MonoSol 2005-0001
`
`Plaintiffs' Exhibit
`PTX 215
`
`Reckitt Benckiser Pharms. Inc., et al.
`v. Watson Labs., Inc., et al.
`(1:13-cv-01674-RGA)(Con.)
`
`Mylan v. MonoSol
`IPR2017-00200
`
`

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`DRUG CONTENT UNIFORMITY IN POLYMERIC FILMS
`
`1037
`
`Summary of Film Characterization Studies and Reported Drug Content Uniformityr'Assay Results from 21 Literature Search
`
`TABLE l
`
`Polymer(s)
`
`Drug
`
`EUD E100
`
`Piroxiearn
`
`EC, HPC
`
`Lidoeaine HCI
`
`EC, CHT
`glutamate
`PCL
`
`PHCI, Nifedipine
`
`Chlorhexidine
`
`HPC
`
`Lidocaine
`
`Polyearbophil,
`EUD S100
`CHT, PVA,
`PEO, PVP
`
`Plasmid DNA,
`|3—Galactosidase
`Model drug
`
`PLGA, CHT
`glutainate
`
`Ipriilavone
`
`FAA, CHT
`HCI
`Potato starch,
`potato starch
`acetate
`
`Acyclovir
`
`Tirnolol, Sotalol—HCl
`
`Film Characterization
`Studies
`
`Assay
`Results
`
`Reference
`
`Transparency and SEM, peel adhesion
`test, drug—polymer interaction
`study, in vitro membrane
`permeation study
`In vitro dissolution, DSC, IR,
`measurement of pore size
`distribution, adhesion of films
`In vitro drug release, morphology
`(SEM)
`In vivo test
`
`In vitro permeation, dissolution
`studies, determination of penetration
`rate and release rate
`
`Release studies, rabbit immunization
`studies
`Swelling and erosion studies, in vitro
`drug release, in vivo animal studies,
`thermal transitions, Fourier
`transform infrared spectroscopy
`(FTIR), tensile testing
`Morphology, water absorption
`capability, degradation, in vitro
`dissolution, drug content uniformity,
`in vitro drug release
`Hydration, rheology, mucoadhesion,
`drug release, permeation
`In vitro release, weight loss and water
`content
`
`Not Reported
`
`Lin et al., 1995
`
`Not Reported
`
`Kohda et al., 1997
`
`Not Reported
`
`Not Reported
`
`Not Reported
`
`Rernunan-Lopez et al.,
`1998
`
`Medlicott, Holborow,
`Rathbone, Jones, &
`Tucker, 1999
`Okamoto et al., 2001
`
`Not Reported
`
`O.!i and Mumper, 2002
`
`Not Reported
`
`Khoo el al., 2003
`
`Reported
`
`Perugini et al., 2003
`
`Not Reported
`
`Rossi et al., 2003
`
`Not Reported
`
`Tuovinen, Peltonen, &
`Jarvinen, 2003
`
`EUD NE30D,
`PVP
`CHT
`
`Gelatin,
`earrageenan
`CHT
`
`Peneiclovir
`
`Nystatin
`
`Timoiol
`
`Paelitaxel
`
`_
`
`.
`PVA, PVP
`
`Drug content, microscopy, DSC, X-ray
`diffraction, Higuchi release kinetics
`Water uptake, in vitro release, gel
`stability, in vivo studies on hamsters
`Water uptake, drug release,
`washability lest, mucoadhesion
`Stability of paelitaxel, content
`uniformity, release studies, film
`thickness, tensile strength, DSC,
`FTIR, SEM, X-ray diffraction, in
`-vim. implalltation, -histology .
`.
`.
`I Scabra, Ganzarolli,
`DSC, mechanical properties, SEM,
`S-nitrosoglutathione
`dissolution, diffusion ofGSNO
`(GSNO)
`de Oliveira, 2004
`Shi and Burt, 2004
`Not Reported
`Swelling, DSC, X-ray diffraction, in
`Paelitaxel
`Dextran-PCI.
`
`co—polymer vitro release, morphology
`
`Reported
`
`Ahmed et al., 2004
`
`Not Reported
`
`Aksungur et al., 2004
`
`Not Reported
`
`Bonferoni et a]., 2004
`
`Reported
`
`Dhanikula &
`
`Panehagnula, 2004
`
`.
`.
`Not Reported
`
`MonoSol 2005-0002
`
`M0noS0l 2005-0002
`
`(Continued)
`
`are H-rs
`
`l
`
`1-ts.
`
`.=«_i,-,
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`\
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`1038
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`V. A. PERUMAL ET AL.
`
`TABLE 1
`
`(Continued)
`
`Polymcr(s)
`
`Drug
`
`PLGA
`
`Ethacrynic acid
`
`EC, PVT’
`
`PHCI
`
`CHT, PAOMA
`co-polymer
`
`Sodium alginate,
`gelatin
`
`Model drug
`
`Ciprofloxacin l-ICl
`
`CHT, guar gum
`
`Celecoxib
`
`PLGA,
`PVA-g—PLGA
`
`Paciitaxel
`
`Carbopol, PEG,
`HPMC
`
`SDS
`
`Film Characterization
`Studies
`
`Assay
`Results
`
`Reference
`
`In vitro release, SEM, water uptake, pH
`value, weight loss, in vivo eye test
`Thickness, drug content, moisture
`uptake, in vitro drug release, in vitro
`skin penneation
`in vitro drug release, kinetic analysis,
`SEM,
`
`FTIR, X-ray diffraction, in vitro release,
`morphology, mechanical properties,
`swelling
`Swelling, mucoadhesion, in vitro and in
`vivo degradation, drug release
`
`DSC, wide angle X-ray diffraction, size
`exclusion chromatography, SEM, in
`vitro release, in vitro degradation
`Film thickness, drug content, tensile
`strength, measurement of contact
`angle, swelling, erosion, SDS release
`
`Not Reported Wang, Challa, Epstein,
`& Yuan, 2004
`Amnuaikit et al., 2005
`
`Reported
`
`Not Reported
`
`Not Reported
`
`Yoshizawa, Shin—ya,
`Hong, & Kajiuchi,
`2005
`
`Dong, Wang, & Du,
`2006
`
`Not Reported
`
`Haupt, Zioni, Gati,
`Kleinstern, &
`Rubinstein, 2006
`Not Reported Westedt et al., 2006
`
`Reported
`
`Yoo et al., 2006
`
`BUD, Eudragit; EC, etliylcellulose; HPMC, hydroxypropylmethyl cellulose; CHT, ehitosan; PHCI, propranolol hydrochloride; PCL
`polycapmlactone; PLGA, poly(D,L lactide—co»«glycolide}; PAA, poly[acrylic acid); PEO, poly(ethylene oxide); PVP, polyvinylpyrrolidone; PAOMA
`polyalkyleneoxide-maleie acid; PVA, poly(vinyl alcohol); PEG, poly(e1.hylene glycol); HPC, hydroxypropyl cellulose; SDS, sodium dodecyl sulphate.
`
`In addition, Dhanilcula and Pancltagnula (2004) only
`films.
`stated that uniformity results in their study indicated that the
`variation in drug distribution was <15‘?/o, but they did not report
`any data, whereas Perugini et al. (2003) reported assay values
`as a statement of drug content being more than 'i'0%. The lack
`of reported data on this crucial characterization property of any
`novel drug delivery system led to the assumption that research-
`ers in this field may also have been experiencing difficulty
`with this aspect of film characterization. Yet no paper to date,
`to the best of our knowledge, in the published pharmaceutical
`literature has highlighted this difficulty. It was only a search of
`patent applications that confirmed the assumption that difficul-
`ties with achieving uniform drug distribution in films did
`indeed exist, as some patent applications that attempted to
`directly address the problems encountered with nonuniformity
`in films were identified. Although the identification of these
`patents continued the existence of this problem, it was intrigu-
`' ing "tl1'at"“tl'ii§" publisheEi"3§harin'aceiitiEaI'"'literatu'rc' Eiiriitted ' "the"
`reporting of assay values, yet revealed the undertaking of other
`complex characterization studies (Table 1) without focusing on
`overcoming this simple but mandatory prerequisite for devel-
`opment of any drug delivery system. In these patent applica-
`tions, it was explained that films prepared via the conventional
`casting technique, as used in the literature, suffered from the
`
`aggregation or conglomeration of particles, which rendered
`them inherently nonuniform in terms of all film components,
`including polymers and drug. It was found that the formation
`of agglomerates randomly distributed the film components as
`well as any active present,
`thus leading to the poor drug
`content uniformity [US Patent No. 60i"4-43,741, 2004). The for-
`mation of agglomerates was attributed to the relatively long
`drying times, which facilitated intermolecular attractive forces,
`convection forces, and air flow which aided in the formation of
`such conglomerates (US Patent No. 60f443,74l, 2004). Some
`approaches
`that attempted to prevent agglomeration are
`described briefly. Schmidt (US Patent No. 4,849,246 in US
`Patent No. 60.5’-143,741, 2004) abandoned the concept that a
`monolayered film may provide accurate dosing and instead
`attempted to solve the problem of aggregation by forming a
`multilayered film. The incorporation of additional excipients,
`i.e. gel
`formers and polyhydric alcohols
`respectively,
`to
`"increase the viscosity of"the film prior to drying in‘ air"-'e'ffoi-t" "to"
`reduce aggregation of the components in the film is described
`(US Patent No. 60i’443,'i'4l, 2004). These methods had the
`disadvantage of requiring additional components, which trans-
`lated to additional cost and manufacturing steps. Furthermore,
`these methods employed the use of time-consuming drying
`methods such as high—temperature air—batl1 using a drying oven,
`
`MonoSol 2005-0003
`
`M0n0S01 2005-0003
`
`t'_3_H T_$ l.
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`t
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`in: 9-rt}
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`DrugDevelopmentandIndustrialPharmacyDownloadedfromini'orrnahealthea1'e.eon1byMichaelChakarislcyon08:19:’13Forpt‘
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`DRUG CONTENT UN[F0t{MI‘i‘Y IN POLYMERIC FILMS
`
`1039
`
`drying tunnel, vacuum dryer, or other such drying equipment,
`all ofwhieh aided in promoting the aggregation ofiil'mco11ipo—
`nents and active.
`In addition, such processes subjected the
`active to prolonged exposure to moisture and elevated temper-
`atures, which might render it ineffective or even harmful (US
`Patent No. 60!4-43,74], 2004). Also, approaches described in
`US Patent No.
`60i443,1r'4l , 2004 for
`enhancing drug
`uniformity,
`required sophisticated drying equipment and
`additional pharmaceutical excipients, which lead to unfeasible
`increased manufacturing costs and multi~step processing.
`Thus, a method that uses minimal additional excipients into the
`formulation, uses simple technology, and also provides uni-
`form drug content throughout the film clearly needed to be
`identified. Instead of considering additional exeipients or intro-
`ducing new expensive and complicated drying technologies, a
`specially designed tray with built—in predetermined wells for
`fonning polymeric films with uniform drug content was pro-
`posed and evaluated in this study. It was expected that this sim-
`ple approaeh, which would involve casting specified volumes of
`polymer—drug mixtures into wells, would lead to improved drug
`uniformity because the drug would be entrapped in each film
`unit, irrespective of the migration of the active within that well
`during drying. Such an improvement will not only be useful in
`the field of buecal drug delivery for formulation optimization,
`but it will also impact on other fields because mucosa! films are
`used for a variety of odter routes of administration, that is, vagi-
`nal, rectal, and ocular.
`Therefore, the aim of this study was to develop and evaluate
`a specially designed silicone—molded tray (SMT) with built-in
`predetermined wells for film casting as a method for achieving
`drug uniformity. Propranolol hydrochloride (PHCI) was used
`as the model drug. Initially, the SMT was evaluated with a
`simple hornopolymeric film containing drug and polymer of
`similar solubilities. Thereafter, its applicability to monolayered
`multipolymeric films with drug and polymers of both similar
`and opposing solubilities was also assessed. In addition to drug
`content uniformity, thickness, and morphology, the films from
`the trays were also characterized in terms of mueoadhesivity
`and in vitro drug release properties. These two properties
`measure retention on the mucosae and drug release behavior,
`respectively, and are essential in the evaluation of drug deliv-
`ery systems for the buccal route.
`
`MATERIALS AND METHODS
`
`Materials
`
`Chito'san"(C‘I-IT) {MW 110' ooo) (Primex"Irigi'edi'en'ts ASA," '
`"
`Avaldsnes, Norway), Hydroxypropytmetliylcellulose (HPMC)
`(Fluka, Buchs, Switzerland), Propranolol I-ICI (PHCI) (Frankel
`Chemicals, Johannesburg, SA), Mucin (Sigma-Aldrich, Dorset
`UK), Lactic Acid (BDH Lab Supplies, Pooie, UK), Perspex
`(Maizey Plastics, Durban, SA), and Teflon (Coated Fabrics,
`Johannesburg, SA) were purchased and used as received.
`
`(Rhom Pharma, Dai'mstadt,
`Eudragit® RS100 (EUDIOO)
`Germany) was donated by Degussa Africa (Pty) Ltd. Wacker
`Silicone M4514 (Elastosil®) {amt Composites, Durban, SA)
`was mixed with its supplied catalyst (T 26) prior to use. All
`other chemicals used were of analytical or reagent grade.
`
`Methods
`
`Preparation of Traysfor Ffim Casting
`Drug containing polymeric solutionsfemulsions were cast
`onto conventional teflon-coated perspex trays (TCPTS) as well
`as onto two other trays, that is, TCPTS with a removable cham-
`ber system and SMTs with built-in wells. The description and
`preparation of these trays are presented hereunder. Digital
`photographs of the trays are presented below in Figure l.
`
`
`
`(bl
`
`
`
`(C)
`
`
`
`FIGURE I. Digital photograplis of trays used for casting of drug-polymeric
`films. (A) Conventional tei‘lor1—coateti perspex tray (TCPT); (B) TCPT with a
`removable chamber system, (i) separate components and (ii) chitmbers inserted
`into TCPT; (C) silicone-molded tray (SMT) (i) without inserts and (ii) with
`teflonrcoated perspex inserts.
`
`MonoSol 2005-0004
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`M0noS01 2005-0004
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`FHGHTS t.r.~.: :14}
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`V. A. PERUMAL ET AL.
`
`Teflon-Coated’ Perspex Trays. TCPTS were prepared by
`gluing together pieces of 4-mm clear perspex (Maizcy Plastics)
`to form a tray of dimensions ll X 7' X 3 cm with an area of
`7’? cm2. Thereafter, the trays were coated with a self-adhesive
`fabric teflon (Cofab, Johannesburg, SA) and were ready for
`immediate use. The TCPT yielded a sheet of film that was then
`cut into individual 1 x 3 cm; film units for analyses. The tray
`is shown in Figure 1A.
`TCPT with a Removable Chamber System. The TCPT was
`prepared as described in the Section “’l"eflon—Coated Perspex
`Trays," and the removable chamber system was prepared by
`gluing together pieces of perspex to form a grid that formed
`16 individual compartments of 1 x 3 cm2 each when inserted
`into the TCPT. These compartments were coated with teflon
`fabric (Cofab). Films that were of l X 3 cm: size were retrieved
`from each compartment. The tray is shown in Figure IB.
`Silicone-Molded Trays. SMTS were prepared by combining
`Wackcr silicone (150 mL) with its catalyst (T 26) (7.5 mL)
`(AMT Composites) in a glass beaker, by stirring with a glass
`rod for approximately 8 min to form a silicone mixture with a
`pot life of 20 min, and then pouring it into a greased wooden
`mold and allowing it to cure at room temperature (20°C) for 5 h.
`The cured silicone was then demolded to yield a flexible sili-
`cone tray with 20 individual
`I x 3 cm2 wells. This tray was
`also investigated with the addition of teflon-coated perspex
`inserts into each tray. The inserts were prepared by cutting
`4—mm clear perspex pieces (Maizey Plastics) into 1 x 3 cm’
`rectangles and coating them with the self-adhesive fabric
`teflon (Cofab). These inserts were then firmly placed into each
`well of the SMT prior to film casting. The SMT yielded indi-
`vidual film units of 1x3 cm: from each well. The tray is
`shown in Figure 1C.
`
`Preparation ofPot'ymer—Drug Solutions‘/Emulsions
`for Fiim Costing
`All PHCl—containing polymeric solutionsfcmulsions were
`prepared at a concentration of 15 mg/mL to ensure that each
`1 X 3 cm3 film unit theoretically contained a 15 mg{3 cm? dose.
`The total volume of PHCI containing polymeric Solution!
`emulsion was cast onto the TCPT, whereas 1 mL of the solution
`was cast into each well of the SMT. All trays containing the cast
`polymeric solutionsfemulsions were allowed to dry in an oven
`{Series 2000, Scientific, South Africa) at 30°C for approxi-
`mately 24 h, until the solvent had evaporated (until constant
`weight). Films were stored in foil bags in a tightly sealed
`amber bottle at room temperature (20°C) until further use. The
`preparation of the"poly'nicriEi solutionsl'eriiiilsions"'for casting
`onto the different trays is described below.
`Homopoiymeric Films. Homopolymeric films containing
`CHT and PHCI were prepared at a 1:1 ratio. The required
`amount of Cl-IT and plasticizcr, that is, glycerol (30% wtiwt of
`polymer weight), was dissolved in a 1% lactic acid solution
`(30 ml.) under magnetic stirring. PHCI was then dissolved in
`
`the above CHT solution. The resulting drug containing poly-
`meric solution was allowed to stand until air bubbles were
`
`removed before casting onto a TCPT or SMT. The quantities
`used ensured that each 1 X 3 cm: film unit would theoretically
`comprise 15 mg PHCI.
`Mulripolymeric Films. Multipolymeric films, in which drug
`and polymers were all of similar solubilities (i.e., PHCl+
`Cl-IT+HPMC) and also those in which drug and polymers
`were of opposing solubilitics (i.e., PllCl + Cl-IT + EUDl00),
`were prepared for evaluation. The films were prepared in a
`l:0.5:0.5 drugtpolymerzpolymcr ratio. Plasticizer was added at
`30% wtiwt of polymer weight.
`Monolayered multipolymeric films, in which PHCI and the
`polymers (CHT and HPMC) were all hydrophilie, were pre-
`pared as follows: CHT and glycerol as plasticizer (30%, wtlwt)
`were dissolved in a ]% lactic acid solution (15 mL), and
`thereafter PHCI was added and allowed to dissolve. HPMC
`
`was dissolved separately in water (15 mL) and then added to
`the PHCI-—CHT preparation and allowed to mix under magnetic
`stirring. When this drug-containing multipolymcric solution
`was homogenously combined. it was cast onto the respective
`trays and dried as described above.
`Monolayered rnultipolymeric films with the hydrophilic
`drug PHCI and a hydrophilic (CHT) as well as a hydrophobic
`polymer (EUD100) were prepared as per a method modified
`from Pcrugini et al. (2003): CHT and glycerol (30%, wtiwt)
`were dissolved in a 1% lactic acid solution (15 mL), and there-
`after PHCI was added and allowed to dissolve. EUDl00 and tri-
`
`ethyl citrate (30%, wtfwt, used as a plastieizer) were separately
`dissolved in acetone (15 mL). Both polymeric solutions were
`brought to the same temperature {20°C) and then combined
`by emulsification (IKA Homogenizer, 9,500 rpm for 5 min).
`During homogenization, the polymeric solution was maintained
`in an ice bath. The resulting drug—coritaining emulsion was cast
`onto the respective trays and dried as described above.
`
`Evaluation ofFiJ'mS
`Assay ofPHCi Poiymeric Films. A 1x3 cmz film, either as a
`unit from the SMT or cut into this specified size with a scalpel
`from the film sheet of a TCPT, was cut into pieces with a surgi-
`cal blade in a mortar. Thereafter, the contents of the mortar
`were transferred into a 100 mL volumetric flask. The mortar
`
`times with the selected solvent system
`was washed several
`(water or waterfcthanol), which was also transferred into the
`flask after each washing. The mixture was then mechanically
`agitated in a shaking water bath maintained at 40°C for 24 h
`befot_‘e_bein_g bropght___up to volume with a_ddi_ti_on_al solvent.
`'Tliis'st6ck'§iilu"tion (0:15 'm'g/rat)‘ was also agiism-.d"ro'r' 5'"miri'
`and then filtered (Milliporc® Filter, 0.45 tun). A subsequent
`1 in 10 dilution was performed before UV analysis ofthe solu-
`tion at 290 mp (UV-Spectrophotometer, 1650 PC, Shimadzu,
`Tokyo, Japan). It should be noted that at the outset,
`it was
`established that all solvents, polymers, and other cxcipients
`employed in this study did not interfere with drug analysis at
`
`'
`
`MonoSol 2005-0005
`
`M0n0S0l 2005-0005
`
`F¥lt3H'l'S I-
`
`sn
`
`in; ml}:
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`

`

`DRUG CONTENT UNIFORMITY IN POLYMERIC FILMS
`
`l04l
`
`Force
`
`(N)
`1 .4
`
`
`
`1.2
`
`1,0
`
`0.3
`
`0.6
`
`0.4
`
`
`
`
`
`0.0
`
`
`0.6
`0.3
`L0
`
`.93
`
`-0.4
`
`
`
`Distance (mm)
`
`FIGURE 2. A typical detachment profile (forcc—distance curve) For the
`mucoadhcsivily testing of a polymeric film.
`
`Appearance and Morphology. Film surface was evaluated
`optically by a digital camera (Nikon Coolpix 5900, Tokyo,
`Japan). Film morphology was also characterized by scanning
`electron microscopy. Samples were mounted on round brass
`stubs (12 mm diameter) using double-backed adhesive tape
`and then Sputter—coated for 8 min at 1.1 LV under argon atmo-
`sphere with gold (Polaron SC 500 Spotter Coater, Watford,
`UK) before examination under the scanning electron micro-
`scope (JBOL JSM—6l00 Scanning Electron Microscope,
`Avaldsnes, Japan). The images were captured on an Ilford
`PANF 50 black and white 35-mm film.
`Thickness Measurements‘. The thickness of each film was
`
`measured at five different locations (center and four corners)
`using an electronic digital micrometer
`(Mitutoyo Co.,
`Kawasaki, Japan). Data are represented as a mean :1: SD of five
`replicate determinations.
`Statistical Analysis. All statistical analyses of data were
`undertaken using GraphPad Instat, version 3.05 (GraphPad
`Software Inc., San Diego, CA, USA), whereas all mathemati-
`cal calculations were undertaken with Microsoft Excel®
`(Version 2002, USA). The assay data were specifically
`analyzed using a Kruskal-Wallis test with Dunn's Post Hoe
`tests, whereas the mucoadhesivity data were analyzed using
`one—way ANOVA with Bonferroni Post Hoc tests. Data were
`considered statistically significant ifp < 0.05.
`
`as tins Ami oi"sc'u§§i'o'i§i"'
`
`Development of Trays for Enhancing Drug Uniformity
`in Films
`
`Table 2 depicts the pictures of trays used in the study for
`film casting and a summary of the assay and morphology of
`films generated. Homopolymeric CHT films were initially
`
`the reported wavelengths. Precision and accuracy tests were
`undertaken and confirmed the validity of the assay method used.
`In Vitro Drug Release Profiles. A modified shaking water
`bath dissolution method was employed to determine drug
`release profiles of the films. The shaking water bath apparatus
`(100 strokes per minute) consisted of a water bath, thermostati-
`cally controlled at 37 i 0.5°C and a mechanical shaker
`platform onto which a bottle holder plate was positioned. Glass
`bottles (125 mL), the caps of which were modified to hold a
`stainless steel basket into which each film was placed so as to
`contain all fragments of the dosage form as it disintegrated dur-
`ing the dissolution process, were secured in the holders of the
`holder plate. The baskets used were dissolution baskets with a
`height of 35 mm, a diameter of 20 mm, and a mesh size of
`0.4 mm. Phosphate-buffered saline (PBS) (100 mL) equili-
`brated to 37 i 0.5°C was used as the dissolution medium.
`
`A minimum of three replicate determinations were performed
`for all dissolution tests. At specified time intervals (0.25; 0.5;
`0.75; 1; 2; 3; 4; S; 6; 7; and 8 h), 2-mL aliquots ofsample were
`removed from each vessel using a syringe and filtered through
`a Mi1lipore® Filter (0.45 pm). An equal volume (2 1nL) of fresh
`PBS was replaced into each dissolution vessel, to ensure a con-
`stant volume of dissolution medium throughout the duration of
`the test. All dissolution samples were analyzed using a UV
`spectrophotometer (Shimadzu) at a wavelength of 289 nm.
`Mucoadhesivity of Films. The mucoadhesivity of the films
`was measured with the aid of a sofiwarc—cont:rollcd penetrometer,
`TA-X'I‘2i texture analyzer (Stable Micro Systems, Surrey, UK)
`equipped with a 5~kg load cell, a force measurement accuracy
`of 0.0025%, and a resolution distance of 0.0025 mm. The pro-
`test, test, and post-test speeds were set at 1.0, 0.5, and 1.0 mmfs,
`respectively, with an acquisition rate of 200 points per second.
`A removable stainless steel probe with dimensions 1X3 cm:
`was used for all measurements. A sample of the prepared poly-
`meric film (1 X3 emz) was attached to the base of the probe
`with cyanoacrylate (supergluc) and prehydrated with PBS
`(pH 6.8, 20 pl.) before being fixed to the mobile arm of the
`TA-XT2i, where the film was allowed to continue to undergo
`hydration for the remaining period of the 2 min prehydration
`phase. In the interim, 1 mL of mucin (30%, wtfwt at 37°C) was
`spread onto a glass slide that was firmly attached to the base
`plate of the TA-XT2t'. Upon completion of the pre-hydration
`period (2 min),
`the film was brought into contact with the
`mucin for 30 s. The mucoadhesive performance of the samples
`was detennined by measuring the maximum detachment force
`(MDF) (mN) andfor work (ml). The MDF represents the force
`..F¢Cl1.!.iI9Fi.‘.° detach th.s..fi1.m.. ft0.91.Fl19..m¥°in».Ti.1~‘.=. area 993?’ .t'1s‘=..
`..
`" forcer’dist'ance'cEir've' wa§"a1§5"dEtE'nai'ii'ed"ts"rep-esehi'mc wdik
`or energy required for detachment of the two systems (mucin!
`polymeric film)
`(Eouani, Piccerelle, Prinderrc, Bouret, &
`Jaochim, 2001). A typical forcefdistance curve generated for
`each mucoadhesivity measurement from which the MDF and‘
`or work performed was determined is illustrated in Figure 2.
`A minimum of 10 replicate determinations was perfonned.
`
`MonoSol 2005-0006
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`M0n0S0l 2005-0006
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`F-'l¥I.'3HTSLit-.2;.<-I}
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`DrugDevelopmentandIndustrialPharmacyDownloadedfrominfcrmahealthcarecombyMichaelChakanslcyon08.-"19.-"13Forpr‘useonly.
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`1042
`
`Tray Type
`
`TCPT
`
`V. A. PERUMAL ET AL.
`
`TABLE 2
`
`Description of Tray Development and Film Characteristics
`
`Picutre of Tray
`
`Assay (%)
`Mean i SD
`
`110.00 i 66.63
`CV= 60.57%
`
`Electron Micrograph of Film
`
`
`
`TCPT with removable
`chambers
`
`116.33 i 28.3]
`CV = 24.34%
`
`SMT
`
`104.06 i 3.31
`CV = 3.13%
`
`SMT with teflon-coated
`
`perspex inserts
`
`104.84 i 1.30
`
`CV = 1.24%
`
`"‘ ' TCPT, -teflon-coated perspex tray; SMT, si|icone—molded tray.
`
`prepared by employing the conventional casting technique
`whereby the polymeric solution is cast onto TCPTS to form a
`sheet of film that is cut into individual film units of desired
`
`sizes. This yielded films with uniform surface morphology but
`poor drug content uniformity values, ie., 110.00 i 66.63%,
`
`indicating a large coefficient ofvariation (CV) of 60.57%. The
`poor drug uniformity with these TCPTS was attributed to the
`reasons given in several patent applications, that is, to the for-
`mation of conglomerates and migration of drug throughout the
`tray during the drying process. To prevent this from occurring,
`
`MonoSol 2005-0007
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`M0n0S01 2005-0007
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`4'-t$GHTS.'._
`
`r-.2 Iii}
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`DrugDevelopmentandIndustrialPharmacyDownloadedfrominformaheallhcarecombyMichaelCl1.al<a.I1SlCyon08;’I9.-’13Forpr‘useonly.
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`DrugDevelopmentandIndustrialPharmacyDownloadedfrominformahealthcarecombyMichaelChakansltyon08!19!I3'useonly.
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`DRUG CONTENT UNIFORMITY [N POLYMERIC FILMS
`
`1043
`
`a TCPT with a removable unit that encompassed chambers
`(each chamber = l X 3 cm2) was developed. This was an
`attempt to contain the drug—containing polymeric solution dis-
`pensed into each chamber within that chamber. Although this
`method improved the drug uniformity as compared witli the
`TCPT, that is, the CV decreased from 60.57 to 24.34%, the
`values were still unacceptable for regulatory approval. This
`poor drug uniformity may have been due to seepage of the
`polymeric mixture to adjacent chambers because it was detach-
`able and the solution could seep from one chamber to the next.
`The difficulty also experienced with this type of tray was the
`inability to retrieve the dried films without damage due to
`rigidity of the tray This, coupled with the poor assay values,
`led to the realization that a flexible tray for easy film removal
`was required and that the tray should also possess individual
`predetermined wells completely separate from one another, to
`facilitate entrapment of the polymeric solution.
`One of the suitable materials that satisfy the abovemen-
`tioned factors is silicone, as it can be easily molded to yield a
`flexible product. In addition, silicone products have a rela-
`tive inert state that minimizcs the risk of chemical reaction
`
`with drug (Maillard-Salin, Becourt, & Couarraze, 2000).
`Silicones also resist acids, bases, solvents, chemicals, oils,
`and water. Furthermore, it has been previously used in the
`literature as a component of novel drug delivery systems
`(Maillard-Salin et a1., 2000; Schierholz, Jansen, Jaenicke, &
`Pulverer, 1994).
`Taking these factors into consideration, an SMT with
`20 individual separate wells was developed. Instead of being
`cast as a single film to be cut up into different sizes, a specified
`volume of drug—po1ymeric solution/emulsion was cast
`into
`each well of the SMT and dried to form individual film
`
`units. Films prepared using this tray exhibited assay values of
`104.06 i 3.31%, that is, a CV of 3.18% (‘Table 2). Hence as
`compared with the TCPT method, the SMT method signifi-
`cantly reduced the CV for assay values fi‘om 60.5? to only
`3.18%, thus confirming its suitability to enhance drug content
`uniformity. Also, flexibility of the molded tray enabled the
`easy removal of films for evaluation. However, the films from
`this tray displayed poor surface morphology as they appeared
`
`porous (Table 2). This could possibly be due to the physical
`nature of silicone when it is heated and dried, that is, adhesion
`of the films directly onto the silicone surface may have resulted
`in the film porosity observed. Because the TCPT produced
`films with nonporous, uniform morphology, tef1on—coatcd per-
`spex inserts were designed for insertion into each well to over—
`come the poor surface morphology. This modification, that is,
`using the SMT with inserts, resulted in films that satisfied the
`desired requirements, that is, good surface morphology and
`once again acceptable assay values of 104.84 i 1.30% were
`achieved, as required by eompendial specifications for Pl-1C1
`dosage forms (92—l 07.5%) {British Pharmacopoeia, 2003).
`The above studies showed that the SMT proved succcssfill in
`enhancing drug content uniformity. In addition to drug content
`uniformity, mucoadhesivity and thickness of films from the SMT
`and TCPT were also compared. A comparison of the assay,
`mueoadhesivity, and thickness of films cast onto the TCPT and
`the newly developed SMT with the perspex inserts showed signif-
`icant improvements in uniformity of the films in terms of the
`above properties with the SMT (Table 3). As a result of aggrega-
`tion, the absence of thickness uniformity, as observed in the TCPT
`films, detrimentally affected uniformity of component distribution
`throughout the film. This directly impacted on the mucoadhesive
`property of the individual film doses, as the mucoadhcsive poly-
`mer was randomly distributed, resulting in nonuriiforrn mucoad-
`hcsive perfonnance of films from the TCPT.
`
`Reproducibility Study
`As the SMT with inserts showed excellent assay values and
`acceptable film surface morphology, this tray was selected for
`reproducibility studies to validate this method of film prepara-
`tion. Three batches of the homopolymerie films, i.e., PHC! and
`Cl-IT, were prepared as described in the Section “I-lomopo1y-
`meric Films,” using three different SMTs with teflon—coated
`perspex inserts. These batches were subjected to characteriza-
`tion studies in terms of assays, drug release, mucoadhesion,
`and thickness measurements. The assay, mucoadhesion, and
`thickness data obtained for the three formulations for the repro-
`ducibility study are shown in Table 4.
`
`TABLE 3
`
`Summary of Results for Characterization Studies on Films Prepared with the TCPT
`and SMT Methods of Film Casting
`
`TCPT
`.
`.
`Characterization __.._j_..j..
`
`SMT
`
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`
`Assay (%)
`Mucoadhcsivity
`(INN)
`Thickness (mm)
`
`110.00 i 66.63
`154 1r 82
`
`0.21 i 0.10
`
`60.5?
`53.68
`
`47.62
`
`106.8? x 0.59
`134 i 28
`
`0.55
`20.88
`
`0.13 i 0.02
`
`15.38
`
`TCPT, teflon-coated perspex tray; SMT, silicone-molded tray.
`
`MonoSol 2005-0008
`
`M0n0S0l 2005-0008
`
`assure l'_1mta'.~t_}
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`DrugDevelopmentandIndustrialPharmacyDownloadedfrominformahealthcareeombyMichaelChakanslcyon08!19;‘13Forpr'useonly.
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`1044
`
`V. A. PERUMAL ET AL.
`
`TABLE 4
`
`Summary of Results for Characterization Studies to Evaluate Reproducibility of the SMT for Film Casting
`
`Characterization
`Study
`
`Assay(%)
`Mucoadhcsivity
`MDF (mN)
`Thickness(rnm)
`
`Tray A
`Mean 1" SD
`
`_,
`CV (96)
`
`Tray B
`.
`Mean i SD
`
`106.87 1 0.59
`134 i 28
`
`0.55
`20.88
`
`104.34 : 1.30
`168 i 45
`
`CV (96)
`
`1.24
`26.97
`
`Tray C
`Mean ir SD
`
`104.06 1 3.31
`143 i 26
`
`0.13 1 0.02
`
`15.38
`
`0.13 i 0.02
`
`15.38
`
`0.10 i 0.01
`
`CV (%)
`
`3.19
`18.40
`
`10.00
`
`SMT, silicone-molded tray; MDF, maximum detachment force.
`
`The CV for assay values for each tray was low, indicating
`minimal intra—tray variability. Also these values were all within
`the cornpendial specifications of 92-107.5% (British Pharmaco-
`poeia, 2003). The mean assay values between the three trays
`were statistically analyzed using a Kruskal—Wallis test with
`Dunn’s Post Hoe tests. Data were considered statistically signifi-
`cant ifp < .05. Statistical analyses indicated no significant differ-
`ences between the three trays for assays because p=.3407. The
`int:m—batch variability for the mucoadhesivity offilms from the
`SMTs was less than 30% and was consistent with those reported
`in the literature for other preparations (Eouani et al., 200:;
`Shojaei, Paulson, & Honary, 2000). The differences between the
`mean MDF values for mucoadhesion of the three trays were sta-
`tistically analyzed using one-way ANOVA with Bonferroni Post
`Hoe tests. Statistical analyses indicated no significant differences
`between the three trays for muooadhesivity because p = .2922.
`Minimal intra-tray variability for thickness was noted as CV5
`were very low, i.e., less than 16% for all three trays.
`The in vitro drug release profiles of films from the three
`trays were also compared, as shown in Figure 3. The profiles
`for films from all three trays appeared to be almost superim-
`posabie. To confirm the similarity of these dissolution profiles,
`
`120
`
`100
`
`itDrug
`
`released 888
`
`"firm {H}
`
`FIGURE 3.
`Drug release profiles of films prepared f