lnternah<mal Journal of Pharm;,ceutics 2~ (2000) 63-\70
`
`XP001183717
`international
`journal of
`pharmaceutics
`
`www.dscvicr.oom(locatc/iJpharrn
`
`Influence of Vi tam in E TPGS on the properties of
`hydrophilic films produced by hot-melt extrusion
`
`MichaeJ A. Repka*, James W. McGinity
`College of PhamuU"}'. University of Tl·xas at Austin. Austin. TY 787/.?, USA
`
`Re<:eived 21 December 1999; n:ceived in reVIsed forrn 27 Mardi 2000. accepted 27 March 20()()
`
`-- - - - - - -
`
`- - - ----
`Abstra('t
`
`Films containing hydroxypropykellulose (HPC) and polyethylene oxide (P~9J were prepared using a Randcastle
`extruder (Model 750) with and wirhom Vitamin E TPGS (TPGS, o-a-tocopheryl polyethylene glycol !OCX> succinatd
`as an additive. Conventional plasticizer~ induding polyethylene glycol 400 (PEG 400), triethyl citrate (TEC), and
`acctyitributyl citrate (ATBC) were also incorporated into films containing a .50:50 blend of HPC and PEO. The
`physical- mechanical properties including tensilt: strength (TS) and percent elongation (%E) were determined on an
`lnstron according ro the ASTM standards. Glass transition temperatures ( T~) of the extruded films were determined
`utilizing a DSC 2920 M,Jdulated differential scanning calorimeter and THERMAL ANALYST 2000 software. Gt:l
`permeation chromatography was u:;cd to study the stability of the polymer fibns under the processing conditions. The
`addition of J, 3, and 5% Vitamin E TPGS, respectively, decreased the glass transition temperature of the extruded
`ftlrns t;Ontaining either a 50:50 or 80:20 ratio of HPC to PEO in an almost linear fashion. In addition, the presence
`of 3°!1> Vitamin E TPGS lowered the T, over II °C when compared with the HPCiPEO 50:50 blend film without
`TPGS, thus functioning as a plasticizer. The tensile ~trength dccrcnscd with increasing concentrations of TPGS, and
`the 0/oE incr<!ased over 3-fold when compared with the HPC/PEO film that contained no additives. The film
`containing 3% Vitamin E TPGS had a similar tt~nsile stn~ngth to that of the films c:ont.ai.oing 3% PEG 400, and a
`3-fold increase in perccut elongation whcu compared with tl1t filtll.s containi11g 3% TEC and J% ATBC. Iu addition,
`the Vitamin E TPGS facilitated the processing of the HPC/PEO films by decreasing the barre! pressure, drive amps,
`and torque of the extruder equipment.~) 2000 Ebevier Science B.V. All rights reserved.
`
`1\e\words: Vitamin E TPGS~ Hot melt; Ext•-uded films: HydroxypropylcellulosG~ Physical mechanical properties; Glass transition
`temperature; Polyelhylcne oxide
`----------------·----------------------------------
`
`• Corr,,spondiug author. Tel.: + t-512-471-tl8-11: fax: + 1-
`512-471-2746.
`£-mail add•·ess: m.repka@.matl.uteKa1i..cdu (M.A. Repka\.
`
`I. introduction
`
`Vitamin F TPGS NF (TPGS, D-::x-tocopheryl
`polyethylene glycol \000 succinate) has been uti(cid:173)
`lized for numerous applications in phannacemical
`dosage forms. Its chemical structure coma ins both
`
`0~78-517J/OO/$ - s<:.e ti·om ma11er «.:' 2000 Elsevier Sc,.,nce B.V. All rights reserved.
`Pll: SO'l78-5J7J(00)00418-X
`
`SNS[lOCID· <Xi> ............ ' 1fl3717A_I .. >
`
`MSL_0003140
`
`RBP_TEVA05017998
`
`TEVA EXHIBIT 1042
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`64
`
`M.A. Repka, J. W. /IJcGinity
`
`International loumal of Phannaccuti,:s 202 120001 63·· 70 X PQQ 1183 71 7
`
`a lipopbilic and a hydropbilic moiety, making it
`similar to a convemional surface-active agent (Fig.
`!). The chemical properties l)r lhis distinctive com(cid:173)
`pound have suggested its use as a solubilizer, all
`emulsifier, ao absorption enhancer, and as a wa(cid:173)
`ter-soluble source of vitamin E (Eastman Chemi(cid:173)
`cal Company, 1998). TPGS has a melting point of
`approxi.miuely 38°C and irs degradation tempera(cid:173)
`ture bas been reported tO be 199.3°C. 'T'hesc phys(cid:173)
`ical properties coupled with its chemical properties
`make TPGS a potential candidate for hot-melt
`ext.rusiou applications.
`Several studies have demonstrated the ctTecrs of
`TPGS as an absorption enhancer (Traber et al .. ,
`1986, 1987; Sokol et al., !99Ja,b; Argao et a!.,
`l 992; Sokol er al., 1993; Chang et a!., 1996;
`Btidgers et al., 1998). Sokol et ul. (1993) con(cid:173)
`ducted a multi-center trial of TPGS for treatment
`of vitamin E deficiency in children witb chronic
`cboles.tasis . 'll1ese researchers reported that TPOS
`appeared to be a safe and effective form of vitamin
`E for reversing or preventing vitamin E deficiency
`during chronic childhood cbolestasis. Traber et al.
`( 1986) proposed a mechanism for enhanced <X- to(cid:173)
`copherol absorption by TPGS. Since TPGS can
`fonn micelles, it can cross from the intestinal
`lumen 1nto the mresri11al cel!s. "This mechanism has
`suggested the use 0f TPGS as a controlled drug
`deliveJy vehicle. Other studies have demonstrated
`an enhanced absm·ption of vitamin D in chronic
`cholesta tic liver disease or infancy and childhood
`(Argao et al., 1992) and unproved absorption of a
`model HI.V protease inhibitor (Bridgers et al.,
`1998 ). lsmailos et a l. (1994) concluded that 'l1>GS
`increased the solubility of cyclosporine, resulting
`i.n an increased bioavailability and thus an in(cid:173)
`creased absorption.
`
`I Chc.mJc"l ~tructurc of rhe pnncipal component of
`Fig
`Vitamin E TPGS.
`
`the
`Several studies have a \so demonstn1ted
`value of TPGS as a water-soluble vitamin E sup(cid:173)
`plement ( Hidiroglou et a!., 1993; Traber et a!.,
`1994; Di.mitrov et al., 1996; Socha et al., 199"/).
`Socha et al. ( 1997) concluded that oral TPGS
`supplementation of cholestatic children can
`quickly llOrmalize serum vitamin E levels. Dim(cid:173)
`itrov et a!. (1996) reported rhat in cases of
`cholestasis and other forms or lipid malabsorp·
`tion, oral adminislration of TPGS is the treatmem
`of ciloice.
`Few, if any, studies have been reported in tbe
`literature concerning
`the physical mechanical
`properties of Vitamin E TPGS in hydrophilic fi.l.Ir.s
`produced by a hot-melt extrusion technique. Due
`10 rhe tmique properties of TPGS as a solubili.zer,
`absorption enhancer and a potential controlled
`drug release vehicle, transdcmtal and transnn.1·
`cosa! applications are also possible. The \'>t~jecJ.ive
`of this study is
`to investigate the influence of
`Vitamin E TPGS on tbe properties of hydrophilic
`films produced by a hot-melt extrusion technique.
`In addition, the effect of TPGS as a processing aid
`for hot-melt extrusion is reported.
`
`2. Materials and methods
`
`2.1. Materials
`
`VItamin E TPGS NF was provided by Eastman
`Chemical Company (Kingsport, TN). Hydrox·
`ypropylcellulose (HPC) (KluceJ® HF; molecular
`we1gbt (MW), I 150 000) was obtained from the
`Aqualon
`DEL
`Company
`(Wilmiogtoo,
`Polyerhylene oxide resin (PEO) (PolyOx*' WSR;
`MW, 1 000 000) and polyethylene glycol 400 NF
`(PEG 400) (Carbowax® 400) were obtained from
`Un1on Carbide Corp. (Danbury, CT). Triethyl
`citrate (TECJ and acctyltributyl citrate <ATBCJ
`were. provided by Morfiex, Inc. (Greensboro, NC).
`
`2.2. Processing methods
`
`2.2. I. Matenal preparatwn and blending
`HPC aud PEO were dried at 50°C for 24 h
`prior to mixing. Vitamin E TPGS was freeze(cid:173)
`dried, lyophilized, and sieved (60 mesh) prior to
`
`MSL_0003141
`
`RBP_TEVA05017999
`
`TEVA EXHIBIT 1042
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`M.A. Repka, 1. Hi. AJcGml/_1'
`
`International Journal vf Pha11nace<llics 202 (2000) 63 · 70
`
`XPOOI 183717
`65
`
`blending with rhe two ratios of HPC and PEO
`(50:50 and 80:20). The plasticizers were incorpo(cid:173)
`rated slowly into a Liquid-Solids Blender.,.. (Pa(cid:173)
`terson-Kelley Co.l containing
`the HPC/PEO
`blends. All additives were blended for ~0 min. 'J11e
`batcb size was 1.0 kg..
`
`.2.2.2. Hot-melt extrusion
`A Randcastle Microuuder', (Model RCP-0750)
`was pre-heated to J 70°C melr temperature. For
`purging purposes, polyethylene pellets wt•re added
`to the hopper and passed through the extruder for
`5 mill Hbis procedw·e was repeated for each indi(cid:173)
`vidual batcb). The blends of HPC;PEO and Vita(cid:173)
`min E TPGS or Qlasricizer was placed in the
`hopper and exrrudcdt0013'r.ain a homogeneous
`film with a thickness range from 10 to 13 nul (I
`mi.!= 25.4 J.lm or 0.001 inch) or 0.254·-0330 mm.
`The extrusion temperatures for each film were
`depe11dent on the fotTnulation extruded. The films
`were extruded at their respective optimal rem per a·
`tures, ranging from 180 to 190°C. Processing time
`was less tban 2 min for all tllms produced. Tile
`film was collected in mils, labeled, and scaled in 5
`mil polyethylene bags (25°C, 50% relative humid(cid:173)
`ity). The width of the fil.rns produced was approx(cid:173)
`imately 5.00 inches ( ± 0.25). Random samples
`were taken from the extruded films for testing.
`Initial testing was conunenced after 7 days of
`storage.
`
`2.3. Mechanical 1esting appararu:>
`
`The physical-mechanical properties of the films
`were distinguished utilizing an lllstron 4201 tcst(cid:173)
`mg apparatus with a head speed of 10 mmfmin.
`The standard test method for tensile properties of
`thin plastic sheeting by the American Socie[y for
`Testing Materials, method D 882-95a, was used to
`investigate the mechanical properties. Six samples
`from each formulation were tested. The initial
`grip separation was 100 mm. Testing conditions
`for all films were 25°C and 50% relative humidity.
`
`2.4. Calculations
`
`force or load (F)
`Tensile strength (a)=
`MA
`
`where F is the maxi.mwn load and MA is the
`minimwn cross-sectional area of the film speci(cid:173)
`men. Results were converted to megaPascal units
`(MPa) .
`
`where L., refers to the initial length of rhc film
`sample and L is the elongation at the moment or
`rupture.
`
`Elongation percent= ex 100
`
`2.5. Physical characteri=arion
`
`Di.!Terential scanning calorimetry (DSC 2920
`Modulated DSC, and f'HERMAL ANALYST 2000
`software: TA Instrwnems, New Castle, DE) was
`milized to determine glass transition temperatures
`( T,). lJitrahigh pure nitrogen was used as the
`purge gas at a flow rate of 1 SO mljmm. Approxl(cid:173)
`mately 5 -·10 mg of sample was weighed and
`scaled in a nonhctmetic aluminum pan. All stud(cid:173)
`ies had a temperature ramp speed set at 10°C/
`min.
`Gel permeation chromatography (GPC) was
`used to provide a qualitative study of the polymer
`blend stability. A Waters system,
`including a
`WlSP model 710B auto sampler and a model 510
`salven t deli very system, was utilized. Ultrahy(cid:173)
`drogel"" 1000 and 2000 columns connected
`iu series and a model 410 diLTerential refractome(cid:173)
`ter were
`detector. Distilled
`used
`as
`the
`water containing 0.1 M sodi~Lm nitrate was uti(cid:173)
`lized as the mobile phase at a flow rate of l
`mljmiu.
`
`2.6. Statistical analy.vi.l'
`
`Calculations were performed in the following
`rnauuer.
`
`Statistical analysis was determined utili.ziug
`one-way analysis. of variance. A statistically sig(cid:173)
`nificant d1fference was considered when P < 0.05.
`
`MSL_0003142
`
`RBP_TEVA05018000
`
`TEVA EXHIBIT 1042
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`66
`
`M.A. Repka, J.I·'V. McGinily
`
`lntemariona/ Journal of _Pha•·maceulia 20.? (:?.0001 63-70
`
`XP001183717
`
`46 , - - - · · • "»> ' " " " " " " " " "
`
`4(\ ~ ·-
`
`-
`
`35 , ......... ..
`
`~: r.···· __ ··_"· __ _
`
`:.-~-~-~i~~ii~·iiiR
`~.!!.~~.1PE0{~2())_
`[
`__ J
`
`:zo .;. ............... .
`15 ., .................. _ _._ .. ..
`
`................ _ . _ ___ ._..l
`
`0%
`
`3%
`1%
`Percent Vitamin f TPGS
`
`5%
`
`Fig. 2. Glass transition temperatures of films containing ditTer(cid:173)
`c:rtt levels of V•tamin E TPGS incorporated iuto two forulula(cid:173)
`tions of HPC/PEO bot-melt extruded films (n = 4).
`
`\..
`
`BPCIPEO :50 50
`TPOS5% - - -
`........................................
`
`-41.1
`
`-41.%
`~
`
`~ -4M -t • .. .6
`
`Iii:
`01
`:!
`
`-41.8
`
`-UI
`
`-l-1
`
`II
`
`zs
`
`i
`!
`!
`\ i
`-+~' ............ ,_ ___ +-----!
`. 100
`50
`7:1
`TemperatlD"e ('C)
`
`Fig. \. OiiTcrcntial scanning calorimetry thermograrns of hot(cid:173)
`mel! ""~rruded films consisting of HPC/PEO in a ~O:SO raliL~
`(dashed line) and the HPC/PEO 50:50 ratio with 5% Vitamjo
`E TPGS as an addihve (solid line).
`
`40r-·~~~~~----------~~
`35
`lO +------
`•• 25
`E 20
`"' ,_ 1 s
`10
`5
`0
`
`PeG 4IMI Vlt E ll'GS TEC 3'11.
`l'lo
`)'Y,
`l"ig. 4. Glass transition temperatures of HPC/PEO (50:50)
`bot-melt <'xtruded films containing Vitamin E TPGS and thrC'~
`conventional plasticizers (n"' 4).
`
`ATBC 3'11.
`
`0'4
`
`3. Results and discussion
`
`As seen from Fig. 2, the glass transition temper(cid:173)
`atures of the two formlllarion ratios of HPC and
`PEO decreased in an almost linear fashiou wtth
`the addition of 1, ~ and 5% Vitamin E TPCIS.
`Although the T.., of the HPC/PEO (80:20) film
`with no TPGS present was slightly higher than
`rhar of rhe 50:50 ratio, wtth rhe addition of only
`1% TPGS. tbe Ts of Lhe two films were almost
`equivalent. ln addition, the inc0rporation of 5%
`TPGS into the HPCjPEO films (50:50 and 80:20)
`lowered the glass transition temperatures by ap(cid:173)
`proxima !Ciy
`l 7 and l8"C, respective! y (36.0 to
`19 soc, and 39.7 to 2l.:i 0 C), compared with the
`HPC/PEO fllms with uo additives CP < 0.05) (Fig.
`3). By lowering the glass transition temperature,
`TPGS acts as a plasticizer for the two polymer(cid:173)
`blended films. 1l1ese effects are a result of the
`TPGS weakeni11g the mterrnolecular attractions
`within the polymer blends and iucreasing the
`free voluJJ1(\ allowing the polymer
`pol.ymers'
`chaiu-; to move more easily and 10 become more
`flexible (Gutierre7-Rocca and McGinity, 1993;
`Wheatley, and Sreuernagel, 1997).
`The Tg of the HPC/PEO (50:50 ratio) film
`containing ~% TPGS and t"hree other conven(cid:173)
`tional plasticizers at the same concentration was
`determmed (Fig. 4). The film containing TPGS
`(3%) lowered the glass transition temperature over
`II oc from the HPCjPEO, 50:50 blend film (36.0
`to 24.9°C). In addition, the 3ryo TPGS-incorpo(cid:173)
`rated film reduced the T& to rhc same degree as
`the ~%PEG 400, and was significantly better than
`films containing 3% TEC and 3% ATBC <P <
`0.05). The efficiency of a plasticizer is related to
`its chemical structure and the interaction between
`its l'unctiot1al groups with those of the polymer or
`polymers (Gutierrez-Rocca a11d McGinity, 1994).
`The ampiphilic nilturc of the TPGS molecule,
`with the polyethylene glywl moiety serving as the
`polar head, enables it to function as a plasticizer
`for
`the
`two hydrophilic polymers
`(Eastman
`Cherrucal Company. J 998).
`Fig. Sa,b show the tcnsi.lc strength and percent
`elonga Lion, respectively, or the two HPCjPEO
`polymer blends as a function of incrensmg per(cid:173)
`centages of VitamiJ1 E TPGS. The tensile strengrh
`(TS) ts indire-etly proportional to the percentage
`
`BNSt::<X.:t D <XP ...
`
`118371"1A
`
`~
`
`.,.
`
`MSL_0003143
`
`RBP_TEVA05018001
`
`TEVA EXHIBIT 1042
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`M.A. Repka, J. W. MrGinity
`
`lril<:l'natwnal Journal of Pharmaceutics 101 i2000i 63-70
`
`XP001183717
`67
`
`of TPGS, while the percent elongation (%E) is
`directly proportional. No differences in these two
`physical-mechanical properties were round for
`the two HPCjPEO blends. 1bis finding is not
`surprising since there were no significant differ(cid:173)
`ences in the glass transition temperatures between
`the two polymer blends at each level of TPGS
`ine0rporated. The percent eloogati011 increased
`over J-fold for the 5% TPGS-cootaining film
`when compared with films containing no TPGS
`tP < 0.05). These findings are also consistent with
`tbe T 2 data that were presented earlier. Plasticiza(cid:173)
`tion of a polymer will decrease the polymeric
`intermolecular interactions to provide a greater
`freedom of movement
`polymeric
`for
`the
`molecules. Therefore, the film is more deformable
`(Wang et al., 1996). The tensile strength is de(cid:173)
`creased, and
`flexibility and elongation
`is
`ill(cid:173)
`creased, as is reponed in this study.
`The physical-mechanical studies demonstrate
`the comparable effectiveness of Vitamin E TPGS
`as a plasticizer (Fig. 6a,b). Tbc 3% TPGS-incor-
`
`50
`i 40
`!.
`i 30
`c: t 20
`"' .!!
`! 10
`{!
`
`0
`(a)
`
`25
`
`c: 20
`
`.Sl J 15
`"' i 10
`
`!. 5
`
`0
`
`(b)
`
`D%
`
`3"111
`1%
`Percent Vitamin E TPGS
`
`Porc:ent Vitamin E TPGB
`
`Fig. 5. (a) l'ensile strength and (b) p~rccnt elongation of
`difl .... oeut level; or Vitawiu E TPGS lfOCOrjJOfat<:d into twu
`formulatoons of HPC/PEO hot-melt extruded films (n = (l).
`
`(a)
`
`PEG 400 VItamin E TEC :J% A TBC 3%
`3%
`TPGS3%
`
`0%
`
`(b)
`
`PEG 400 Vitamin E TEC 3% ATBC 3'4
`TPGS 3%
`3%
`
`0%
`
`Fog. 6. (a) Tensile strcn&tb and lbl percent elongation or
`HPC/PEO 50:50 ratio hot-mdt extrude-d films cootammg Vita(cid:173)
`min E TPGS nnd thru conventional plastici7.ers (n- 6).
`
`pora ted film had a similar tensile strength to that
`of the 3% PEG 400-containmg film (17.9 com(cid:173)
`pared with 14.8 MPa). However, tbe TS of the
`TPGS-contatning film was significantly lower than
`the films incorporated with 3% TEC, ~% ATHC
`aod tbe HPCjPEO film (50:50 blend) containing
`no additives. TI1e ~% TPGS film also exhibited an
`almost 3-fold
`increase
`in percent elongation
`(14.9%) when compared with that of the TEC,
`ATBC. and 0% TPGS-containing films (6.4, 5.8
`and 4. 7%. respectively). Thus,
`the hydrophil.ic
`moiety of the Vitamin E TPGS molecule was
`more effective in dismpting the intennok..cular
`interactions of the HPC/PEO 50:50 film, allowi.ng
`a greater degree ot' polymer chain freedom than
`either TEC l'r ATBC. Only the ~% PEG 400-in(cid:173)
`corporated film had a )!.reater perC'..etlt elongation
`(21.3%) than the T1lGS tilm. Tb1s may be ex(cid:173)
`plained by the lower molecular weight of PEG
`compiired with the TPGS. I femamaki et al. ( 1994)
`presented
`similar
`finrlings. These
`researchers
`
`BNSOOCID. <%>'
`
`. 1 l83717'A_I_>
`
`MSL_0003144
`
`RBP_TEVA05018002
`
`TEVA EXHIBIT 1042
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`68
`
`Af.A. Repka. J.IV. ft1cGmity
`
`lntcrnallonal fo11mal of Phannacr:uncs 202 (2000! 6.1 70
`
`XP001183717
`
`found that percent elongation or ductility was
`primarily attributed lO the molecular weight or
`the polymeric plasticizer. As the tnolecular weight
`or size of the PEG (or PEG moiety) is increased.
`rhe mole fraction of available hydroxyl groups ro
`interact. with the reactive sites of molecules will
`decrease (Rowe, 1976). In this case, the PEG
`moiety is of higher molecular weight than the
`PEG 400 molecule, therefore decreasing t.he abil(cid:173)
`ity of TPGS to interact with the reactive hydroxyl
`groups of the HPC and PEO. Thus, the TPGS
`film would be less elastic. In addition, PEG is
`composed of tbe same structural unit as PEO, but
`has a much lower molecular weight than PEO.
`Since PEG and PEO have the same repeating
`unit, they were completely miscible in the solid
`state (Zbang and McGinity, 1999). Tbe PEG
`molecules between PEO chaius were able to more
`effectively weaken t.l1e cohesive inr.eractions be(cid:173)
`tween the PEO chains, thereby increasing the
`inter-cbai.n space between
`the PEO molecules.
`However, as was reported by Repka et al.. 1999,
`the PEG 400-comaining fiLms may have stability
`concerns upon aging.
`"Ihe i11tluence of V1tarnin E TPGS on process(cid:173)
`ing conditions of hot-melt extruded films is re(cid:173)
`poned in Table 1. In a bot-melt extrusion process,
`polymers are subjected ro both thermal and shear(cid:173)
`ing stresses. The temperarure can contribute w
`depolymerization of polymer chains, whereas
`chain scission may result from the shearing effects
`of the screw (Zhang and McGi.oity, 1999). In the
`absence of TPGS, films could not be processed at
`tso•c due to the high viscosity of the polymer
`blend and a torque that exceeded the capacity of
`tbe extruder (50 N m). The processing tempera(cid:173)
`ture had to be increased r.o a minimum of 190°C
`
`to obtain a HPCjPEO 50:50 rati\1 film. Increasing
`the temperature is the most common practice to
`facilitate a polymer extrusion process i.n the plas(cid:173)
`tic ind~tstry. Melt viscosity decreases exponen(cid:173)
`tially wirb respect to an increase i.n temperature
`(Nielsen, 1977). At 180°C, a film with as little as
`1 ryo TPGS could be produced. However, as the
`percent TPGS increased, the barrel pressure, drive
`amps, and torque all decreased significantly <P <
`0.05). Th\IS, in addition to TPGS plasticizing the
`HPCJPEO films, it was also an excellent process(cid:173)
`ing aid in tbe extiUsion process. Indeed, due to
`the decrease in melt viscosity with increasing
`TPGS concentration, the films incorporated witb
`TPGS could be produced at a lower temperature
`and/or a higher screw speed. "ll1is would decrease
`the potential for degradation of both the poly(cid:173)
`mers and drugs rhar may be incorporated in the
`fil.m.
`Fig. 7 shows the results from the (3PC studies.
`As one can observe, there is a shift to the left of
`the curve represenung tbe film containi.1.1g 3%
`TPGS compared with that of rhe curve of the
`HPCfPEO 50:50 ratio film with no additives.
`These findings demonsrrared that TPGS decreased
`the degradation and chain scission of the polymer
`blend and help stabilize the PEO that is suscepti(cid:173)
`bLe to rhermal oxidation. In addition, when Vita(cid:173)
`min E 0.5"/r, was added to the powder blend, there
`was no further shift than occurred with the 3%
`TPGS-incor·porated .film.
`Vitamin E TPGS is a viable candidate for in(cid:173)
`corporation into hot-melt extruded films com(cid:173)
`posed of HPC and PEO. TPGS functioned as a
`plasticizer for these hydrophilic films since it low(cid:173)
`ered the glass transition temperature and
`in(cid:173)
`creased
`the percent elongation as the TPGS
`
`Tabl~ I
`Pro~:essing condJUons for h(>l-melt extruded films containmg a 50:50 ratio or hydro~ypropylcellulosc to polyethylene oxide with
`Vitamm E TPGS a~ an additi vc (n = 4)
`
`Vitamm E TPGS 1%)
`
`Melt temperature: (°C)
`Prc:ssu rc: (psi)
`Drive lA)
`Torque (N m)
`·--·-·-- ---·-·······-··-·······-···-·--··--··· .. ····-·····-· .. ·-----.. ·--·----·---
`0
`> 3000
`180
`;> 4.00
`25
`Overload
`190
`()
`3.84
`'!lllll
`40
`40
`:n
`I
`180
`1800
`HJ6
`40
`J
`180
`1500
`2.8
`40
`2.6)
`5
`2.07
`180
`40
`1100
`21
`----·-·····-············-·--··-·········-··-····----·--·····-······-···-············---·---·············-·········---·---···----······--·······-····················-········
`
`Screw spcc:d
`
`BNSOOCID: <XP ..
`
`......... ' 103717A. _ _I_>
`
`MSL_0003145
`
`RBP_TEVA05018003
`
`TEVA EXHIBIT 1042
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`M.A. RC!pka. ). I·V. McGinity
`
`lntcmalional h•urnal of Pharmac:culics 202 12000) 63 70
`
`XP001183717
`69
`
`' I
`
`I
`I
`
`' I
`
`I
`I
`I
`I
`I
`
`I . . I
`.
`I . I
`I . I
`
`D.IIO
`
`2.511
`
`..
`• 2.110
`1
`.. '.so
`' Q ..
`
`I
`
`'.110
`
`I
`I
`I
`
`. I
`' I • I
`I • '
`
`HJ>CfPEO 50:50 - (cid:173)
`
`TPGS 3% - - --
`
`I
`I
`I
`
`I
`
`'11.
`
`!Jver d.seas,e nf infancy and childhood. Pectiarr. Res.
`146 150.
`, Silver, 1.. and Collin, M
`Rridg~r~. A ... V1ckc:rs, A .. Yu. l
`1998. Vitamiu E-TI'GS c.nhaoccs
`the absorpt10l\ of a
`m<'Xiel f-JIV protease inhibitor by inhibiting an apk:ally
`polarized efftux system. PharroSci. Suppl. I ( J) S-76 .
`Chang. T.. Benet, L.Z., Hebert. M.F., 1996. The etlect of
`water-soluble vnamm Eon cyclosporine pharmaook.mctics
`m healthy volunteers. Clio. Pl1annacol. Ther. 59, 297-.~03.
`Dimitrov, N.Y .. Meyer-Lc:ecc. C., McMillan . .1.. Gilliland. 0 ..
`PerloiT, M .. Malone, W .. \996. Plasma alpha-tocopherol
`concentrations after >upplemt·ntarion with water and fat
`>Oiublc vitarolll. E. Am. J. Clin. Nutr. 64, ~29-J:~5.
`Eastman Cbemic.1l Company, 1\198. Vitamin E TI><Js NF.
`Propertic~ and
`applications, Publi..:ation EFC-2261\ .
`Kmgsport. TN, Octobc:r.
`Gutierrez-Rocca. J.C., McGinity. J.W., 199.~. lnfil.lencc of
`aging on the pbysical-mcchanical properties of acrylic resin
`fi ltns cast from aquc:oU> dispersions and organic solutions.
`Drug Dcv. Ind. Pbarm. 19, 315-1>2.
`Gutierrez-Rocca, J.C., McGinity .
`lnfillence o!'
`.I.W., 1994.
`wattr soluble and insulubh: pla~ti~,;i<Gcrs ou the phy>t<;<~l :.nd
`mechanical propert1es of acrylic rcsm copolymers. Int. .1.
`!'harm. 103, 293-301.
`Heillllrnaki, .I.T., Lehtola. V.M .. N1kupaavo, P .. Yhruust .
`.I.K, 1994. Me.cbanical >tnd moistllre permeability proper·
`tics of aqueous-based hydroxypropyl mcthylcc:llulosc coal·
`tog systems plasticized wilh polye.lhylene glycol. Int. J.
`Ph.arm. \\2. 191-·196.
`Htdrroglou. N .. Wolyoetz. M.S .. Mc:!)owefl. L.R., Papas.
`AM., i\utaplt, M. Wilkmson .. N.S ..
`\993. Serwn total
`cholesterol.
`high-dcn51ty
`lipoprotein-cbolcsterol
`and
`rriglycende concenrrarioo~ in bmbs following supplemen(cid:173)
`tation with various forms of tocopherol. Rcprod. Nutr.
`Dev. ~:1. 263--268.
`lsmai!os. G .. Rcppas. C .. Ma~hcras, P .. 199-l. Euuanccmcnt of
`c•y~:losponn A
`solub1hty
`by
`o-alpha-tocopheryl(cid:173)
`p<Jiycthylcnc-glycol-1000 su..:cinatc (TPGS). Eur. J. Pharm.
`Set. I. 269-271.
`N1clsec. I E .. 1977. Polymer Rcology. Marcel Dekker, New
`York. pp. :ll-44.
`Repka, M.A., Gerding, T.G .. Repka. S.L., McGinity, J.W.,
`1999. Lu.fil.loencc of plastici;:crs and drugs ou the physical(cid:173)
`rn<~ch.anic'al properties of hydro~<ypropylcellulose films pre(cid:173)
`pared by ltot melt extruston. Drug Dcv. fnd. Pbarm. 25.
`6~~-6~-n.
`Rowe. R.C., 1976. Microinctenration -···a merh,)d lor measur(cid:173)
`ing the clastic prOperties and hardness of film< 00 C4?nVCl1•
`J. Pharm.
`llonal\y coated
`tablets
`(communications).
`Pharmaool. 28. 310- 311.
`Sucha, P., Kolctzko, B., Pawlowska, J., Proszynska. K ..
`Sm:ha. J., 1997. Treatment ol' cholcstalil: children wah
`water-soluble vitamin E (alph.a-tocopheryl polyethylene
`glycol '"ecinate:l: eiTects ''" <erum vitamin F. lipid perox.
`ides, and polyunsaturated fatty acids . .1. Pediatr. Gastrocn·
`tcrol. Nutr. 24.189-193.
`
`D.SII
`
`____ ....
`O.DD
`t.DO
`
`.. _______ .. _
`
`2.110
`
`:1.011
`to1 ...... -..
`
`•
`
`4.00
`
`5.011
`
`Fig. 7. Gel permeation chromarograms of' hot-melt extruded
`tilms e<)nsisting of HPC/PEO in a 50:50 ratio and the HPC/
`PEO 50:50 ratio witb 5% Vitamin r: TPGS as an .additive
`(n =6).
`
`content increased. TPGS was also found to func·
`tion comparably with the conventional plasticizers
`tested. Vitamin E TPGS was also an excellent
`processing aid, decreasing barrel presstire, drive
`amps, and torque as the TPGS percent increased.
`TPGS rnay also act to prevent. polymer degrada.
`tioo wben utilized in the extrusion process. In
`summary, the unique properties of Vitamin E
`TPGS can function to promote more applicaliom
`and opportunities in wound care and in transder(cid:173)
`mal)transmucosal drug delivery.
`
`Ackno~·ledgt'ments
`
`Micbael A. Repka would like lO tbaok rbe
`American Fouudation for Pharmaceutical Educa(cid:173)
`tion for irs suppon ol' this study and other re(cid:173)
`search endeavors.
`
`Rererenccs
`
`Argao. E.A .. Heubi, J.E., Holl1s. B.W .. Tsang. R.C .. 1992.
`D-Aipba-tocopheryl polyethylene: glycol-1000 succinate en(cid:173)
`hances the absorption of vitamin D in chrome cholestauc
`
`BNSDOCID <XP
`
`, 1S3717A
`
`I >
`
`MSL_0003146
`
`RBP_TEVA05018004
`
`TEVA EXHIBIT 1042
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`70
`
`Af.A. Repka, .I.W. ft.1c(iinily lnt~mauonal Journal of Pharmar·eulic.< 202 (2001)) 6.1--70
`
`XP00118371l
`
`SokoL R.J., Juhnson. K.E .. Karr~r. F.M., Narkewicz, M.R..
`Kam, 1., eta!., 199la. lmprovcmcnt of cyclosporin absorp(cid:173)
`uon m chtldrcn aflcr hvcr transplantation by means of
`water-soluble vitamin E. Lancet 3;\8. 212··215.
`Sokol, R.J., Johnson, K.E .. Karrer, F.M., Narkcwicz, M.R ..
`Kam, I., el aL 1991 b. Improvement of cyclosporin absorp(cid:173)
`tion in childtcn after hvcr transplantation by means of
`water-soluble vitamin E. Lancet 3J8. 697.
`Sokol, R.J .. Butler-Simon. N .. Conner. C., Heubi . .J.F.., Sina(cid:173)
`tra. F.R., Suchy, F . .l., Heyman. M.B .. PerTault, J., Roth(cid:173)
`baWl>, R.J., l.evy. J .. et a!.. 199:1. Multicenter tnal of
`D-alph<Ho.:opb.:ryl polyethylene glycol 1000 .succinate for
`trr.atmenl of vitamin E deficiency in children witb chronic
`cholc:stasis. Gaslroeotrrology 104, 177.7-17.l5.
`Ttabca, M.G., Kayd<n. H.J .. Green, .l.B .. GJ<:eu. M.H., 198(j.
`Absorption or wattr·rrusctble forms of vitarrnu E
`tn a
`patient with ,:holesrasi~ and in thotnCtc dtJct-r.annulattd
`r·ats. Am. J. Clio. Nutr. 44, 914-923.
`Traher, M.G .. Tnellman, CA., Rindler, M J. Kayden. H.J.,
`
`inracr TPGS
`(D-alpha-rowpheryl
`1987. Upral<c of
`polyethylene glycol 1000 succtnat<•) a water--misctbk form
`of vitamin E by lwman cells iD vitro. Gastrc>enterology 93.
`975 9l>5.
`Trab~r. M.G .. Schiano, T.D., St~cphcn. A.C.. Kay;kn. H.J.,
`Shike. M .. 1994. Efficacy of water-soluhlc vitamtn E tn the
`trc~tmcnt of vitamin E malabsorption in short·bowcl ;y11·
`dromc. Am . .1. C:lin. Nutr. 59, 1270-1274.
`Wang. C.. Zhaug, G., Shab, N.H., lnfcld. M.H., Malick,
`A.W .• McGinity. J.W., 1996. Mechanical properties of
`stngle pellets containmg acrylic polymers. Pharrn. Dc:v.
`Techno!. J, 711-222.
`Whcaclcy. T.A .. Stcucraagcl. C.R., !997. Latex emulsions for
`controlle<J dntg dclivay.
`Jn: McGiwty. J. W.
`(Ed ).
`Aqueous Polymeric Coatings For Pharmaceutical Dosagt·
`Forms. Second eel. Marcel Oekker. New y.._,rk. pp U-
`52.
`Zhang. F .. McGintty, .J.W .. 1999. Properties of sustain,d-rc(cid:173)
`leasc tablets prepared by hot-wclc extrusion. Pharro. lkv.
`T~chnol. 4. 241-250.
`
`8NSOOCID. •XP.
`
`·' l837l7A ____ I_>
`
`MSL_0003147
`
`RBP_TEVA05018005
`
`TEVA EXHIBIT 1042
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC