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`Teva Pharm. v. Indivior, IPR2016-00280
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`European Journal of Pharmaceutics and Biopharmaceutics 77 (2011) 187–199
`
`Contents lists available at ScienceDirect
`
`European Journal of Pharmaceutics and Biopharmaceutics
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / e j p b
`
`Review article
`Manufacture and characterization of mucoadhesive buccal films
`⇑
`
`Javier O. Morales, Jason T. McConville
`
`College of Pharmacy, University of Texas at Austin, Austin, USA
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Article history:
`Received 26 May 2010
`Accepted in revised form 29 November 2010
`Available online 3 December 2010
`
`Keywords:
`Buccal drug delivery
`Oral mucosa
`Mucoadhesion
`Permeation
`Mucoadhesive polymers
`Buccal patches
`
`1. Introduction
`
`The buccal route of administration has a number of advantages including bypassing the gastrointestinal
`tract and the hepatic first pass effect. Mucoadhesive films are retentive dosage forms and release drug
`directly into a biological substrate. Furthermore, films have improved patient compliance due to their
`small size and reduced thickness, compared for example to lozenges and tablets. The development of
`mucoadhesive buccal films has increased dramatically over the past decade because it is a promising
`delivery alternative to various therapeutic classes including peptides, vaccines, and nanoparticles. The
`‘‘film casting process’’ involves casting of aqueous solutions and/or organic solvents to yield films suitable
`for this administration route. Over the last decade, hot-melt extrusion has been explored as an alternative
`manufacturing process and has yielded promising results. Characterization of critical properties such as
`the mucoadhesive strength, drug content uniformity, and permeation rate represent the major research
`areas in the design of buccal films. This review will consider the literature that describes the manufacture
`and characterization of mucoadhesive buccal films.
`
`Ó 2010 Elsevier B.V. All rights reserved.
`
`Films as dosage forms have gained relevance in the pharmaceu-
`tical arena as novel, patient friendly, convenient products. More re-
`cently, orally disintegrating films (or strips) have come to light,
`thanks to their improved mechanical properties [1]. This translates
`into a less friable dosage form compared to most commercialized
`orally disintegrating tablets, which usually require special packag-
`ing [2]. Mucoadhesive buccal films share some of these advantages
`and more. Due to their small size and thickness, they have im-
`proved patient compliance, compared to tablets [3–5]. Moreover,
`since mucoadhesion implies attachment to the buccal mucosa,
`films can be formulated to exhibit a systemic or local action [6].
`Many mucoadhesive buccal films have been formulated to release
`drug locally in order to treat fungal infections in the oral cavity
`such as oral candidiasis [7–11]. Due to the versatility of the manu-
`facturing processes, the release can be oriented either towards the
`buccal mucosa or towards the oral cavity; in this latter case, it can
`provide controlled release via gastrointestinal (GI) tract adminis-
`tration. Alternatively, films can be formulated to release the drug
`towards the buccal mucosa. Films releasing drug towards the buc-
`cal mucosa exhibit the advantage of avoiding the first pass effect
`by directing absorption through the venous system that drains
`from the cheek [12]. Previously, many articles have reviewed the
`
`⇑ Corresponding author. College of Pharmacy, University of Texas at Austin, 1
`
`University Station A1920, Austin, TX 78712, United States. Tel.: +1 512 232 4088;
`fax: +1 512 471 7474.
`E-mail address: jtmcconville@mail.utexas.edu (J.T. McConville).
`
`0939-6411/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
`doi:10.1016/j.ejpb.2010.11.023
`
`development of mucoadhesive buccal systems in global terms
`[13–17], or their specific attributes such as permeation enhancers
`[18] or mucoadhesive polymers [19–21]. This article reviews the
`relevant literature which provides a background for understanding
`the rationale behind the formulation of mucoadhesive buccal films,
`as well as reviewing the most crucial characterization techniques
`for these dosage forms. The reader should notice that the literature
`use the term film and patch interchangeably.
`
`1.1. Physicochemical properties of the oral mucosa
`
`The oral mucosa presents differently depending on the region of
`the oral cavity being considered [22]. The masticatory mucosa cov-
`ers those areas that are involved in mechanical processes, such as
`mastication or speech, and includes the gingival and hard palate.
`This masticatory region is stratified and has a keratinized layer
`on its surface, similar to the structure found at the epidermis,
`and covers about 25% of the oral cavity [23]. The specialized muco-
`sa covers about 15%, corresponding to the dorsum of the tongue,
`and is a stratified tissue with keratinized as well as non-keratin-
`ized domains [24]. Finally, the lining mucosa covers the remaining
`60% of the oral cavity, consisting of the inner cheeks, floor of the
`mouth, and underside of the tongue. This lining epithelium is strat-
`ified and non-keratinized on its surface [25]. The buccal mucosa
`covers the inner cheeks and is classified as part of the lining muco-
`sa, having approximately 40–50 cell layers resulting in an epithe-
`lium 500–600 lm thick (Fig. 1) [26]. The epithelium is attached
`to underlying structures by a connective tissue or lamina propia,
`separated by a basal lamina. These lining mucosa and the lamina
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`
`ity barrier is located in the upper region of the epithelium and is
`correlated with the rich lipid content of this zone. As well as the
`keratinized epithelium, the intercellular space of the buccal muco-
`sa is rich in lipids, but it is the difference in composition and the
`absence of the keratin layer that accounts for its permeation char-
`acteristics [32,34–37]. The lipid composition in the buccal epithe-
`lium has a higher content of phospholipids, cholesterol esters,
`and glycosylceramides, while the content of ceramides is minimal,
`compared to the skin and keratinized regions of the oral cavity
`[32]. This composition results in a higher concentration of polar
`lipids in the intercellular space [34]. Therefore, it is not only due
`to the highly organized lipid lamellae found in the keratinized epi-
`thelia, but also the nature of the lipid content that accounts for the
`increased permeation of the buccal mucosa compared to the skin
`and other keratinized epithelia.
`Due to the polar nature of the lipids in the intercellular space,
`two different domains can be differentiated in the buccal epithe-
`lium: the lipophilic domain, corresponding to the cell membranes
`of the stratified epithelium, and the hydrophilic domain, corre-
`sponding to the extruded content from the membrane-coating
`granules, into the intercellular space. These two domains have
`led to postulate the existence of different routes of transport
`through the buccal epithelium, namely the paracellular and the
`transcellular route [22]. The lipophilic nature of the cell mem-
`branes favors the pass of molecules with high log P values across
`the cells. Similar to the absorption mechanism in the small intes-
`tine, it is believed that lipophilic molecules are carried through
`the cytoplasm [18]. However, there still is a lack of evidence sup-
`porting this assumption. The polar nature of the intercellular space
`favors the penetration of more hydrophilic molecules across a
`more tortuous and longer path [38–40]. It has been demonstrated
`that some hydrophilic molecules are subject to carrier-mediated
`transport through the buccal mucosa [41]. Most of the descriptions
`of molecules permeating through the buccal epithelium, in the lit-
`erature, are related to the paracellular route of absorption. In an
`early study, it was found that tritiated water permeated through
`the paracellular route [36]. Using light microscopy autoradiogra-
`phy, it has been determined that water, ethanol, cholesterol, and
`thyrotropin release hormone penetrate through the paracellular
`route as well [42,43]. More recently, it was demonstrated using
`confocal
`laser scanning microscopy that dextrans with 4 and
`10 kDa average molecular weight and labeled with fluorescein iso-
`thiocyanate permeated through the paracellular route [44,45].
`Even though there is no evidence that supports the idea of mole-
`cules permeating through the transcellular route, it is important
`to assess and understand the permeation route in order to deter-
`mine strategies to enhance the absorption of actives when formu-
`lating buccal films.
`
`2. Formulation and manufacture of buccal delivery films
`
`There are many factors in determining the optimum formula-
`tion of buccal delivery films, but three major areas have been
`extensively investigated in the mucoadhesive buccal film litera-
`ture, namely mucoadhesive properties, permeation enhancement,
`and controlled release of drugs. Most of the polymers that are used
`as mucoadhesives are predominantly hydrophilic polymers that
`will swell and allow for chain interactions with the mucin
`molecules in the buccal mucosa [6]. Examples of these swellable
`polymers include hydroxypropyl cellulose (HPC), hydroxypro-
`pylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), sodium
`carboxymethyl cellulose (SCMC), poly(vinyl pyrrolidone) (PVP),
`and chitosan; a full list of polymers used in the manufacture
`of buccal films, with additional descriptions and properties, is
`depicted in Table 1.
`
`Fig. 1. Diagram of a cross section of the buccal mucosa. The keratinized layer is only
`present in most rodent models while the human has a non-keratinized buccal
`mucosa. Adapted from Ref. [39].
`
`propia regions provide mostly mechanical support and no major
`barrier for penetration of actives [12,27]. The connective tissue also
`contains the blood vessels that drain into the lingual, facial, and
`retromandibular veins, which then open into the internal jugular
`vein [12]. This is one of the main advantages of buccal over oral
`delivery: absorption through the buccal epithelium avoids the gas-
`trointestinal tract conditions, such as gastric pH, enzyme content,
`and the first pass effect due to direct absorption into the portal
`vein. Once a given drug molecule reaches the connective tissue,
`it may be readily distributed, thus the permeation barrier is across
`the whole thickness of the stratified epithelium [12].
`The existence of membrane-coating granules in the epidermis
`has been well characterized and it is known to be the precursor
`of the keratin layer or stratum corneum [18,28]. Even though the
`existence of approximately 2 lm in diameter cytoplasmic mem-
`brane-coating granules in the buccal epithelium has been proven,
`less is known in terms of their function; however, the permeation
`barrier is believed to be related to the presence of membrane-
`coating granules in the buccal mucosa [29,30]. Squier described
`these membrane-coating granules as organelles containing amor-
`phous material that is extruded into the intercellular space after
`membrane fusion [29]. More recently, it has been reported that
`some of these granules also contain lipid lamellae domains orga-
`nized to some extent [31]. This fact contrasts with the content of
`the membrane-coating granules in the epidermis, which contains
`very organized, electron-dense lipid lamellae. Therefore, the inter-
`cellular space of the stratified non-keratinized buccal mucosa is
`filled with a combination of amorphous material presenting some
`domains where short stack of lipid lamellae can be observed. This
`important difference in the intercellular space composition is
`responsible for the difference in permeability between the buccal
`and keratinized mucosae for exogenous compounds [32].
`Although the buccal mucosa is more permeable than keratin-
`ized epithelium, the existence of a permeability barrier has been
`described [33]. It was demonstrated that this barrier is located in
`the upper one-third to one-quarter of the epithelium layer using
`horseradish peroxidase, and by following its permeation through
`the epithelium. After topical application, the horseradish peroxi-
`dase only permeated through the first 1–3 cell layers. However,
`when injected subepithelially, it was found to permeate through
`as deep as the connective tissue and up as far as the membrane-
`coating granules zone was [33]. This suggested that the permeabil-
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`189
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`Table 1 shows that polymers from the families of the poly
`(acrylic acid) (Carbopols) and cellulosic derivatives have been
`extensively used as mucoadhesives, being part of the so-called
`first-generation mucoadhesives [46]. These polymers require to
`be hydrated in order to exhibit their mucoadhesive properties;
`however, a critical degree of hydration limits the phenomenon
`[47]. Above this critical value, overhydration occurs, leading to
`the formation of a slippery mucilage lacking mucoadhesive proper-
`ties. In an early publication, Guo reported that the use of CarbopolÒ
`934P alone exhibited the triple average peeling strength compared
`to the one exhibited by HPMC [48]. More recently, Semalty et al.
`demonstrated using a modified disintegration apparatus that the
`in vitro residence time of films formulated with a combination of
`CarbopolÒ 934P and HPMC E15 was almost the double than films
`containing only HPMC E15 [49]. Moreover, the combined polymers
`exhibited more resistance to rupture, as demonstrated using the
`folding endurance test. Another important polymer widely used
`in the formulation of mucoadhesive films is HPC. In one of the ear-
`liest publication on mucoadhesive films, Anders and Merkle
`showed that the use of different grades of HPC or HEC had superior
`mucoadhesive properties compared to PVP and poly(vinyl alcohol)
`(PVA) as film-forming polymers [50]. More recently, it was re-
`ported that film formulations, containing different ratios of Carbo-
`polÒ and HPC, exhibited longer in vitro residence times when the
`concentration of HPC was increased [51].
`Natural and semi-natural polymers have also been reported in
`the literature as mucoadhesives. Chitosan was first introduced in
`1994 by Guo for its use in mucoadhesive film formulations [48].
`Following CarbopolÒ and HPMC as polymeric matrices for mucoad-
`hesive films, chitosan exhibited better adhesion than acacia in a
`peeling test using an Instron 4201. In a more recent study, Shid-
`haye et al. described the manufacture, permeation, and mucoadhe-
`sive properties of chitosan films, containing gelatin and PVP in
`different proportions, for the buccal delivery of sumatriptan succi-
`nate [52]. It was demonstrated that an increase in the chitosan
`component increased the mucoadhesive strength of films. The
`authors attributed the increasing concentration of chitosan having
`the effect of increasing the number of amine groups that can inter-
`act with the negative charge groups (carboxyl, sulfate, etc.) which
`are present on the buccal epithelium surface [53]. Recently, muco-
`adhesive films have been developed and used as platforms for the
`oral delivery of nanoparticles [54,55]. Cui et al. reported on the
`manufacture of carboxylation chitosan-grafted nanoparticles
`(CCGNs) added to chitosan–ethylenediamine tetraacetic acid (C-
`EDTA) films with a backing layer of ethyl cellulose (EC) [54]. Films
`loaded with CCGNs exhibited higher mucoadhesion than that of
`placebo films. This high mucoadhesion effect was attributed to
`the high number of carboxyl groups that the CCGNs have, increas-
`ing the chance of hydrogen bonding with the mucosa [54].
`It is evident that most of the mucoadhesive polymers explored
`in the literature are hydrophilic or show some of the essential fea-
`tures for mucoadhesion. However, it has been reported that differ-
`ent insoluble EudragitÒ grades can exhibit some mucoadhesive
`properties when used alone [56,57] or in combination with other
`hydrophilic polymers [58]. Films containing propranolol hydro-
`chloride, Eudragit RS100, and triethyl citrate as a plasticizer exhib-
`ited almost three times the mucoadhesion force than that of films
`prepared with chitosan as the mucoadhesive polymer [56]. The
`authors proposed that the plasticizer is responsible for the increase
`in mucoadhesion. However, since the use of a plasticizer is neces-
`sary in Eudragit RS100 films, such film formulations may then be
`suitable for the manufacture of mucoadhesive dosage forms. Salts
`of soluble polymethacrylate derivatives, namely Eudragit S100 and
`L100, have been reported to increase mucoadhesion [59]. This
`study was based on the assumption that ionizable polymers exhi-
`bit the best mucoadhesive characteristics [60–62], which com-
`
`bined with low-swellable properties would allow for better
`patient compliance. It was demonstrated that, even though the
`Eudragit S100 and L100 did not exhibit mucoadhesive properties,
`their sodium and potassium salts performed equally or better than
`the positive mucoadhesive controls, namely CarbopolÒ 934P and
`HPMC [59].
`The body of literature that explores different aspects of formu-
`lating mucoadhesive buccal films is extensive in terms of polymers
`used, mucoadhesive properties, and permeation characteristics for
`formulations. However, only a handful of products have reached
`the market, and currently, only two products for oral mucosal drug
`delivery have been successfully commercialized, and one further
`product has finished a phase 2 clinical study. BioDelivery Sciences
`International have used their BioErodible MucoAdhesive (BEMA™)
`technology platform to develop Onsolis™, a fentanyl buccal soluble
`film indicated to be administered in the buccal mucosa for the
`management of breakthrough pain in patients with cancer [63].
`The formulation contains the mucoadhesive polymers carboxy-
`methyl cellulose, hydroxyethyl cellulose, and polycarbophil, along
`with a backing layer to direct drug release towards the buccal mu-
`cosa. Using the same technology platform, BioDelivery Sciences
`International have completed a phase 2 clinical study for BEMA™
`Buprenorphine with a significant improvement in the primary effi-
`cacy endpoint, SPID-8 (sum of pain intensity differences at 8 h),
`compared to that exhibited by the placebo. The other commercial-
`ized film product is Suboxone™ Film, a buprenorphine and
`naloxone sublingual film. Using a polymeric matrix based on
`polyethylene oxide and hydroxypropylmethyl cellulose, rapid dis-
`solution and absorption are achieved [64].
`The mucoadhesion process and the strategies used to control
`and enhance drug delivery and permeation will be discussed in
`later Sections 4 and 5. The following section will discuss the main
`manufacturing processes involved in making mucoadhesive buccal
`films, namely film casting and hot-melt extrusion.
`
`2.1. Film casting
`
`The film casting method is undoubtedly the most widely used
`manufacturing process for making films found in the literature.
`This is mainly due to the ease of the process and the low cost that
`the system setup incurs at the research laboratory scale. The
`process consists of at least six steps: preparation of the casting
`solution; deareation of the solution; transfer of the appropriate
`volume of solution into a mold; drying the casting solution; cutting
`the final dosage form to contain the desired amount of drug; and
`packaging. During the manufacture of films, particular importance
`is given to the rheological properties of the solution or suspension,
`air bubbles entrapped, content uniformity, and residual solvents in
`the final dosage form [65]. The rheology of the liquid to be casted
`will determine the drying rates and uniformity in terms of the ac-
`tive content as well as the physical appearance of the films. During
`the mixing steps of the manufacturing process, air bubbles are
`inadvertently introduced to the liquid and removal of air is a crit-
`ical step for homogeneity reasons [2]. Films cast from aerated solu-
`tions exhibit an uneven surface and heterogeneous thickness.
`Another recurrent concern in the manufacture of films for buccal
`delivery is the presence of organic solvents. The use of organic sol-
`vents is normally questioned, not only due to problems related to
`solvent collection and residual solvents, but also because organic
`solvents are undesired hazards for the environment and health
`[65]. However, due to the physicochemical properties of both drug
`and excipients, many formulations rely on the use of organic sol-
`vents, in which case they should be selected from ICH Class 3 sol-
`vent list [66]. Even though the current literature on buccal films is
`mostly focused on platforms for specific drugs and diseases, man-
`ufacturing and processing parameters have been systematically
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`Table 1
`Mucoadhesive and film-forming polymers used in the literature.
`
`Mucoadhesive
`polymer in films
`
`Hydroxyethyl
`cellulose (HEC)
`
`Relevant properties and findings
`
`Use in the literature
`
`Non-ionic polymer
`
`[50,58,109,140,156,155]
`
`High swelling properties and rapid erosion [109]
`Low mucoadhesive properties increased by the addition of SCMC
`[58]
`Zero-order release kinetics of miconazole [109] and
`chlorpheniramine [155]
`
`Hydroxypropyl
`cellulose (HPC)
`
`Non-ionic polymer
`
`[8,9,50,51,81,87,88,90,91,122,123,134,137,154,157–162]
`
`Increased swelling in ethylcellulose/HPC films [137]
`Moderate mucoadhesive properties [137,157]
`Zero-order release kinetics of lidocaine [134] and clotrimazole
`[91] associated with erosion square-root of time release kinetics
`of lidocaine [87]
`
`Hydroxypropylmethyl
`cellulose (HPMC)
`
`Non-ionic polymer
`
`[4,48,49,57,58,67,74,82,87,107,109,110,113,117,118,137,138,140,156,157,
`163–166]
`
`Rapid swelling that plateaus [137]
`Moderate mucoadhesive properties [48,137,157]
`Initial burst followed by diffusion of nicotine hydrogen tartrate
`[117]
`
`Sodium
`carboxymethyl
`cellulose (SCMC)
`
`Anionic polymer
`
`[4,11,49,57,58,68,70,71,82,109,110,113,119,137,167]
`
`High swelling properties that does not plateau [137]
`High mucoadhesive properties [58,113,137]
`Zero-order release of miconazole nitrate [109]
`Diffusion governed release of ibuprofen [113]
`
`Poly(vinyl
`pyrrolidone) (PVP)
`
`Non-ionic polymer [111]
`
`[50,52,70,76,79,82,109–114,137–140,168]
`
`As film-forming polymer exhibits non-Fickian release of
`ketorolac [137] and progesterone
`Used to tailor the release of propranolol [114] and miconazole
`[109]
`High swelling properties [111,112,114]
`Used as coadjuvant to increase mucoadhesion [76,113]
`
`Poly(vinylalcohol)
`(PVA)
`
`Non-ionic polymer
`
`[5,50,67,110,112,117,158]
`
`Moderate swelling [67] and mucoadhesive properties [110,112]
`Anomalous release of miconazole [109]
`
`Chitosan
`
`Cationic polymer
`
`[10,48,52,54,56,74,79,80,109,111,112,115,124,125,128,156,157,163,164,
`169–173]
`
`High to moderate swelling [54,58] and mucoadhesive
`properties [48,54,124,128,157]
`Sustained release of miconazole [109]
`
`Alginate, sodium
`
`Anionic polymer
`Rapid swelling and dissolution [58,169]
`High mucoadhesive properties [157]
`
`[55,58,69,82,110,157,163,169,165,174]
`
`Agar
`
`Poor and stable swelling properties
`
`[169]
`
`Carrageenan type k
`
`Poor and stable swelling and moderate mucoadhesive properties
`
`[70]
`
`Acacia
`Guar gum
`
`Poly-L(lactide-co-
`glycolide) (PLGA)
`Polyacrylic acid,
`CarbopolÒ
`
`Polycarbophil
`
`Poly(ethylene oxide)
`
`Very poor mucoadhesion
`As an additive, conveyed moderate swelling and good
`mucoadhesive properties, and anomalous non-Fickian release of
`miconazole
`
`[48]
`[156]
`
`Micromatrices in buccal films to control the release of ipriflavone
`[80]
`Rapid, high, and stable swelling [107,114,117,137]
`
`High mucoadhesive properties [48,157]
`As a film-forming polymer, conveyed sustained release of
`buprenorphine [48]
`Used as an additive to tailor the release of propranolol [114,117]
`
`Non-ionic polymer
`As an additive, conveyed moderate and stable swelling [70]and
`high mucoadhesive properties [58,70,81,87,108,180]
`
`Non-ionic polymer
`High mucoadhesion with high molecular weight [86,89]
`Zero-order release kinetics of clotrimazole [86] and
`tetrahidrocannabinol [89] associated with erosion of the
`polymeric matrix
`
`[80,175]
`
`[3–5,8,11,48,49,51,57,58,69–71,76,107,110,114,117–119,
`135–138,157,166,167,170,176–179,165]
`
`[9,58,70,77,78,81,87,108,117,180]
`
`[86,87,89,94]
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`191
`
`Table 1 (continued)
`
`Mucoadhesive
`polymer in films
`
`Poly(methacrylates)
`
`Relevant properties and findings
`
`Use in the literature
`
`Used as film former, exhibited very poor bioadhesive properties
`and low swelling capability [58,108,114]
`The salt form has high mucoadhesive properties [59]
`
`[56–59,74,75,77,78,108,113,114,180]
`
`reported. Examples of these research areas are related to the
`composition of the casting solution [53,96,118,140], drug concen-
`tration, the drug addition process, and cast solution rheology
`[70,71].
`Since the early development of medicated films, content unifor-
`mity has been a major challenge for the pharmaceutical scientist.
`Schmidt proposed one of the earliest approaches to increase the
`drug uniformity of medicated films [72], by stating that the non-
`uniformity of films is inherent to their monolayered nature.
`Schmidt proposed a multistep method for the manufacture of mul-
`tilayered films to overcome the heterogeneity of the monolayered
`form. However, Yang et al. reported that using the protocol pro-
`posed by Schmidt did not render uniform films [73] and went onto
`say that to overcome the non-uniformity of films, a manufacturing
`process for orally disintegrating films could be easily adapted for
`the manufacture of mucoadhesive buccal films. Yang et al. indi-
`cated that self-aggregation was one of the main reasons why films
`usually show poor uniformity, and in particular the drying process
`was found to be crucial in preventing aggregation or conglomera-
`tion of the ingredients of the film formulation [73]. During an
`inherently long drying process, intermolecular attractive and con-
`vective forces are favored, leading to the problem of self-aggrega-
`tion. In order to avoid non-uniformity, addition of viscous agents
`such as gel formers or polyhydric alcohols was proposed to allevi-
`ate potential self-aggregation [73].
`Recently, one of the main challenges in the film casting process,
`content uniformity along the casting surface, has been addressed
`[74]. Film characterization in terms of mucoadhesive, mechanical,
`permeation, and release properties has been widely investigated.
`However, prior to 2007, few reports pertaining to drug content
`uniformity can be found [70,86,99–101,141,151,153]. The most
`common approach to measure the content uniformity is the deter-
`mination of drug by weight and not by casting area. Perumal et al.
`postulate that the determination by weight is erroneous because
`the final dosage form is determined by area instead of weight in
`the particular case of films. They demonstrate that custom-made
`silicone-molded trays, with individual casting wells for each dos-
`age form, improved several characteristics significantly, including
`the content uniformity per casting area unit, mucoadhesive prop-
`erties, drug release, and thickness uniformity of monopolymeric
`or multipolymeric films [74]. Even though this approach may solve
`the problem of uniformity per dosage form, it does not guarantee
`the uniformity along the dosage unit itself and also imposes limi-
`tations on scaling up possibilities.
`
`2.2. Hot-melt extrusion of films
`
`In hot-melt extrusion, a blend of pharmaceutical ingredients is
`molten and then forced through an orifice (the die) to yield a more
`homogeneous material
`in different shapes, such as granules,
`tablets, or films [83]. Hot-melt extrusion has been used for the
`manufacture of controlled-release matrix tablets, pellets, and gran-
`ules [84], as well as orally disintegrating films [85]. However, only
`a handful of articles have reported the use of hot-melt extrusion for
`manufacturing mucoadhesive buccal films. Repka and coworkers
`have extensively conducted research on the use of hot-melt extru-
`sion for the manufacture of mucoadhesive buccal films, evaluating
`different matrix formers and additives for the processing of the
`
`blend [86–88,81,9,89]. In an early publication, it was found that
`even though films containing exclusively HPC could not be ob-
`tained, the addition of plasticizers, such as PEG 8000, triethyl cit-
`rate, or acetyltributyl citrate, allowed for the manufacture of
`thin, flexible, and stable HPC films over 6 months [90]. It has also
`been found that increasing the molecular weight of HPC decreases
`the release of hot-melt extruded films and allows for zero-order
`drug release [91]. According to the models applied [92,93], the
`drug release was solely determined by erosion of the buccal film.
`The most recent publications on mucoadhesive extruded buccal
`films involve the inclusion of D9-tetrahydrocannabinol (THC) and
`its hemiglutarate ester prodrug (THC-HG) [81,94,89]. Successful
`mucoadhesive films could be obtained for THC at 120, 160, and
`200 °C while still containing at least 94% of the active ingredient.
`The greatest degradation to cannabinol was observed at 200 °C
`(1.6%) [81]. For the formulation of the thermally labile prodrug
`THC-HG, the type of plasticizer was found to be crucial on the
`post-processing stability [94]. The degradation of the drug in pres-
`ence of PEG 8000, triacetin, or vitamin E succinate as plasticizers
`was found to be 1.7%, 1.1%, and 0.4% respectively, the latter being
`the most efficient plasticizer in preventing degradation at 90 °C
`and 130 °C [94].
`
`3. Mucoadhesive and mechanical properties of buccal films
`
`3.1. Overview of mucoadhesion
`
`Bioadhesion is the general term describing adhesion between
`any biological and synthetic surface. Mucoadhesion is a specific
`term describing the particular interaction of a mucosal membrane
`with a synthetic surface [95]. The phenomenon of mucoadhesion
`has been explained by applying any of the five theories of adhesion
`into the interaction of the dosage form and the biological substrate
`[13,95,96]. The reader is directed to detailed explanations of the
`electronic [97], adsorption [98,99], wetting [47,100], diffusion
`[47,101], and fracture theory [102]; in this article, we briefly sum-
`marize theories related to mucoadhesion theory. Since mucoadhe-
`sive buccal films include the interaction of a dry polymeric matrix
`that undergoes hydration, drug release, and sometimes erosion,
`the phenomenon is very complex. Smart has defined four possible
`scenarios for the analysis of the mucoadhesion process based on
`the hydration state of the dosage form and on the amount of mu-
`cus layer available for mucoadhesion [103]. Mucoadhesive buccal
`films can be classified as a ‘‘case 3’’ scenario since they are solid
`dry substrates that come in contact with a mucosa having thin or
`discontinuous mucus layers [103]. Relevant to the analysis of the
`mucoadhesion of polymeric films on the buccal mucosa are the
`adhesion theories of adsorption and diffusion. The adsorption the-
`ory states that the main contributors to the adhesive bond are the
`inter-polymer interactions, such as hydrogen bonds and van der
`Waals forces [104]. The diffusion theory assumes that polymeric
`chains from the solid substrate, i.e. the mucoadhesive film, and
`the biological substrate, i.e. mucin in the mucosa layer, interdiffuse
`across the adhesive interface [95]. Important variables in this pro-
`cess are the diffusion coefficient of the polymer into the mucin
`layer and vice versa, the contact time, and the molecular chain
`length and their mobility [105,106].
`
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`
`Most of the mucoadhesive phenomena have two main stages
`that control the performance of the dosage form: the contact stage
`and the consolidation stage (Fig. 2) [17,62]. Since mucoadhesive
`films are dosage forms that are brought in contact with the biolog-
`ical membrane by the patient, the contact stage is initiated by the
`patient. During the contact process, the film will start