Int J Pharm Bio Sci 2013 Jan; 4(1): (P) 899 - 908
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`Review Article Novel drug delivery system
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`ISSN
`0975-6299
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`International Journal of Pharma and Bio Sciences
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`MOUTH DISSOLVING FILMS : A REVIEW
`
`THAKUR SMRITI*
`
`
`School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences and Technology,
`Baddi (173205), Distt. Solan (H.P.), India.
`
`ABSTRACT
`
`The purpose of current review is to enlighten the present and future prospective on
`Mouth dissolving film drug delivery system. Now a days, we observe padietric and
`geriatric patients facing the problem of dysphasia due to administration of monolithic
`solid dosage form, which are also seen in the case of fast dissolving tablets. Hence
`mouth dissolving film is proved to be better alternative in such cases. This fast
`dissolving drug delivery system is suited for the drugs which undergo high first pass
`metabolism and is used for improving bioavailability. Mouth dissolving film consists of
`thin oral strip; which release active ingredients immediately after uptake into oral cavity.
`These films have potential to deliver a drug systematically through intragastric,
`sublingual or buccal route of administration and also has been used for local action. The
`present review provides an account of various formulation considerations, method of
`preparation, and quality control of mouth dissolving films.
`
`KEYWORDS: Mouth dissolving films, Solvent casting method, Fast dissolving drug delivery,
`First pass metabolism, Buccal route.
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` THAKUR SMRITI
`School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences
`and Technology, Baddi (173205), Dist. Solan (H.P.), India.
`
`This article can be downloaded from www.ijpbs.net
`P - 899
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` *Corresponding author
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`Int J Pharm Bio Sci 2013 Jan; 4(1): (P) 899 - 908
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`INTRODUCTION
`
`
`Fast Drug Delivery Systems are rapidly gaining
`interest in the pharmaceutical industry. These
`systems either dissolve or disintegrate generally
`within a minute without needing water or
`chewing. These systems offer superior clinical
`profiles with potentional oro mucosal absorption
`thus
`increasing
`the drug bioavailability with
`respect to oral administration. Recently thin films
`have been proposed which rapidly dissolves or
`disintegrates into buccal cavity. Mouth dissolving
`films are novel dosage forms that disintegrates
`or dissolves in the oral cavity. These are ultra
`thin postage stamp size with an active agent or
`pharmaceutical excipients. These dosage forms
`are placed on the tongue or any mucosal tissue.
`When wet with saliva, the films rapidly hydrates
`and adheres on to the site of application. It
`rapidly dissolves or disintegrates to release the
`medicine
`for mucosal absorption or with
`modification, allows for oral GIT absorption with
`quick dissolving properties. An important benefit
`of these dosage forms is accurate dosing as
`compared to liquid dosage form, no water is
`needed and there is no fear of choking as
`compared
`to
`tablets and capsules. Fast-
`dissolving oral delivery systems are solid dosage
`forms, which disintegrate or dissolve within 1
`minute when placed
`in
`the mouth without
`drinking of water or chewing. After disintegrating
`in the mouth, enhanced the clinical effect of drug
`through pre-gastric absorption
`from mouth
`pharynx and oesophagus as the saliva passes
`down
`into
`the stomach.
`In such cases,
`bioavailability of drug is significantly greater than
`those observed from conventional tablet dosage
`form1. More recently, Fast-dissolving buccal film
`drug delivery systems have rapidly gained
`acceptance as an
`important new way of
`administering drugs. They are usually used for
`pharmaceutical and nutraceutical products. It is
`the newest frontier in drug delivery technology
`that provides a very convenient means of taking
`medications and supplements. Fast dissolving
`films are also applicable when local action in the
`mouth is desirable such as local anesthetic for
`toothaches, oral ulcers, cold sores, or teething1,2.
`
`
`
`Fast dissolving film is prepared using hydrophilic
`polymers that rapidly dissolve/disintegrate in the
`mouth within few seconds without water and
`eliminates the fear of chocking as an alternative
`to fast dissolving tablets.
`
`Special features of Mouth dissolving films3,4
` Thin elegant film
` Available in various size and shape
` Unobstructive
` Excellent mucoadhesion
` Fast disintegration
` Rapid release
`
`Advantages
` Oral dissolving films can be administered
`without water, anywhere, any time.
` Due to the presence of larger surface area,
`films provides
` rapid disintegrating and
`dissolution in the oral cavity.
` Oral dissolving films are flexible and portable
`in nature so
`they provide ease
`in
`transportation, during consumer handling
`and storage.
` Suitability for geriatric and pediatric patients,
`who experience difficulties in swallowing
`mentally ill, the developmentally disable and
`the patients who are un-cooperative, or are
`on reduced
`liquid
`intake plans or are
`nauseated5.
` Beneficial in cases such as motion sickness,
`acute pain, suede episodes of allergic attack
`or coughing, where an ultra rapid onset of
`action required.
` Stability for longer duration of time, since the
`drug remains in solid dosage form till it is
`consumed. So, it combines advantage of
`solid dosage form in terms of stability and
`liquid
`dosage
`form
`in
`terms
`of
`bioavailability6.
` As compared liquid formulations, precision in
`the administered dose is ensured from each
`strip of the film.
` The oral or buccal mucosa being highly
`vascularized, drugs can be absorbed directly
`and can enter
`the systemic circulation
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`Int J Pharm Bio Sci 2013 Jan; 4(1): (P) 899 - 908
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`hepatic
`first‐pass
`undergoing
`without
`can be
`metabolism. This advantage
`exploited
`in preparing products with
`improved oral bioavailability of molecules
`that undergo first pass effect.
` The sublingual and buccal delivery of a drug
`via thin film has the potential to improve the
`onset of action,
`lower
`the dosing, and
`enhance the efficacy and safety profile of the
`medicament.
`like
` Provide new business opportunity
`product differentiation, product promotion,
`patent
` extension.
`
`Disadvantages
` High doses cannot be incorporated .
` Dose uniformity is a technical challenge.
`
`
`
`
`
` Hygroscopic in nature.
` Require special packaging
`stability and safety.
`
`for products
`
`suitable drug
`
`
`characterstics of
`Ideal
`candidate
` The drug should have pleasant taste.
` The drug to be incorporated have low dose
`upto 40 mg.
` The drug with smaller and moderate
`molecular weight are preferable.
` The drug should have good stability and
`solubility in water as well as in saliva.
` It should be partially unionized at the pH of
`oral cavity.
` It should have the ability to permeate oral
`mucosal tissue.
`
`Table 1
`General Composition of MDF
`
`Ingredients
`Active pharmaceutical ingredient
`Hydrophilic polymer
`Plasticizer
`Colors, Flavors, Fillers
`
`Concentration (%)
`1-25
`40-50
`0-20
`0-40
`
`Sr.No.
`1.
`2.
`3.
`4.
`
`
`Active Pharmaceutical Ingredient7-12
`A typical composition of the film contains 1-25%
`w/w of the drug. Variety of APIs can be delivered
`through
`fast dissolving
`films. Small dose
`molecules are
`the best candidates
`to be
`incorporated in Oral fast dissolving film. It is
`always useful to have micronized API which will
`improve the texture of the film and also for better
`dissolution and uniformity
`in
`the Oral
`fast
`
`
`dissolving films. A no. of molecules can be
`incorporated, they may include Cough/ cold
`remedies
`(antitussives,
`expectorants),
`antianxiety drugs, cardiovascular agents, erectile
`dysfunction
`drugs,
`antihistaminincs, GIT
`disorders, nausea, pain and CNS (antiparkinson
`disease). Examples of some drugs that can be
`incorporated in Mouth dissolving films are listed
`in Table 2.
`
`Table 2
`List of Drug molecules that can be incorporated in MDF
`
`Dose (mg)
`
`Drug
`Chlorpheniramine maleate
`Loperamide
`Triplolidine hydrochloride
`Famotidine
`Azatidine maleate
`Sumatriptan succinate
`Ketoprofen
`Nicotine
`Loratidine
`Cetrizine
`Omeprazole
`
`4
`2
`2.5
`10
`1.0
`35
`12.5
`2
`10
`5-10
`10-20
`
`
`
`Therapeutic Class
`Antiallergic
`Antidiarroheal
`Antihistaminic
`Antacid
`Antihistaminic
`Antimigraine
`Analgesic
`Smoking Cessation
`Antihistaminic
`Antihistaminic
`Proton pump inhibitor
`
`
`
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`Int J Pharm Bio Sci 2013 Jan; 4(1): (P) 899 - 908
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`Film Forming Polymers13-14
`for
`A variety of polymers are available
`preparation of mouth dissolving
`films. The
`polymers can be used alone or in combination
`to improve hydrophilicity, flexibility, mouth feel
`and solubility characteristics of
` mouth
`dissolving
`films. The stiffness of
`the
`film
`depends on the type of polymer and the amount
`of polymer in the formulation. The various
`polymers which can be used for making mouth
`dissolving films must be water soluble with low
`molecular weight and excellent film forming
`capacity, since the primary use of all thin film
`oral dosage forms relies on their disintegration
`in the saliva of the oral cavity. The polymer
`employed should be non-toxic, non-irritant with
`good wetting and spreadability property. The
`polymer should not be very expensive and
`should be readily available. Water soluble
`polymer that may be used include natural gums
`such as xanthan, guar, acacia, tragacanth other
`available polymers include cellulose or cellulose
`derivatives, hydroxypropylmethyl cellulose with
`different grades like HPMC E15, HPMC E5,
`HPMC
`K4M,
`HPMC
`K100,
`hydroxyethylcellulose,
`hydroxypropylcelluose,
`carboxymethylcellulose,
`polyvinylpyrrolidone,
`polyvinyl alcohol, pullulan, gelatin. Modified
`starches are also used for preparation. The
`physicochemical characteristic of the polymer or
`polymers selected for film formulation play a
`vital
`role
`in determining
`the
`resultant
`disintegration time of the cast thin film oral
`dosage form.
`
`Plasticizer15-17
`Plasticizer is a vital ingredient of the fast
`dissolving films. Plasticizer helps to improve the
`flexibility of the strip and reduces the brittleness
`of the films. It significantly improves the film
`forming properties by
`reducing
`the glass
`transition temperature of the polymer. The
`chemical structure and concentration of
`plasticizers play an important role in alleviating
`the glass
`transition
`temperature of
`the
`polymers. The selection of plasticizer will
`depend upon its compatibility with the polymer
`and also the type of solvent employed in the
`casting of the film. The flow of polymer will get
`
`
`better with the use of plasticizer and enhances
`the strength of the polymer. Glycerol, Propylene
`glycol,
`low molecular weight polyethylene
`glycols, phthalate derivatives
`like dimethyl,
`diethyl and dibutyl phthalate, citrate derivatives
`such astributyl, triethyl, acetyl citrate, triacetin
`and castor oil are some of the commonly used
`plasticizer excipients. Typically the plasticizers
`are used in the concentration of 0–20 percent;
`w/w of dry polymer weight. However,
`inappropriate use of plasticizer may lead to film
`cracking, splitting and peeling of the strip. It is
`also reported that the use of certain plasticizers
`may also affect the absorption rate of the drug.
`
`Sweetening agents18
`
`Sweeteners have become the important part of
`pharmaceutical products
`intended
`to be
`disintegrated or dissolved in the oral cavity.
`Sweeteners can be used either alone or in
`combination. Both natural as well as artificial
`sweeteners are used in the formulation of these
`mouth dissolving film. The classical source of
`sweetener
`is sucrose, dextrose,
`fructose,
`glucose, liquid glucose and isomaltose. The
`sweetness of fructose is perceived rapidly in the
`mouth as compared to sucrose and dextrose.
`Fructose is sweeter than sorbitol and mannitol
`and
`thus used widely as a sweetener.
`Polyhydric alcohols such as sorbitol, mannitol,
`and isomalt can be used in combination as they
`additionally provide good mouth‐feel and
`cooling sensation. Polyhydric alcohols are less
`carcinogenic and do not have bitter after taste
`which is a vital aspect in formulating oral
`preparations. Saccharin,
`cyclamate
`and
`aspartame are
`the
`first generation of
`the
`artificial sweeteners followed by acesulfame‐K,
`sucralose, alitame and neotame which
`fall
`under
`the
`second
`generation
`artificial
`sweeteners.
`
`Saliva stimulating agents19
`The purpose of saliva stimulating agent is to
`increase the rate of production of saliva that
`would aid in the faster disintegration. These
`agents are used alone or in combination.
`Examples : Citric acid, Tartaric acid, Ascorbic
`acid, Malic acid.
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`Int J Pharm Bio Sci 2013 Jan; 4(1): (P) 899 - 908
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`Flavoring agents20
`It was observed that age plays a significant role
`in the taste fondness. Flavoring agents can be
`selected from synthetic flavor oils, oleo resins,
`extract derived from various parts of the plants
`like leaves, fruits and flower. Peppermint oil,
`cinnamon oil, oil of nutmeg are examples of
`flavor oils while vanilla, cocoa, coffee, chocolate
`and citrus are fruity flavors. Apple, raspberry,
`cherry, pineapple are few examples of fruit
`essence type.
`
`Coloring agents
`Pigments such as titanium dioxide or FD & C
`approved coloring agents are incorporated (not
`
`1. Solvent casting method
`Fast dissolving films are preferably formulated using the solvent casting method, whereby the water
`soluble ingredients are dissolved to form a clear viscous solution and the drug along with other
`excipients is dissolved in a suitable solvent then both the solutions are mixed and stirred and finally
`casted into the Petri plate and dried.
`
`exceeding concentration levels of 1 percent;
`w/w) in OS when some of the formulation
`ingredients or drugs are present in an insoluble
`or suspension form.
`
`METHOD OF PREPARATION OF MOUTH
`DISSOLVING FILMS21-2
`One or a combination of the following processes
`can be used
`to manufacture
`the Mouth
`dissolving film:
` Solvent casting method
` Hot-melt extrusion
` Semisolid casting
` Solid dispersion extrusion
` Rolling
`
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`Water soluble ingredients are dissolved in water
`
`
`API and other agents are dissolved in suitable solvent to form a clear viscous solution
`
`
`
`
`
`
`
`
`
`
`
`
`
`Both the solutions are mixed
`
`Degassed under vacuum
`
`Resulting solution is cast as a film
`
`
`
`
`
`
`
`
`Film is dried in drying oven and collected
`2. Hot melt extrusion
`Hot melt extrusion method has various benefits; those are fewer operation units, minimum product
`wastage, better content uniformity, an anhydrous process, absence of organic solvents.
`In hot melt extrusion method-
`
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`
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`
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`Drug is mixed with carriers in solid form.
`
`
`
`
`The extruder having heaters melts the mixture
`
`Finally the melt is shaped in films by the dies
`
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`Int J Pharm Bio Sci 2013 Jan; 4(1): (P) 899 - 908
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`3. Semisolid casting method
`This method is preferably adopted when acid insoluble polymers are to be used in the preparation of
`the films. Acid-insoluble polymers used to prepare films include: cellulose acetate phthalate, cellulose
`acetate butyrate. Acid insoluble polymer and film forming polymer should be used in the ratio of 1:4.
`
`Solution of water soluble film forming polymer is prepared.
`
`
`
`
`
`
`
`Resulting solution is added to a solution of acid insoluble polymer.
`
`
`
`Appropriate amount of plasticizer is added so that gels mass is obtained.
`
`
`Finally the gel mass is casted into the films or ribbons using heat controlled drums.
`
`
`4. Solid dispersion extrusion method
`The term solid dispersions refer to the dispersion of one or more active ingredients in an inert carrier
`in a solid state in the presence of amorphous hydrophilic polymers.
`
`
`Drug is dissolved in a suitable liquid solvent.
`
`
`
`Then solution is incorporated into melt of polyethylene glycol, obtainable below 700C.
`
`
`Finally the solid dispersions are shaped into the films by means of dies.
`
`
`Precautions while preparing solid dispersions
`The selected solvent or dissolved drug may not be miscible with the melt of polyethylene glycol and
`polymeric form of drug precipitated in the solid dispersions may get affected by the liquid solvent
`used.
`
`5. Rolling method
`In this method the film is prepared by preparation of a pre-mix, the addition of an active and
`subsequent formation of a film.
`
`
`Prepare pre-mix with film forming polymer, polar solvent and other additives except a drug.
`
`
`Add pre mix to master batch feed tank.
`
`Fed it via a 1st metering pump and control valve to either or both of the 1st and 2nd mixer.
`
`Add required amount of drug to the desired mixer.
`
`Blend the drug with master batch pre mix to give a uniform matrix.
`
`Then a specific amount of uniform matrix is then fed to the pan through 2nd metering pumps.
`
`The film is finally formed on the substrate and carried away via the support roller.
`
`The wet film is then dried using controlled bottom drying.
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`Int J Pharm Bio Sci 2013 Jan; 4(1): (P) 899 - 908
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`Tear resistance24
`Tear resistance of plastic film or sheeting is a
`complex function of its ultimate resistance to
`rupture. Basically a very low rate of loading
`51mm (2 in)/min is employed and is designed
`to measure the force (that is generally found
`near the onset of tearing) required to tear the
`specimen is recorded as the tear resistance
`value in Newton‟s (or pounds-force).
`
`Folding endurance25-26
`Folding endurance is determined by repeated
`folding of the strip at the same place till the
`strip breaks. The number of times the film is
`folded without breaking is computed as the
`folding endurance value.
`
`Organoleptic evaluation27-28
`For evaluation of psychophysical evaluation of
`the product, special controlled human taste
`panels are used. In-vitro methods of utilizing
`taste sensors, specially designed apparatus
`and drug release by modified pharmacopoeial
`methods are being used for this purpose.
`These in-vitro taste assessment apparatus
`methodologies are well suited
`for high-
`throughput
`taste
`screening
`of
`oral
`pharmaceutical formulations.
`
`Morphology Studies29
` Scanning electron microscopy (SEM) study
`refers the differences between the upper and
`lower side of the films. It also helps in the
`determination of the distribution of API. Near-
`infrared chemical imaging (NIR-CI) study helps
`in determining the difference between drug
`distributions
`in drug
`loaded
`films and
`recrystallization.
`
`Surface pH of film
`Surface pH of films is determined by placing
`the film on the surface of 1.5% w/v agar gel
`followed by placing pH paper (pH range 1-11)
`on films. The change in the color of pH paper
`was observed and reported.
`
`
`
`
`EVALUATION
`Thickness
`The thickness of the film is determined by
`screw gauge or micrometer at different points
`of the films. This is essential to ascertain
`uniformity in the thickness of the film as this is
`directly related to the accuracy of dose in the
`strip.
`
`Dryness/Tack test24
`
`About eight stages of film drying process have
`been identified and they are set-to-touch, dust-
`free, tack-free (surface dry), dry-to-touch, dry-
`hard, dry through (dry-to-handle), dry-to-recoat
`and dry print-free. Although these tests are
`primarily used for paint films, most of the
`studies can be adapted intricately to evaluate
`pharmaceutical orally fast dissolving film. Tack
`is the tenacity with which the strip adheres to
`an accessory (a piece of paper) that has been
`pressed into contact with the strip. Instruments
`are available for this study.
`
`Tensile strength24
`Tensile strength is the maximum stress applied
`to a point at which the strip specimen breaks. It
`is calculated by the applied load at rupture
`divided by the cross-sectional area of the strip
`as given in the equation below
`Tensile strength = Load at breakage/ Strip
`thickness × Strip Width
`
`Percent elongation24
`is applied, a strip sample
`When stress
`stretches and this is referred to as strain. Strain
`is basically the deformation of strip divided by
`the original dimension of the sample. Generally
`elongation of strip increases as the plasticizer.
`% Elongation = Increase in length ×100 /
`Original length
`
`Young’s Modulus24
`
`Young’s modulus or elastic modulus is the
`measure of stiffness of strip. It is represented
`as the ratio of applied stress over strain in the
`region of elastic deformation. Hard and brittle
`strips demonstrate a high tensile strength and
`young’s modulus with small elongation.
`
`
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`Swelling property30
`Film swelling studies is conducted using the
`simulated saliva solution. Each film sample is
`weighed and placed in a pre-weighed stainless
`steel wire mesh. The mesh containing the film
`sample is submerged into 15ml medium in a
`plastic container. Increase in the weight of the
`film was determined at preset time interval until
`a constant weight was observed.
`The degree of swelling was calculated using
`parameters
`S.I = Wt – Wo/Wo
`Where S.I is the swelling index, Wt is the
`weight of the film at time”t”, and Wo is the
`weight of film at t = 0.
`
`Transparency31-32
`
`The
`films can be
`the
`transparency of
`simple
`UV
`a
`determined
`using
`spectrophotometer. Cut the film samples into
`rectangles and placed on the internal side of
`the spectrophotometer cell. The determine
`transmittance of
`films at 600 nm. The
`transparency of the films was calculated as
`follows:
`Transparency = (logT600)/b = - €c
`Where T600 is transmittance at 600 nm and b
`the film thickness (mm) and c is concentration.
`
`Assay/ Content uniformity
`This is determined by any standard assay
`method described for the particular API in any
`of
`the standard pharmacopoeia. Content
`uniformity is determined by estimating the API
`content in individual strip. Limit of content
`uniformity is 85–115 percent.
`
`Disintegration time33
`The disintegration time limit of 30 s or less for
`orally disintegrating tablets described in CDER
`guidance can be applied to fast dissolving oral
`strips. Although, no official guidance
`is
`available for oral fast disintegrating films strips,
`this may be used as a qualitative guideline for
`quality control test or at the development
`stage. Pharmacopoeial disintegrating
`test
`apparatus may be used for this study. Typical
`disintegration time for strips is 5–30s.
`
`Dissolution test34
`
`Dissolution testing can be performed using the
`standard basket or paddle apparatus. The
`dissolution medium will essentially be selected
`as per the sink conditions and highest dose of
`the API. Many times the dissolution test can be
`difficult due to tendency of the strip to float onto
`the dissolution medium when
`the paddle
`apparatus is employed.
`
`Table3
`Marketed Formulations of MDF35-37.
`
`
`Sr.No.
`
`Product
`
`1.
`
`2.
`
`3.
`
`4.
`5.
`
`6.
`
`Ondansetron rapidfilm®
`
`Donepezil rapidfilm®
`
`Triaminic thin strips®
`
`Loratidine strips
`Caffiene strips
`
`Zuplenz
`
`7.
`
`Suboxone®
`
`Indication
`It is used in the prevention of chemotherapy
`and radiation‐induced nausea and vomiting and
`prevention of postoperative nausea and
`vomiting.
`Treatment of mild to moderately severe
`dementia of the Alzheimer's type.
`It reduces cough due to minor throat and
`bronchial irritation as may occur with a cold. It
`relieves itchy, watery eyes due to
`hay fever.
`Allergy
`CNS stimulant
`Prevention of postoperative, highly an
`Moderately emetogenic cancer chemo therapy
`and radiotherapy induced nausea and vomiting.
`
`Sublingual film indicated for maintenance
`treatment of opioid dependence and should be
`used as part of a complete treatment plan to
`include counseling and psychosocial support .
`
`8.
`
`Zelaper
`
`Treatment for Parkinson's disease.
`
`Company
`
`Labtec Gmbc
`
`Labtec Gmbc
`
`NovaritisPharmaceuticals
`
`Hughes Medical Cooperation
`Hughes Medical Cooperation
`
`Pharmfilm® technology
`
`Reckitt Benckiser Pharmaceuticals
`Inc
`
`Valeant Pharmaceuticals
`International Inc
`
`This article can be downloaded from www.ijpbs.net
`P - 906
`
`
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`
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2021 - 8/10
`
`

`
`Int J Pharm Bio Sci 2013 Jan; 4(1): (P) 899 - 908
`
`
`
`CONCLUSION
`
`
`Mouth dissolving films are not well defined in
`the literature but, no doubt a revolutionary and
`an innovative drug delivery system for all the
`population
`groups,
`specifically
`geriatric,
`pediatric patients and patients with swallowing
`difficulties. MDFs are also having a great
`
`
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`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2021 - 10/10