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`
`Current Drug Delivery, 2013, 10, 667-684
`667
`An Introduction to Fast Dissolving Oral Thin Film Drug Delivery Systems:
`A Review
`
`Harsha Kathpalia* and Aasavari Gupte
`
`Vivekanand Education Society’s College of Pharmacy, Hashu Advani Memorial Complex, behind Collector Colony,
`Chembur (E), Mumbai - 400 074, India
`
`Abstract: Many pharmaceutical companies are switching their products from tablets to fast dissolving oral thin films
`(OTFs). Films have all the advantages of tablets (precise dosage, easy administration) and those of liquid dosage forms
`(easy swallowing, rapid bioavailability). Statistics have shown that four out of five patients prefer orally disintegrating
`dosage forms over conventional solid oral dosages forms. Pediatric, geriatric, bedridden, emetic patients and those with
`Central Nervous System disorders, have difficulty in swallowing or chewing solid dosage forms. Many of these patients
`are non-compliant in administering solid dosage forms due to fear of choking. OTFs when placed on the tip or the floor of
`the tongue are instantly wet by saliva. As a result, OTFs rapidly hydrate and then disintegrate and/or dissolve to release
`the medication for local and/or systemic absorption. This technology provides a good platform for patent non- infringing
`product development and for increasing the patent life-cycle of the existing products. The application of fast dissolving
`oral thin films is not only limited to buccal fast dissolving system, but also expands to other applications like gastro-
`retentive, sublingual delivery systems. This review highlights the composition including the details of various types of
`polymers both natural and synthetic, the different types of manufacturing techniques, packaging materials and evaluation
`tests for the OTFs.
`Keywords: Film forming polymers, Lycoat, Monoammonium glycyrrhizinate, Oral thin films, Patent non-infringing product
`development, Solvent casting method.
`
`INTRODUCTION
`
`Fast dissolving drug delivery systems were first devel-
`oped in the late 1970s as an alternative to conventional dos-
`age forms. These systems consist of solid dosage forms that
`disintegrate and dissolve quickly in the oral cavity without
`the need of water [1]. Fast dissolving drug delivery systems
`include orally disintegrating tablets (ODTs) and oral thin
`films (OTFs). The Centre for Drug Evaluation and Research
`(CDER) defines ODTs as, “a solid dosage form containing
`medicinal substances which disintegrates rapidly, usually
`within a matter of seconds, when placed upon the tongue”
`[2]. USFDA defines OTFs as, “a thin, flexible, non-friable
`polymeric film strip containing one or more dispersed active
`pharmaceutical ingredients (APIs) which is intended to be placed
`on the tongue for rapid disintegration or dissolution in the
`saliva prior to swallowing for delivery into the gastrointesti-
`nal tract” [3]. OTFs are coming into their own as mainstream
`pharmaceutical products. The first approved prescription
`OTF was Zuplenz (Ondansetron hydrochloride- 4 mg, 8 mg)
`which was approved in 2010. The second approved one was
`Suboxone (Buprenorphine and Naloxone). Statistics have
`shown that four out of five patients prefer orally disintegrat-
`ing dosage forms over conventional solid oral dosages forms
`[4]. These factors, coupled with convenience and compliance
`
`*Address correspondence to this author at the Vivekanand Education Soci-
`ety’s College of Pharmacy, Hashu Advani Memorial Complex, behind Col-
`lector Colony, Chembur (E), Mumbai-400 074, India; Tel: 022-6114 4144,
`022-2554 3600; Fax: 022-2554 3925;
`E-mail: hkathpalia2007@rediffmail.com
`
`advantages, have been (and will continue to) pave the way
`for ODT and OTF drug product growth.
` This review highlights the various types of polymers, the
`different types of packaging materials manufacturing tech-
`niques and evaluation tests for the oral films.
`
`Need for Preparing Fast Dissolving OTFs
`
`Pediatric, geriatric, bedridden, emetic patients and those
`with Central Nervous System disorders, have difficulty in
`swallowing or chewing solid dosage forms. Many of these
`patients are non-compliant in administering solid dosage
`forms due to fear of choking. Even in the case of ODTs, fear
`of choking is associated which can be hazardous. Fast dis-
`solving oral thin film drug delivery system is a better alterna-
`tive to ODTs. OTFs when placed on the tip or the floor of
`the tongue are instantly wet by saliva. As a result, OTFs rap-
`idly hydrate and then disintegrate and/or dissolve to release
`the medication for local and/or systemic absorption. ODTs
`are friable and may break during transport and handling.
`Thus, fast dissolving oral thin film drug delivery systems are
`being developed.
`
`Advantages of OTF
`1). Ease of administration for mentally ill and non-
`compliant patients
`2). Useful in situations where rapid onset of action is re-
`quired such as in motion sickness, allergic attack,
`coughing or asthma
`
`
`
` 1875-5704/13 $58.00+.00
`
`© 2013 Bentham Science Publishers
`
`MONOSOL RX EXHIBIT 2010 page 0001
`
`Plaintiffs' Exhibit
`
`Reckitt Benckiser Pharms. Inc., et al.
`v. Watson Labs., Inc., et al.
`(1:13-cv-01674-RGA)(Con.)
`
`PTX 212
`
`

`
`668 Current Drug Delivery, 2013, Vol. 10, No. 6
`
`Kathpalia and Gupte
`
`3). Has wide range of applications in pharmaceuticals, Rx
`Prescriptions and OTC medications for treating pain,
`cough/cold, gastro-esophageal reflux disease, erectile
`dysfunction, sleep disorders, dietary supplements, etc
`[4].
`4). No water is required for the administration and hence
`suitable during travelling
`5). Some drugs are absorbed from the mouth, pharynx and
`esophagus as the saliva passes down into the stomach,
`enhancing bioavailability of drugs
`6). May offer improved bioavailability for poorly water
`soluble drugs by offering large surface area as the film
`disintegrates and dissolves rapidly
`7). Leaves minimal or no residue in the mouth after admini-
`stration
`8). Has ability to provide advantages of liquid medication in
`the form of solid preparation
`9). Adaptable to existing processing and packaging machinery
`10). Cost-effective
`11). Gives accurate dosing as compared to liquids
`12). Provides good chemical stability
`13). Free of need of measuring, which is an essential draw-
`back in liquids [5].
`14). Offers market expansion and product differentiation
`15). Can be developed and launched within 12-16 months,
`thus provides improved product development life-cycle
`time [4].
`
`Disadvantages of OTF
`1). Dose uniformity is difficult to maintain
`2). Only those active pharmaceutical ingredients (APIs)
`having small dose can be incorporated [6].
`3). Research has proven that concentration level of active
`pharmaceutical ingredient (API) can be improved up to
`50% w/w. Novartis Consumer Health's Gas-X® thin
`strip has 62.5 mg of Simethicone per strip [4].
`4). Require expensive packaging
`5). Since OTFs dissolve quickly, dose termination is impos-
`sible
`6). OTFs is not official in any pharmacopoeia
`
`FORMULATION OF FAST DISSOLVING OTFs
`
`Formulation includes consideration regarding mechanical
`properties, taste masking, fast dissolving, physical appear-
`ance, mouth feel. Fast dissolving oral thin films are generally
`with an area of 5-20 cm2. APIs can be incorporated upto 50
`mg [7]. From the regulatory point of view, all the excipients
`used should be generally regarded as safe (GRAS) listed and
`should be used as per Inactive Ingredients Limit (IIG limit).
`Various components of fast dissolving oral thin films are
`shown in (Table 1).
`
`Table 1. Composition of Fast Dissolving Oral Thin Films [8].
`
`Components
`
`Active pharmaceutical ingredients
`
`Film forming polymers
`
`Plasticizers
`
`Surfactants
`
`Sweetening agents
`
`Saliva stimulating agents
`
`Superdisintegrants
`
`Coloring agents
`
`Flavoring agents
`
`% w/w
`
`5-50
`
`Upto45
`
`0-20
`
`q. s.
`
`3-6
`
`2-6
`
`Upto 8
`
`Upto 1
`
`Upto 10
`
`Active Pharmaceutical Ingredients (APIs)
`
`Since the size of the thin films has to be small enough to
`be conveniently placed on the tongue, those active pharma-
`ceutical ingredients with high dose are not suitable candi-
`dates for incorporation into fast dissolving oral thin films [9].
`
`Ideal Characteristics of APIs to be Incorporated into Fast
`Dissolving OTFs
`1). Low dose
`2). Palatability
`3). Small molecular weight
`4). Solubility and stability in saliva
`
`Some of the suitable candidates for incorporation into
`thin film formulation are given in (Table 2).
` Water soluble APIs exist in the dissolved state or as solid
`solution and there is no problem of uniformity of distribu-
`tion. But water insoluble APIs have to be homogenously
`distributed so as to have an acceptable drug content uniform-
`ity. Water insoluble APIs can also be added as milled, mi-
`cronized or in the form of nanocrystals or microcapsules [10]
`in order to maintain smooth texture of the film and also for
`fast dissolution.
`Lou et al. formulated Chlorpheniramine maleate mi-
`•
`croparticles by encapsulating Chlorpheniramine maleate
`into Eudragit EPO by spray drying of water-in-oil emul-
`sion method. The optimized microparticles were incor-
`porated into OTF with satisfactory weight and drug con-
`tent uniformity and acceptable physical strength. OTFs
`disintegrated immediately (in less than 40 seconds) in
`simulated saliva solutions [11].
`Sievens-Figueroa et al. formulated OTFs of hy-
`droxypropyl methyl cellulose (HPMC) by incorporating
`API in the form of nanosuspension. They transformed
`nanosuspension produced from wet stirred media mill-
`ing (WSMM) into polymer films containing drug loaded
`nanoparticles by mixing with HPMC E15 LV solution
`containing glycerin followed by film casting and drying [12].
`
`•
`
`MONOSOL RX EXHIBIT 2010 page 0002
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`

`
`An Introduction to Fast Dissolving Oral Thin Film Drug Delivery Systems
`
`Current Drug Delivery, 2013, Vol. 10, No. 6 669
`
`Table 2. Suitable Candidates for Incorporation into Thin
`Film Formulation.
`
`Active Pharmaceutical
`Ingredients
`
`Category
`
`Dose (mg)
`
`Levocetrizine
`Loratadine
`
`Ketorolac
`Indomethacin
`Valdecoxib
`Piroxicam
`
`Zolmitriptan
`Sumatriptan succinate
`
`Mirtazapine
`
`Buspirone
`
`Carvedilol
`
`Glipizide
`
`Galantamine
`Donepezil
`
`Anti-histaminic
`
`NSAIDs
`
`Anti-migraine
`
`Anti-depressant
`
`Anxiolytic
`
` -blocker
`
`Anti-diabetic
`
`Anti-Alzheimer
`
`Nitroglycerine derivatives
`
`Vasodilator
`
`Benzocaine
`
`
`
`Buprenorphine/Naloxone
`
`Opioid analgesic
`
`Ondansetron
`
`Antacid
`
`5, 10
`10
`
`10
`25
`10, 20
`10, 20
`
`2.5, 5
`35, 70
`
`15, 30, 45
`
`5, 15, 30
`
`3.125, 6.25, 12.5,
`25
`
`2.5, 5
`
`4, 8, 12
`5, 10
`
`0.3, 0.6
`
`
`
`2.5-10
`
`10
`
`d-Amphetamine
`
`Anti-inflammatory
`
`12.5, 25
`
`Clonazepam
`
`Ondansetron
`
`Loperamide
`
`Buprenorphine
`Naloxone
`
`d-Amphetamine
`
`Anti-tussive
`
`Anti-emetic
`
`Anti-diarrheal
`
`Treatment of opioid
`addiction
`
`Treatment attention
`deficit hyperactive
`disorder
`
`15, 30
`
`8-24
`
`2
`
`2, 4, 16, 24
`
`0.5, 1, 4, 6
`
`10, 20
`
`Clonazepam
`
`Anti-epileptic
`
`0.5, 1, 1.5
`
` As the thin OTF formulation is to be placed on tongue,
`those drugs having bitter and unpleasant taste may cause
`vomiting sensation and may be inacceptable by the patient.
`Hence, various taste masking technologies for bitter drugs
`like microencapsulation, inclusion complexation with cyclo-
`dextrins, complexation with ion-exchange resins are being
`practiced.
`Prednisolone drug particles were masked by ethyl cellu-
`•
`lose and Eudragit E by emulsion solvent evaporation
`technique and incorporated into ODT. This technique
`can be further extended to OTF formulation [13].
`
`•
`
`•
`
`•
`
`In fast dissolving OTF formulation for treating erectile
`dysfunction, hydroxylpropyl-beta-cyclodextrin (HP- -CD)
`was used as a taste masking agent [14].
`Preis et al. developed taste masked orodispersible film
`containing Dimenhydrinate using HP- -CD as a taste
`masking agent [15].
`Ion exchange resin like Amberlite IRP 69 was used to
`formulate taste masked fast dissolving orally consum-
`able films of Dextromethorphan [16].
`
`Film Forming Polymers
`
`Since the film formulation rapidly disintegrates and dis-
`solves in oral cavity, the film forming polymers used must
`be water soluble. The polymers can be used alone or in com-
`bination with others in order to obtain the desired film which
`should be tough enough so that there won't be any damage
`while handling or during transportation and at the same time
`showing fast dissolution in the mouth. The robustness of the
`film depends on the type and amount of polymer used in the
`formulation. The disintegration time of the polymers is in-
`creased by increasing the molecular weight of polymer film
`bases [17]. Since polymers are the major components of the
`film formulation along with the APIs, their proportion re-
`lated to each other is governed by 2 factors:
`a). Minimum % w/w concentration of polymer required to
`form matrix which incorporates APIs and other excipients
`with desirable mechanical and viscoelastic properties.
`b). % w/v concentration of polymer in solution to be casted
`as film which is governed by the desired viscosity. Vis-
`cosity should be optimum enough to prevent suspended
`solids from settling and to form a smooth spreadable
`film [18].
`
`Ideal Properties of Polymers
`1). Non-toxic
`2). Non-irritant
`3). Bland
`4). Good mouth feel
`5). Should be stable for long period
`6). Should not alter properties of the active pharmaceutical
`ingredient or other excipients of the formulation
`Inexpensive
`7).
`8). Should have good wettability and spreadability
`9). Should not retard the disintegration time of the film
`10). Should have optimum peel strength and tensile strength
`
`NATURAL POLYMERS
`Gum Polysaccharides
` Gum polysaccharides like gum arabic, -carageenan, and
`sodium alginate are some of the potential polymers for film
`formation. They can be used in combination with others so
`as to provide primary film structure and rapid dissolving
`characteristics. Some examples are shown in (Table 3).
`
`MONOSOL RX EXHIBIT 2010 page 0003
`
`

`
`670 Current Drug Delivery, 2013, Vol. 10, No. 6
`
`Kathpalia and Gupte
`
`residues. It is a fungal exopolysaccharide produced from
`starch by black yeast Aureobasidium pullulan [24]. Bender
`and Wallenfels discovered the enzyme pullulanase, which
`specifically hydrolyzes (16) linkage in pullulan and con-
`verts the polysaccharide to maltotriose. Catley and co-
`workers established the occurrence of a minor percentage of
`randomly distributed maltotetraose subunits in pullulan [25].
`The regular occurrence of (16) linkage in pullulan inter-
`rupts a linear amylase chain. This unique pattern of linkage
`is responsible for the structural flexibility of pullulan, result-
`ing in distinct film forming characteristics [26]. Pullulan PI-
`20 grade is the deionised form of pullulan having an average
`molecular weight of 2,00,000 daltons and possess excellent
`film forming properties. Pullulan is used in range 0.3-15%
`w/w [27].
`
`Advantages
`a). Addition of these can improve can improve dissolution
`of films in mouth
`b). Reduces tensile strength only to a minimal extent
`
`Table 3. Film Composition and the Resulting Dissolution
`Time [19].
`
`Film Composition
`
`Dissolution Time
`(Seconds)
`
`Gum arabic (1.25%) along with sodium alginate
`(2.5%) and low viscosity carboxy methyl cellulose
`(1.25%) and water
`
` -carageenan (1.25%) along with sodium alginate
`(2.5%) and low viscosity carboxy methyl cellulose
`(1.25%) and water
`
`Polydextrose (1.25%) along with sodium alginate
`(2.5%) and low viscosity carboxy methyl cellulose
`(1.25%) and water
`
`20
`
`28
`
`12.60
`
`Gelatin
` Gelatin consists of a mixture of purified protein fractions
`obtained either by partial acid hydrolysis which is called as
`type A gelatin or by partial alkaline hydrolysis which is
`called as type B gelatin of animal collagen. Gelatin is pre-
`pared by the thermal denaturation of collagen isolated from
`animal skin, bones and fish skins [20]. It is readily soluble in
`water above 40º C and it forms viscous solution of randomly
`coiled polypeptide chains. Mammalian gelatins have better
`physical properties and thermostability than most of the fish
`gelatins due to their higher amino acid content. The proper-
`ties and film forming ability of gelatin is directly related to
`the molecular weight of the gelatin, i.e., the higher the aver-
`age molecular weight, better the quality of the film. The mo-
`lecular weight distribution depends mainly on the degree of
`cross-linking of collagen fibers and the extraction procedure
`used. Gelatin films could be formed from 20-30% gelatin,
`10-30% plasticizer (glycerin or sorbitol) and 40-70% water
`followed by drying the gelatin gel [21].
`
`Advantages of Gelatin Films
`a). Dissolve rapidly
`b). Films are excellent carriers for flavors
`c). Films produce a smooth mouth feel [22].
`• Ghorwade et al. formulated Montelukast sodium fast
`dissolving films using gelatin as a film base (3.54%
`w/w). It was observed that films had desired tensile
`strength and optimum in vitro dissolution time [23].
`
`Pullulan
`
`Pullulan is a biopolymer. It is water soluble, neutral lin-
`ear polysaccharide consisting of (16) linked maltotriose
`
`d).
`
`e).
`f).
`
`Advantages of Pullulan
`a).
`It is non-hygroscopic
`b).
`It is impermeable to oxygen Impermeability of pullulan
`films to oxygen is suitable for protection of readily oxi-
`dized fats and vitamins in food. Pullulan films have 300
`times stronger oxygen barrier than HPMC films and 9
`times stronger oxygen barrier than gelatin films of the
`same thickness [28].
`c). No branching in structure in contrast to gum arabic,
`forming much stronger films [29].
`It is easily soluble in cold and hot water to make clear
`and viscous solution
`It also has high adhesion and film forming abilities
`It is a nonionic polysaccharide and is bio-compatible,
`biodegradable
`It is non-toxic, non-immunogenic, non-mutagenic and
`non-carcinogenic [30].
`h). Pullulan films are thermally stable and possess anti-
`static and elastic properties
`i). Pullulan films can be developed into compression molding
`j). Pullulan films are highly water soluble, colorless, taste-
`less, odorless, transparent and flexible
`• Mishra et al. formulated rapidly dissolving films of
`Cetirizine hydrochloride using pullulan (15% w/w) as a
`film forming agent. They found that the amount of plas-
`ticizer was critical for film formation and separation
`properties. Acceptable mechanical properties and in vi-
`tro disintegration time were obtained [31].
`• Orally disintegrating film formulation of Nicotine is
`shown in (Table 4).
`
`g).
`
`Starch
`
`Starch is the major carbohydrate reserve in plant tubers
`and seed endosperm where it is found as granules. Each
`granule contains millions of amylopectin molecules accom-
`panied by smaller amylase molecules. Amylose is responsi-
`ble for the film forming capacity of starch [33].
`
`MONOSOL RX EXHIBIT 2010 page 0004
`
`

`
`An Introduction to Fast Dissolving Oral Thin Film Drug Delivery Systems
`
`Current Drug Delivery, 2013, Vol. 10, No. 6 671
`
`Table 4. Nicotine Orally Disintegrating Film.
`
`Ingredients
`
`Nicotine base
`
`Alginic acid
`
`Pullulan
`
`Purified water
`
`Sucralose
`
`Solutol H15
`
`Sucrose fatty acid esters D-1811
`
`Alcohol
`
`Glycerin
`
`Triethyl citrate
`
`Tween 80
`
`Span 80
`
`Peppermint oil
`
`Menthol
`
`FD & C Yellow #6
`
`TOTAL
`
`Amount per Film (mg)
`
`1.00
`
`0.50
`
`29.48
`
`0.0038
`
`0.48
`
`1.00
`
`1.00
`
`0.00
`
`3.20
`
`2.00
`
`0.60
`
`0.10
`
`0.40
`
`0.20
`
`0.04
`
`40.00
`
` In above formulation, hydroalchoholic vehicle was used [32].
`
`Advantages of Starch
`a). Starch films are biodegradable
`b). Starch films are transparent or translucent
`c). Starch films are flavorless, tasteless and colorless [34].
`
`Disadvantages of Starch
`a). Starch films have poor mechanical strength
`b). Film forming conditions have an effect on crystallinity
`of the starch films and their properties
`Films of high-amylose corn starch or potato starch were
`
`more stable during aging, lost little of their elongation and
`had slight or no increase in tensile strength [35]. Films from
`cassava starch had good flexibility and low water permeability,
`indicating the potential application as edible film former [36].
` Modified starch, due to its low cost, is being widely used
`in combination with pullulan.
`
`Lycoat
` Lycoat is a novel granular hydroxypropyl starch polymer
`obtained from pea starch that has been designed especially
`for fast dissolving OTFs. It is manufactured by Roquette
`Pharma.
`
`Advantages of Lycoat
`a). Lycoat disperses easily in cold water without formation
`of lumps
`
`•
`
`b).
`
`It can be used alone as film forming polymer to formu-
`late fast dissolving OTFs with excellent functionality
`without the need of additional film forming agent
`[37].
`c).
`It is neutral in taste
`It forms films without the use of organic solvents
`d).
`e). APIs can be loaded in crystalline form or they can be
`solubilized in an organic solvent
`Popescu et al. formulated oral disintegrating films of
`Benzocaine using Lycoat RS 720 as a film forming
`polymer. They concluded that Lycoat RS 720 alone was
`capable of producing orally disintegrating films. It also
`offered dose homogeneity and fast dissolution [38].
`• Doaa et al. formulated Tianeptine sodium orodispersible
`films using Lycoat NG 73 as a film forming polymer.
`They concluded that the films made up of Lycoat NG 73
`showed the highest dissolution rate, suitable in vitro dis-
`integration time and satisfactory physico-mechanical
`properties as compared to those made up of other poly-
`mers [39].
`
`Maltodextrin
` Maltodextrin is a non- sweet nutritive saccharide poly-
`mer. It is produced by partial hydrolysis of starch. Maltodex-
`trin consists of D-glucose units connected in chains of vari-
`able length. The glucose units are primarily linked with
`(14) glycosidic bond. Maltodextrin is typically composed
`of a mixture of chains that vary from 3-19 glucose units [40].
`Maltodextrins are classified by DE (dextrose equivalent) and
`have DE between 3-20. Higher the DE value, shorter the
`glucose chains, higher the sweetness and higher the solubil-
`ity [18]. Maltodextrin is used in the range of 2-10% w/w
`[41].
`Cilurzo et al. formulated Nicotine fast dissolving films
`•
`made of maltodextrin. They found that on decreasing the
`DE value of maltodextrin, the tenacity of the film im-
`proved [42].
`
`SYNTHETIC POLYMERS
`Hydroxypropylmethyl Cellulose (HPMC)
` HPMC or hypromellose is partly O-methylated and O-(2-
`hydroxypropylated) cellulose [43]. Depending upon the vis-
`cosity grades, concentrations of 2-20% w/w are used for film
`forming solutions [44]. Lower grades of HPMC like HPMC
`E3, HPMC E5and HPMC E15 are particularly used for film
`formation because of their low viscosity [45]. Lower grades
`are used with aqueous solvent [38]. Additives are incorpo-
`rated to improve specific properties of films. Several studies
`have been carried out to investigate the influence of additives
`on physico-chemical properties of HPMC films. Lipids such
`as waxes, triglycerides (tristearin), fatty acids (stearic acid,
`palmitic acid) result in decreased water affinity and moisture
`transfer due to their high hydrophobic properties [23].
`
`Advantages of HPMC
`a).
`It has good film forming properties and excellent ac-
`ceptability
`
`MONOSOL RX EXHIBIT 2010 page 0005
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`

`
`672 Current Drug Delivery, 2013, Vol. 10, No. 6
`
`Kathpalia and Gupte
`
`•
`
`b). HPMC forms transparent, tough and flexible films in
`aqueous solutions [43].
`• Nishimura et al. formulated Prochlorperazine oral disin-
`tegrating film using of HPMC (7.4% w/w) in combina-
`tion with low substituted HPC (1.3% w/w). Films
`showed excellent stability and desired dissolution profile
`[45].
`Shimoda et al. prepared fast dissolving OTFs containing
`Dexamethasone using HPMC (7.4% w/w) in combina-
`tion with low substituted HPC (1.3% w/w). 90% of
`Dexamethasone was found to be dissolved within 5
`minutes [46].
`Raju S et al. formulated and evaluated flash release oral
`films of Metoclopramide hydrochloride. The formula-
`tion released 99.40% of drug within 30 seconds [47].
`Joshi et al. formulated and evaluated mouth dissolving
`films of Domperidone. The film was prepared by sol-
`vent casting technique utilizing HPMC E15 as film
`forming agent and PEG 400 as plasticizer. The film con-
`taining HPMC E15 (500 mg) showed greater dissolution
`(more than 75% within 15 minutes), satisfactory in vitro
`disintegration time (45 seconds) and suitable physico-
`mechanical properties [48].
`• Orally disintegrating film formulation of Diclofenac is
`shown in (Table 5).
`
`•
`
`•
`
`Table 5. Diclofenac Orally Disintegrating Film [49].
`
`Ingredients
`
`Amount per Film (mg)
`
`Diclofenac free acid
`
`Methocel E5 (HPMC E5)
`
`Methocel E50 (HPMC E50)
`
`Glycerol
`
` -Tocopherol
`
`Spearmint flavor 501495 T
`
`Masking flavor 501483 T
`
`Sodium chloride
`
`Levomenthol
`
`Acesulfame-K
`
`Water
`
`TOTAL
`
`11.08
`
`3.20
`
`4.80
`
`0.70
`
`0.0064
`
`0.70
`
`2.75
`
`0.75
`
`1.50
`
`0.75
`
`37.00
`
`26.23
`
`Polyvinyl Alcohol (PVA)
`
`Poly (vinyl alcohol) (PVA), a polyhydroxy polymer, is
`the synthetic, water-soluble polymer which is produced
`commercially by the hydrolysis of poly (vinyl acetate)
`(PVAc). To improve its deformability, PVA is usually plas-
`ticized by low molecular compounds mostly containing polar
`groups, which associate with hydroxyl groups of PVA chain
`(with or without water assistance) developing hydrogen bonds.
`
`Advantages of PVA
`a). PVA has excellent film forming and emulsifying properties
`b).
`It is resistant to oil and grease
`c). PVA is odorless and nontoxic
`d). PVA has high oxygen and aroma barrier properties
`e). PVA has high enough tensile strength and satisfactory
`flexibility
`f). High biodegradability [50].
`• Kulkarni et al. formulated mouth dissolving films con-
`taining Rofecoxib where, PVA (4%w/w) was used to as
`film forming polymer. They found that, with increasing
`the concentration of PVA, elasticity of the film in-
`creased and release of the drug occurred within 1 minute
`[51].
` Ondansetron RapidFilm formulation is shown in (Table 6).
`
`Table 6. Ondansetron RapidFilm Formulation.
`
`Ingredients
`
`Ondansetron base
`
`Mowiol (Poly vinyl alcohol)
`
`Polyethylene glycol
`
`Glycerol anhydrous
`
`Rice starch
`
`Acesulfame-K
`
`Titanium dioxide
`
`Menthol
`
`Polysorbate
`
`TOTAL
`
`Amount per film (mg)
`
`8.00
`
`22.00
`
`6.00
`
`2.00
`
`10.00
`
`0.20
`
`0.30
`
`1.00
`
`1.00
`
`50.50
`
` Dissolution profiles of Ondansetron film coated tablet,
`oral dissolving tablet (Zofran 8 mg and 4 mg) and RapidFilm
`(8 mg and 4 mg) were compared. Dissolution studies were
`carried out in USP apparatus Type I (paddle), using 900 ml
`of 0.1 N HCl buffered water at pH 1.0 at 100 rpm and 37o C.
`The results of the dissolution study can be summarized as
`follows:
`• Ondansetron film coated tablet showed 0.8% drug re-
`lease in one minute while at the time point of 10 min-
`utes; it showed 103.3% drug release.
`• Orally dissolving tablet (8 mg) showed 100.30% drug
`release in one minute while RapidFilm (8 mg) showed
`97.10% drug release in one minute. At the time point of
`10 minutes, both the formulations showed 100.80% drug
`release.
`• Orally dissolving tablet (4 mg) showed 102.30% drug
`release in one minute while RapidFilm (4 mg) showed
`71.80% drug release in one minute. At the time point of
`10 minutes, orally dissolving tablet (4 mg) showed
`
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`
`

`
`An Introduction to Fast Dissolving Oral Thin Film Drug Delivery Systems
`
`Current Drug Delivery, 2013, Vol. 10, No. 6 673
`
`101.80% drug release in one minute while RapidFilm
`(4 mg) showed 105.20% drug release.
`From the above data, it can be concluded that though the
`
`drug release from orally dissolving tablet is faster than
`RapidFilm initially, at the time point of 10 minutes, drug
`release from both the formulations is comparable and both
`are better formulations as compared to Ondansetron film
`coated tablet [52].
`
`Polyethylene Oxide (PEO)
`
`Polyethylene oxide is a synthetic polyether. It is available
`in a wide range of molecular weights. Usually 3-5% w/w
`solution is used for film formation [53].
`
`Advantages of PEO
`a). PEO has a high melting point
`b).
`It has good structural integrity
`c).
`It has low glass transition temperature
`d).
`It has low toxicity and biocompatibility
`e).
`It is highly hydrophilic with good film forming capacity
`[18].
`Sumitha et al. formulated rapid disintegrating films of
`Ondansetron using PEO N10 and HPMC E15. It was
`observed that incorporation of PEO helped in faster dis-
`integration and provided good elegance to the film [54].
`Representative formulation of Donepezil hydrochloride
`orally disintegrating film is shown in (Table 7).
`
`•
`
`•
`
`Donepezil
`of
`Formulation
`Table 7. Representative
`Hydrochloride Orally Disintegrating Film [52].
`
`Ingredients
`
`Amount per Film (mg)
`
`Donepezil hydrochloride
`
`Polyethyleneoxide
`
`Tween 80
`
`Glycerol anhydrous
`
`Citric acid anhydrous
`
`Titanium dioxide
`
`Acesulfame-K
`
`Anise flavor
`
`Peppermint flavor
`
`TOTAL
`
`10.00
`
`50.00
`
`1.00
`
`12.00
`
`1.00
`
`0.50
`
`1.50
`
`1.65
`
`3.84
`
`81.49
`
`Polyvinyl Pyrrolidone (PVP)
`
`Soluble polyvinyl pyrrolidoneis synthesized by radical
`polymerization of N-vinyl pyrrolidone in 2-propanol. The
`soluble PVP products of pharmaceutical quality are
`designated as Povidone in the USP. Soluble PVP products
`are marketed under bran name Kollidon®. PVP range
`
`comprises of products of different K-values. The K-value is
`associated with themean molecular weight. Itis included as
`part of the trade name and is calculated from the relative
`viscosity in water. Different grades of PVP and their mean
`molecular weight is shown in (Table 8).
`
`Table 8. Different Grades of PVP and their Mean Molecular
`Weight.
`
`Grades of PVP
`
`Mean Molecular Weight
`
`Povidone K 12
`
`Povidone K 25
`
`Povidone K 30
`
`Povidone K 90
`
`2000-3000
`
`28000-34000
`
`44000-54000
`
`1000000-1500000
`
`Advantages of PVP
`a). PVP is readily soluble in water and most other solvents
`b). PVP has a very good film forming capacity
`c).
`It has ability of to form a water-soluble complexes with
`insoluble APIs which can improve their release rate and
`solubility
`It is non-toxic and chemically inert
`d).
`It is temperature resistant, pH-stable and colorless [55].
`e).
`f). Films are clear, glossy and hard [56].
`• Gaisford et al. formulated PVP films containing
`Indomathacin to evaluate the potential of isothermal
`calorimetry to monitor and characterize crystallization in
`drug-loaded fast dissolving oral films [57].
`Cheun et al. formulated mouth dissolving film of Car-
`bamazepine using PVP K30 as film forming polymer.
`They found that crystallization of Carbamazepine oc-
`curred due to hygroscopicity of PVP [58].
`• Ali et al. formulated Diphenhydramine and Ibuprofen
`strips with Kollidon K-90. Diphenhydramine films
`showed disintegration time of 50 seconds while that of
`Ibuprofen strips was 5-6 times higher [59].
` Major manufacturing companies of the polymers are
`shown in (Table 9).
`
`•
`
`Plasticizers
`
`Plasticizers aid in improving the flexibility and reduce
`the brittleness of the film by reducing the glass transition
`temperature of the polymer. Plasticizers also improve the
`tensile strength and reduce brittleness. The plasticizer should
`be compatible with the polymer and the solvent used. Plasti-
`cizers also enhance the tensile strength of the polymers [60,
`61]. Glycerol, propylene glycol, low molecular weight poly-
`ethylene glycols, citrate derivatives such as tributyl citrate,
`triethyl citrate, triacetin and castor oil are some of the com-
`monly used plasticizers [62-68]. Inappropriate or extensive
`use of plasticizer can cause film cracking; splitting and peel-
`
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`
`

`
`674 Current Drug Delivery, 2013, Vol. 10, No. 6
`
`Kathpalia and Gupte
`
`ing of the film. Some plasticizers also affect the absorption
`rate of the drug [51]. The plasticizer should impart the per-
`manent flexibility to the film. Plasticization takes place by
`two mechanisms: internal plasticization which involves
`chemical interaction of molecular groups of the polymer
`itself and external plasticization where, a physically active
`plasticizer is externally added. External plasticization does
`not involve chemical interactions in the product and hence, it
`is the preferred mechanism of plasticization [68]. Cellulosic
`hydrophilic polymers are easily plasticized with hydroxyl
`containing plasticizers like polyethylene glycol, propylene
`glycol, glycerol and polyols. In contrast, less hydrophilic
`cellulosic polymers are plasticized wit