shown in Fig.8[91].

Fig.8–Schematic illustration of the apparatus used for dissolution studies of flms.The flm dosage form(1 cm2) was attached to a 3 cm diameter weight using double adhesive tape(reproduced from Ref.[91]).

7.6.Surface morphology

The morphology of the flm should appear homogeneous and continuous to ensure the uniform distribution of drug throughout the polymeric mixture.Self-aggregation might take place during drying because of the intermolecular and convective forces leading to wrinkled surface in flms.Additionally, interaction between drug and polymers,and the crystalline nature of the drug,may result in the formation of rough surface in the flms[92].Hence,assessing the surface morphology and texture is crucial to assure uniform distribution of drugs without any interaction with the polymers in the flm formulation. Various surface characteristics such as surface texture(smooth or rough),thickness,and drug distribution(aggregated or scattered)of the flm can be observed using light microscopy, scanning electron microscopy(SEM),transmission electron microscopy(TEM)and related imaging techniques[83].Among all,the scientists have more clung to SEM as a reliable method for examining the surface morphology of the flms.The operation is carried out by mounting the flms on stubs,sputter coated with gold in an inert environment,and subsequentlythe photographs are taken at a suitable magnifcation.This approach can be utilized for close observation of size,shape and the number of pores on the surface of polymeric flms.Most recently,there are a number of studies on the use of SEM in evaluating the role of chemical composition of the flm on the crystallinity,morphology and texture[12].

8.Packaging of thin flms

Packaging is crucial to provide mechanical protection as well astokeepthestabilityofthinflmformulations.Itactsasabarrier tothemoisture,light,andoxygen.Anumberofchoicesareavailableforpackagingthepolymericthinflms,butnotallareeffective to preserve the integrity and physical properties of the product. Aluminum foils are most commonly used and considered ideal forflmpackagingasitpreventstheflmfrommoistureandlight degradation.Similarly,lidding foil has been employed if tamper proof packaging is needed.Films are subjected to multi-track sealing to achieve an accurate airtight seal between the upper and lower pack foils[17].The most commonly available sizes of flmsare3×2 cm2and2×2 cm2.Thepackagedflmsarechecked thoroughlybeforebeingpackedintoasecondarypackagingcontainer[22].The packing of manufactured flm in foil,paper or plasticpouchesiscost-effective,easytohandle,andallowseasy formation of the fexible pouch by either vertical or horizontal forming method during product flling[4].

Nowadays,the strips are available in both single dose sachets and multiple-unit blisters.A single dose sachet with a name Pocketpaks?for cool mint Listerine was introduced by Pfzer consumer healthcare.Similarly,a tear notch/slit/cut-off is manufactured to ensure convenience for the consumer to peel-off the pack.This technique is automated and computer-driven process[17].APR-Labtec launched a patented packaging system with the name Rapid card for the Rapid?flms.The rapid card has same size as a credit card and contains three flms on each side,which can be removed individually[22].

9.Routes for the administration of thin flms

9.1.Oral route

Developing polymeric flms has made it possible to improve the drug bioavailability and patient adherence to drug therapyviathe oral route,especially buccal and sublingual route.The anatomical and physiological characteristics of buccal mucosa, such as the existence of smooth muscles with high vascular perfusion,easy accessibility,and bypassing of frst pass metabolism make it a favorable route for the drug delivery[72]. The oral cavity consists of lips,cheek,tongue,hard palate,soft palate and foor of the mouth[2].Fig.9 demonstrates the common site for administration of flms to buccal and sublingual mucosa.Compared with the other mucosa,the buccal and sublingual routes are preferable because it provides better permeability of the drug[94].

Lesch and co-workers reported the water penetration across the buccal mucosa to be 10 times higher than skin[95].Similarly, the oral mucosa was found to be 4–4000 times more permeable to a hydrophilic drug than the skin[96].The sublingual route is targeted for the delivery of drug exhibiting high permeability across the mucosa and is utilized for the treatment of acute disorders.On the other hand,the buccal route is preferred for the treatment of chronic disease,when an extended release of the drug is desired[18].Direct access to the systemic circulation through the internal jugular vein is possible with buccal drug delivery[36].

However,systemic drug delivery in the oral cavity may be extremely challenging due to an unfavorable oral environment and physiological barriers.For achieving a promising therapeutic effect,the drug must be released from the formulation to the delivery site(e.g.sublingual or buccal region)and should penetrate the oral mucosa to reach the systemic circulation.The existence of several environmental related factors such as fuid volume,pH,enzyme activity and the permeability of oral mucosa determines the fate of drug absorption in the oral mucosa.On the other side,the amount of secretion of saliva impedes the residence of drug at the delivery site due to washing out of the drug.Similarly,the swallowing of drugs might occur before the absorption of the drug through the oral mucosa[2,93].Hence,while developing the oral formulation like polymeric flms,all the point should be taken into account for obtaining higher therapeutic bioavailability as well as the patient adherence to the dosage form.

Filmscontainingthepolymericblendwouldbeanidealplatform for the delivery of drugs in the oral cavity because of its comfort and fexibility[97].Over the last decade,there has been an enormous rise in the development of buccal flms as an alternative drug delivery for various classes such as antiinfammatory,analgesics,anesthetic drugs and proteins and peptides.Of recent,mucoadhesive flms have been used as a delivery platform for transmucosal buccal delivery of Biopharmaceutics Classifcation System(BCS)Class II drugs particularly targeting the opioid analgesics like fentanyl citrate, which is available with a trademark name such as Onsolis?/ Breakyl?for treating immense pain[26].Similarly,the mucoadhesiveflmremainsattachedtothebuccalareawithoutshowing any erratic absorption profle,resulting in less interand intra-individual variability[72].Oral thin flms(OTFs)are comparabletothedisintegratingsystem,whichissoakedinsaliva and stick to the site of application.The rate of disintegration is rapid,allowing the drug to release and followed by the oromucosal absorption.Many drugs that undergo degradation in the GI tract are being administered employing this route[98].

Fig.9–Demonstration of common site for application of flm in buccal and sublingual mucosa(reproduced from Ref.[93]).

In context to the commercially marketed product of the oral thin flm,the nutraceuticals and over-the-counter drugs were among the frst to be introduced in the market,and included the incorporated active such as vitamins,herbal and nonherbal extracts.In 2001,Pfzer introduced a thin flm product of Listerine Pocketpaks?developed as mouth freshener.The company Bio-flm has been putting an endeavor to develop oral thin flms.Not only the pharmaceuticals but they are also using nutraceuticals such as vitamins,aphrodisiac,energy boosters,and appetite suppressor that targets a specifc population of the certain age group.The energy booster consists of various compounds such as caffeine,guarana,and green tea extract to maintain the energy levels[17].A number of companies have been attempting to develop a drug delivery platform based on polymeric flms.Most of them have already succeeded in obtaining a flm with rapid release along with better therapeutic outcomes[2].The companies with their technology platform based on polymeric flm are listed in the Table 2.

Table 2–List of commercialized thin flms for drug delivery.

9.2.Ocular route

More than 90%of the marketed ocular formulations are in the form of solutions or suspension;however,this conventional dosage form lacks in achieving promising therapeutic success [99].The frequent instillation of eye drops is needed to elicit a therapeutic response.This usually leads to patient noncompliance and pulsed administration.Furthermore,the topically applied drugs to the eye generally enter the systemic circulationviathe nasolacrimal duct system,which possibly cause side effects and systemic toxicity as well[100]. With the aim of enhancing the ocular bioavailability and overcoming the ocular drug delivery barriers,the development of ophthalmic flm becomes popular these days[84].The ophthalmic flms result in the reduction of dose frequency,less systemic side effects and better therapeutic outcomes.Therefore,ophthalmic flms could open exciting opportunities as a delivery platform of therapeutics to replace the traditional dosage forms for achieving high therapeutic success and patient adherence.So far,the list of drugs formulated in ophthalmic flms is presented below in Table 3.

The fow of tear across the outer surface of the cornea is continuous,which impedes the drug diffusion leading to low bioavailability(1–7%)of drugs[108].Generally,the drug with higher lipophilicity encounters many problems as it cannot be dissolved in the aqueous medium of the eye.Since the drug causes discomfort in the eye,it induces blinking,and therefore causing washing out of the signifcant amount of drug. Therefore,the success of the effective development of flms to be delivered to the eye relies on the comprehensive knowledge of the drug,the constraints to ocular drug delivery,and the excipients used.Hence,all these factors should be considered during the formulation of ocular flms.

9.3.Transdermal route

Drug-loaded transdermal flms are the alternative to replace the existing transdermal dosage form.Numerous sustained or controlled delivery systems have been devised,where a drug is either dissolved or dispersed in the flms[71].The flmformingsystemhasbeenpracticedforthetransdermaldelivery of steroidal hormones,analgesics,local anesthesia and antiemetic for systemic effects[109–111].

Onlyasmallnumberofdrugsarebeingdesignedforthetransdermaldeliveryofflmsasseveralfactorsaffectthebioavailability of drug such as molecular size,polarity,pH of the drug,state of the skin hydration,subcutaneous reservoir of drug and drug metabolism by skin fora[112].Similarly,the hydration of skin is crucial for increasing drug absorption,which is possible by usinghumectantintheflmformulation.Thephysiologicalfactors such as regional skin site,nature of stratum corneum,the thickness of skin,and density of appendages also infuence the overall outcome of the therapeutic effects of the drug[113].

Table 3–List of drugs used in ocular flms.

The thin flm may possess better therapeutic effcacy and patient acceptance compared to the common transdermal dosage forms such as patches or gels[114].Due to occlusive properties of transdermal patches,it prevents the permeation of water vapor from the skin surface and causes severe pain at the time of peeling.However,polymeric thin flms could be a highly promising alternative for transdermal drug delivery because of the ease of application,fexibility and better cosmetic appearance[29].

10.Future scope of development and conclusion

The formulation of a drug into various flms has been popular in recent years.Several undesirable drawbacks associated with conventional dosage forms such as inconvenience of administration,lower bioavailability and patient non-compliance have pushed the development of novel polymeric thin flms as a drug delivery platform.This drug delivery platform is being under surveillance from both start-up and established pharmaceutical companies.The companies strive to design a wide range of thin flms for oral,buccal,sublingual,ocular and transdermal routes.Therefore,as an alternative to conventional dosage forms,polymeric thin flms are expected to stand out as a dosage form to overcome the limitations posed by existing dosage forms.The flm dosage form encounters several challenges during the phases of formulation development and manufacture.Such issues should be addressed to optimize the overall formulation even after transferring to large-scale manufacturing.The future looks very promising for the flm technology in the time to come as new technologies are rapidly introduced to prepare thin flms.

Acknowledgments

This work was supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government (MSIP)(No.2015R1A5A1008958).This work was also supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(No.2015R1D1A1A02062278).

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*< class="emphasis_italic">Corresponding author.

.College of Pharmacy,Chung-Ang University,84 Heukseok-ro,Dongjak-gu,Seoul 06974,Republic of Korea. Tel.:+82 2 820 5606;fax:+82 2 816 7338.

E-mail address:jaehwi@cau.ac.kr(J.Lee).1These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.ajps.2016.05.004

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