Professional Documents
Culture Documents
National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, C/o. B.V. Patel Pharmaceutical
Education and Research Development Centre, S.G. Highway, Thaltej, Ahmedabad-380054, India
Abstract: The ultimate goal of any drug delivery system is the successful delivery of the drug to the body; however, pa-
tient compliance must not be overlooked. Fast dissolving drug delivery systems, such as, Mouth Dissolving Films (MDF),
offer a convenient way of dosing medications, not only to special population groups with swallowing difficulties such as
children and the elderly, but also to the general population. MDF are the novel dosage forms that disintegrate and dissolve
within the oral cavity. Intra-oral absorption permits rapid onset of action and helps by-pass first-pass effects, thereby re-
ducing the unit dose required to produce desired therapeutic effect. The present review provides an overview of various
polymers that can be employed in the manufacture of MDF and highlights the effect of polymers and plasticizers on vari-
ous physico-mechanical properties of MDF. It further gives a brief account of formulation of MDF and problems faced
during its manufacture.
Keywords: Mouth dissolving films, intraoral, film forming polymers, glass transition temperature, tensile strength, blooming.
gies that are in the form of tablets. However, Mouth Dissolv- drugs as well. Oral mucosal delivery via MDF could become
ing Tablets (MDT) are associated with certain limitations, a preferential delivery method for therapies in which rapid
such as: absorption is desired, including those used to manage pain,
allergies, sleep difficulties, and central nervous system dis-
1. Despite the short disintegration/dissolution times of
MDT, the fear of taking solid tablets and the risk of orders. Some of the commercially available MDF are listed
in Table 1.
choking persists [10].
The review will subsequently deal with the brief outlines
2. For their production , many MDT requires the expensive
for the selection of various excipients/ ingredients for the
lyophilisation process,
development of MDF.
3. MDT are sometimes difficult to carry, store and handle
(fragility and friability) [5]. SELECTION OF DRUG CANDIDATE FOR MDF
4. MDT requires specialized and expensive packaging and Before selecting MDF as drug delivery systems, it is im-
processing. portant to take into consideration, the properties of the drug
The above mentioned limitations of MDT have paved the candidate, like taste, irritancy, allergenicity and adverse
way for development of Mouth Dissolving Films (MDF) as properties such as discolouration or erosion of the teeth [7].
fast drug delivery systems. MDF are gaining interest as an Drug should have sufficient water-solubility and intraoral
alternative to MDT to definitely eliminate patients fear of absorption. In case of poorly soluble drugs, the solubility of
choking [11]. drug should be enhanced by the use of water-soluble salts or
complex. Even if the drug has little or no intra-oral absorp-
MOUTH DISSOLVING FILMS (MDF) tion, rapid onset of action due to rapid dissolution within oral
cavity and hence rapid absorption through GIT can be a driv-
A film or strip can be defined as a dosage form that em- ing force in the selection of MDF as dosage forms.
ploys a water-dissolving polymer (generally a hydrocolloid,
which may be a bioadhesive polymer), which allows the The amount of medicament that can be used in the MDF
dosage form to quickly hydrate, adhere, and dissolve to re- depends on the dose needed to provide an effective amount
lease the drug when placed on the tongue or in the oral cav- of the medicament. However, intraoral absorption directly
ity [12,13]. They are also known as fast-dispersing, mouth into systemic circulation permits dose reduction. In order to
dissolving, orally disintegrating, fast-melting, Quick- maintain its fast-dissolving characteristics, the thickness of
dissolving films [14]. MDF can provide a convenient and the film should be carefully controlled. This limits its load-
effective vehicle for delivering active ingredients such as ing capacity for API to some extent [10]. The amount of
pharmaceutical compounds and breath freshening agents, to drug that can be loaded onto a film delivery system is guided
the mucosa of humans and animals [15]. It allows the drug to by visual inspection results for blooming when loading vari-
be delivered to the blood stream either intragastrically, buc- ous levels of API onto film. Some of the API with their dose,
cally or sublingually [16]. As soon as MDF are taken, rapid to be used per one strip of MDF are mentioned in Table 2
absorption of drug, through the sublingual route is possible, [19, 20, 21, 22]. The maximum loading of API depends on
which finally leads to quick onset of drug action. the compatibility of the film forming polymers with APIs
and parameters such as pH of the system. Generally the
The proper selection of incorporated excipients/ ingredi- amount at which the drug doesnt bloom to the surface is
ents for formulating MDF is very important as MDF have to incorporated. Studies have shown that upto 10.1% benzo-
disintegrate and/or dissolve quickly into the oral cavity. Be- caine can be delivered in edible film systems consisting of
sides water-dissolving polymer, the formulation may include polymers, plasticizers, benzocaine or caffeine, sweeteners,
other components depending on its intended use [17], viz. flavors, colorants, and processing aids without blooming. In
pharmaceutical agents, antimicrobial agents, nutraceutical another system, which was a buccal film delivery system
ingredients, plasticizers, surfactants, colorants, sweetening containing polymers, benzocaine, and colorants upto 17.2%
agents, saliva stimulating agents, flavors, flavor enhancers benzocaine could be delivered without blooming [18].
and other excipients. A typical composition contains the fol-
lowing excipients: SELECTION OF POLYMER
Drug 1 - 25 % The physical and mechanical properties of the MDF de-
Water-soluble polymers 40 - 50 % pend on the characteristics of film-forming polymer, which
forms 20 to 75% (w/w) of total dry wt. of the MDF [19, 23].
Plasticizers 0 - 20 % The selection of polymer, therefore, is one of the most im-
Fillers, colour, flavour etc. 0 - 40 % portant and critical parameter for the successful development
of the formulation. The polymers used should have good
As polymers and plasticizers form the main body of
hydrophilicity, rapid disintegration, good mouth feel, and
MDF, therefore, their properties greatly affect the character-
suitable mechanical properties. Along with its good solubil-
istics of MDF.
ity, the polymer should have sufficient mechanical, physico-
To date, the commercial launch of MDF is primarily in chemical and permeability properties. In order to remain
OTC products addressing therapeutic categories such as intact against the internal and external stresses developed
cough/cold, sore throat, and antacid/gas relief as well as a during storage and especially when exposed to environ-
number of nutritional supplement applications. However, it mental conditions, a film should have high mechanical
is finding increased use as a delivery system for prescription strength with sufficient elongation and elasticity properties.
A Review on Mouth Dissolving Films Current Drug Delivery, 2009, Vol. 6, No. 5 471
Folic Acid 15
Loratidine 10 20
Caffeine 2.5
Ondansetron 4-8
Simethicone 62.5
Phenylephrine HCl 10
Famotidine 10 Ulcers
These properties of films developed from the polymers are whereas a hard and tough polymer is characterized by a high
dominated by polymer chemistry, solvent effects, and addi- TS, EM and E/B [24]. Hence, it is suggested that a film
tives such as plasticizer, sugars, and humectants. The poly- should have a moderately high TS, E/B and Strain but a low
mers used in the films are cellulose derivatives (hydroxypro- EM [25].
pylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, carboxymethyl cellulose), synthetic polymers Glass Transition Temperature (Tg)
(polyvinyl alcohol, polyethylene glycol, polyacrylic acid, The Glass transition temperature, Tg, is the temperature
methylmethacrylate copolymer, polyvinyl pyrrolidone, car- at which brittle polymer becomes soft or plastic. Cohesive
boxyvinyl polymer), natural gums (xanthan gum, tragacanth strength and inter-chain attraction, and, thus glass transition
gum, guar gum, acacia gum, arabic gum), starch derivatives temperature (Tg) of the polymer are related to the presence,
(amylose, high amylose starch, hydroxypropylated high concentration, location and relative polarities of functional
amylose starch), polysaccharides (dextrin, pectin, chitin, groups along the polymer chain, rigidity of the polymer
chitosan, levan, sodium alginate) and peptides (elsinan, col- backbone, bulkiness of side groups and also molecular
lagen, gelatin, zein, gluten, soy protein isolate, whey protein weight of the polymer. Polymer with low Tg form films that
isolate, casein) and others [20]. are flexible, with a low elastic modulus and exceptionally
high percent elongation [26]. Films formed with polymer
PHYSICO-MECHANICAL PROPERTIES OF FILMS having very high values of Tg are stiff, with a high elastic
Tensile Strength, Elastic Modulus, Elongation at Break modulus and a very low percent elongation. Above parame-
ters dictate the selection of polymers to obtain desired MDF.
The tensile testing gives an indication of the film strength Therefore it is important to consider all the above parameters
and elasticity of the film, reflected by the parameters, strain, of the polymer. Tg values of some of the important polymers
tensile strength (TS), elastic modulus (EM) and elongation at have been enlisted in Table 3.
break (E/B). Strain is the geometrical measure of deforma-
tion representing the relative displacement between particles EFFECT OF POLYMERS
in a material body, when stress induced by either external
force or temperature change. A high strain value indicates The first material employed to produce edible films was
that the film is strong and elastic. Tensile strength is the pullulan, a glucan consisting of maltotriose units, produced
stress at which a material breaks or permanently deforms. from starch by the fungus Aureobasidium pullulans [27].
Tensile strength is an intensive property and, consequently, This review further deals with brief introduction to various
does not depend on the size of the test specimen. However, it polymers that are being used widely.
is dependent on the preparation of the specimen and the tem-
perature of the test environment and material. An elastic Hydroxypropyl Methylcellulose
modulus also referred as youngs modulus, is the mathemati- Hydroxypropyl Methylcellulose (HPMC) is known for its
cal description of a material's tendency to be deformed elas- good film forming properties and has excellent acceptability.
tically when a force is applied to it. The elongation-to-break Lower grades of HPMC like Methocel E3, Methocel E5 and
(also called ultimate elongation) is the strain on a material Methocel E15 are particularly used for MDFs because of
when it breaks and it gives an indication of toughness and their low viscosity. The Tg of HPMC grades were deter-
stretch-ability prior to breakage. These parameters dictate the mined to be 160, 170, and 175 oC, respectively [29]. For the
end-use handling properties and mechanical performance of HPMC E series, the maximum puncture strength of the E
the films. series increased when the molecular weight of the polymer
A soft and weak polymer is characterized by a low TS, increased: E3 < E5 < E15 < E50. Mishra and Amin (2009)
EM and E/B; a hard and brittle polymer is defined by a mod- formulated and developed taste-masked fast dissolving film
erate TS, high EM and low E/B; a soft and tough polymer is of cetirizine using HPMC with various viscosity grades (i.e.,
characterized by a moderate TS, low EM and high E/B; E3, E5 and E15) as the film-forming polymer, and solvent
Polymer Molecular wt, g/mol. Glass transition temp., K Tensile strength, MPa
casting as a method of manufacture [30]. They found that the molecular weight. HPC is commercially available in a num-
in vitro disintegration time and in vitro dissolution profiles ber of different grades, which have different solution viscosi-
of the MDF were highly affected with the various grades of ties. The molecular weight of the HPC ranges from about
HPMC and concluded that HPMC E3 LV was the most suit- 50,000 to about 1,250,000 [33]. It is known that films
able grade for the manufacture of MDFs. In another study, it formed with polymers having very high glass transition temp
is found that Methocel E3 (with 5% glycerol) has in-vivo values are stiff [26], therefore, cellulose (Tg = 500) is not
disintegration time of 6 seconds and in-vivo dissolution time suitable as film forming polymer. Its synthetic derivatives,
of 37 seconds [30]. Dinge and Nagarsenker (2008) formu- such as HPC, HPMC having comparatively lower Tg values
lated fast dissolving films containing HPMC (Methocel E3, are therefore preferred. Because of relatively high glass tran-
E5, E15), xanthan gum, and xylitol for intraoral delivery of sition temperatures (compared to other film forming poly-
Triclosan. The solubility of TC was improved by incorpora- mers) of HPC [34], the formed films were shown to exhibit
tion of solubilizers such as HPBCD and poloxamer 407. brittle fracture and were found to be stiff, with a high elastic
From the in vitro and in vivo evaluation, it was concluded modulus and a very low percent elongation (less than 5%)
that films could be considered as an innovative dosage form [26]. Typically slow dissolving, the films have good carrying
to improve delivery of TC [13]. capacity and reasonable clarity.
Peh and Wong (1999) have investigated the mechanical
and in vitro bioadhesive strength of SCMC films (sodium Pullulan
carboxymethyl cellulose/polyethylene glycol 400/carbopol Pullulan is a water soluble, neutral linear polysaccharide
934P) and HPMC films (hydroxypropylmethyl cellu- consisting of 1, 6-linked maltotriose residues. It is a fungal
lose/polyethylene glycol 400/carbopol 934P) as drug vehicle exopolysaccharide produced from starch by Aureobasidium
for buccal delivery. HPMC films were found to be tougher, pullulans [28]. Films formed with pullulan are highly water-
more elastic, more bioadhesive in vivo and swelled in a more soluble, colorless, tasteless, odourless, transparent, flexible,
tolerable manner in the oral cavity compared to SCMC films possess low permeability to oil and oxygen, and heat-
[24]. sealable. These properties make them an ideal material for
edible films [35]. Pullulan-based films are easy to manufac-
Poly (Ethylene Oxide) ture, however, the use of this material is limited by its low
availability and high costs. To overcome this limitation Tong
Poly (ethylene oxide) is a nonionic, high molecular
et al. (2008) blended them with other compatible polymers
weight water-soluble polymer. Poly (ethylene oxide) (PEO)
is a thermoplastic semicrystalline polymer with a melting that are abundant and lower in cost, such as sodium alginate
and CMC. Kawahara et al. studied the dependence of prepa-
point ranging from 60 oC to 75 o C and a glass transition tem-
ration temperature on the Mechanical properties of a Pullu-
perature of 67 oC. PEO films, because of their negative
lan Film. It was found that the films obtained at higher tem-
glass transition temperature (67 oC) [31] and chemical
perature were more brittle, less flexible than films formed at
structure of PEO, were found to be flexible with a low elastic
lower temperature. Pullulan has been shown to have in-vivo
modulus and exceptionally high percent elongation. PEO
films exhibit higher bioadhesivity because of the extremely disintegration time of 6 seconds and in-vivo dissolution time
of 48 seconds.
flexible PEO structure, which can result in stronger inter-
penetration of the polymer and mucin chains [26]. It is com-
Modified Carboxymethyl Cellulose
mercially available under tradename of POLYOX. Polyox
polymer that may be used in the oral film is Polyox N-80. CMC is a cellulose derivative which has been enzymati-
Polyox N-80 has an approximate molecular weight of cally modified to reduce molecular weight. This type of ma-
200,000 and a viscosity of about 65 to 115 mPa/s (5% aque- terial is ideal for applications requiring a fast dissolving
ous solution at 25 oC) [32]. They exhibit many properties base. Also capable of carrying a range of active components,
that are typical of other classes of water-soluble polymers CMC has a neutral flavour and produces films with excellent
lubricity, binding, water retention, thickening, and film for- clarity and good dimensional stability [36].
mation. In a study, various grades of Polyox were analysed
for mechanical properties. It was found that the increase in Pectin
molecular weight causes an increase in mechanical strength.
It was also found that due to the nature of poly(ethylene ox- Pectin is a carbohydrate obtained from citrus fruits and
ide) chemistry with lower Tg and more flexibility, the punc- apples. Pectins are good film formers with good capacity to
ture strength of PEO is much lower than that of cellulose carry drugs and are particularly suitable for low pH applica-
based MC and HPMC polymers [18]. Polyox N-80 has in- tions. Solubility of the films depends on molecular weight of
vivo disintegration time of 4 seconds and in-vivo dissolution the polymer, but generally it dissolves slowly in the oral cav-
time of 23 seconds which is comparable with the commer- ity [36]. It has been found that pectin (X-939-04) films have
cially available Listerine films. an in-vivo disintegration time of 15 seconds and in-vivo dis-
solution time of 141 seconds [30]. The high intrinsic viscos-
Hydroxypropyl Cellulose ity of pectin prevents formation of thin films with high load-
ing levels of actives. Pectin films are also known to impart
Hydroxypropyl cellulose (HPC) is a non-ionic water- uncomfortable mouth feel during dissolution of the film in
soluble thermoplastic polymer. It is partially substituted poly the mouth. In a study, it was found that degradation of pectin
(hydroxypropyl) ether of cellulose. It is an amorphous poly- (modified pectin) reduces its intrinsic viscosity from 4.9 dl/g
mer that softens between 100 oC and 150 oC based on its to 2.5 dl/g making it more suitable for use in MDF [37].
474 Current Drug Delivery, 2009, Vol. 6, No. 5 Dahiya et al.
Gelatin result of decrease in the Tg, the films formed are more flexi-
ble [43]. Plasticizers also tend to decrease the tensile strength
Gelatin is a heterogeneous mixture of water-soluble pro-
of polymeric films.
teins of high molecular weight. Gelatin is nearly tasteless,
odorless, colorless or slightly yellow, transparent, brittle In a study, the effects of various plasticizers on mechani-
flakes, or powder. Gelatin swells and absorbs 5-10 times its cal properties of methyl cellulose(MC) films were deter-
weight of water to form a gel in aqueous solutions between mined. It was observed that among (polyethylene glycols
30-35C [38]. Derived from the natural protein collagen, [PEG] 400, 1,450, 8,000 and 20,000, glycerol [G] and pro-
gelatin is widely used in food and pharmaceutical industry. pylene glycol [PG]),with the exception of PG, all plasticizers
Gelatin films dissolves rapidly, are excellent carriers for fla- decreased the tensile strength of MC films, with PEG 400
vours and produces a smooth mouth feel [36]. It has been causing the largest decrease. With the exception of PG and
found that gelatin films have an in-vivo disintegration time of PEG 400, all plasticizers increased percent elongation values
8 seconds and in-vivo dissolution time of 40 seconds [30]. of MC films, with PEG 1,450 having the greatest effect.
However, the property of gelatin to form a highly viscous gel Glycerol and PEG were found to be the most effective plas-
(upon hydration with saliva in the mouth) makes it less ac- ticizers for MC [44]. Chetty et al. (2002) investigated the
ceptable for use in MDF in comparison to other polymers. physical and mechanical characteristics of HPC films plasti-
cized with glycerin, propylene glycol or sorbitol. The HPC
Others films displayed increasing puncture strengths with higher
concentrations of polymer. Film strengths were function of
A low molecular weight film forming biopolymer, Po- both the nature and concentration of the plasticizers. Higher
lymerized Rosin (PR) was examined for its drug delivery concentrations (3 % w/w) of glycerin reduced puncture
applications [39]. Neat PR films were found to be slightly forces (from 342.9 g to 80.3 g for the 5 % HPC film) while
brittle and posed the problem of breaking during handling. lower concentration (1 %) was shown to have a negligible
Incorporation of Hydrophobic plasticizers improved the me- effect on the puncture force of HPC films. The increased
chanical properties of films. Cilurzo et al. studied maltodex- plasticizer content of the films caused higher water retention
trins (MDX) with a low dextrose equivalent as film forming by the polymer, which resulted in more flexible films. An
material and their application in the design of oral fast- increase of plasticizer from 1 to 3 % in the 5 % HPC film
dissolving films. It was found that Maltodextrins having low caused a 68 % increase in water retention. Further incre-
dextrose equivalent, plasticized with 1620% w/w glycerine ments of plasticizer concentration showed little reduction of
were found to be suitable for producing fast-dissolving films puncture forces. The authors concluded that the plasticiza-
[11]. tion of hydrophilic films facilitates manipulation of the me-
Choa et al. (2007) prepared edible films from membrane chanical properties of films thereby allowing optimization of
processed soy protein concentrate (MSC) at various film drug delivery rates [45].
forming solution pHs, and their mechanical, barrier, and However, Plasticizers have disadvantage of increasing
physical properties were compared with soy protein isolate film permeability to moisture and oxygen, make the film
(SPI) films. They also observed that as the film solution pH more labile to hydrolytic and oxidative degradation [46].
increased from 7 to 10, the resulted MSC films were more
transparent, yellowish, and had lower oxygen permeabilities. FORMULATION ASPECTS OF MOUTH DISSOL-
However, tensile strength (TS), modulus of elasticity (ME) VING FILMS
and water vapor permeabilities of MSC films were not af-
fected by film solution pHs [40]. Various processes like Hot-melt extrusion, Solid disper-
sion extrusion, Rolling, Semi-solid casting, and Solvent cast-
EFFECT OF PLASTICIZERS ing are used to manufacture the films. The current preferred
manufacturing process for producing films is solvent casting.
Plasticizers are the essential additives that are able to Solvent casting involves preparation of solution containing
change hard and brittle films to more pliable and tougher drug and film-forming excipients with volatile solvents fol-
form. Plasticizer is usually low molecular weight organic lowed by casting of a thin coat of solvent blend onto a mov-
solvent, having Tg values of -50oC to -150oC. Most of the ing, inert substrate. Drying of the coated film is done by
polymers used in film coating are either amorphous or have passing through hot air flow such as drying oven to evapo-
very little crystallinity. Most commonly employed plasticiz- rate the solvent before die-cutting the dried film into strips.
ers are glycerol, propylene glycol, sorbitol, and/or polyethyl- Mashru et al. (2005) prepared Salbutamol films using Sol-
ene glycol. The plasticizer may be present in any desired vent-casting method [47]. Triclosan films were also prepared
amount, particularly from 0 to about 50 percent, more typi- by the same method. MDFs can also be produced using hot-
cally from 5 to about 20 by weight of the active containing melt extrusion (HME) technique. This technique involves
formulated film [41]. Plasticizer molecules interpose them- melting of drugexcipients mixture followed by extruding it
selves between the individual polymer strands; thus, break through a die under molten conditions. The thin film is then
down polymer-polymer interactions to a large extent. This cooled to room temperature and die-cut into small strips.
action is facilitated as the polymer plasticizer interaction is Extruders are not common in the pharmaceutical industry
considered to be stronger than the polymer-polymer interac- due to the high cost of the extruders [48]. Prodduturi et al.
tion thus providing greater opportunity to polymer strands to (2007) used this technique to produce Lidocaine films [26].
move past each other. The interaction of the plasticizer with Cilurzo et al. (2008) prepared films using both solvent cast-
the polymer generally decreases the elastic modulus, lowers ing and hot-melt extrusion. It was reported that the solvent-
the softening temperature, and decreases the Tg [42]. As a
A Review on Mouth Dissolving Films Current Drug Delivery, 2009, Vol. 6, No. 5 475
casting method is more reliable for the production of fast- [12] Ghosh, T.K.; Pfister, W.R. Drug delivery to the oral cavity: Mole-
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Received: June 16, 2009 Revised: August 12, 2009 Accepted: August 12, 2009