ELEV]
`
`international Journal cl‘ Phurmuccuucs 163 (1998) 1l5~l2l
`
`international
`journal of
`_
`
`pharmaceutics
`
`The effect of water—soluble polymers on the aqueous solubility
`and complexing abilities of ,6-cycloclextrin
`
`Thorsteinn Loftsson *, Hafrun Frioriksdottir
`
`Irzsliritw of Pliurnmry. Flmrnaacalugy uml 7'u.rit'alngy. Unmcrsiry of Iceland. P.0. Bot‘ um, IS-I27 Reykjavik, Ice/aml
`
`Received l6 July I993’. received in revised form l6 October I997’; accepted 5 November I997
`
`.....,.l..w».«.-..-‘........iom...t -.a......t....e...c.......»...,.;...v.......~,..........c..
`
`w.............v.,....w.l.......................,.».....w...... w..»~...nnm~+..,..M_.M..~._».m»,M...M.¢...w..._._m.u.......sw. lr
`
`Abstract
`
`The purpose of this study was to investigate the effects of both watensoluble polymers and various drugs on the
`solubility of flusyclodextrin (fiCD) in aqueous solution. The solubility of {ICE in water was determined to be 18,6
`mgiml. but addition of 0.25» L00“/’u (wiv) of polyvinylpyrrolidone. and heating in an tlutoclztve 020 140°C for 2040
`min) increased the solubility to 21 mgjml. The aqueous solubility of HCD also increased upon drug»« /1 CD complex
`formation. Both lipopltilic and hydrophilic drugs increased the solubility of /3 CD in water. For example. the solubility
`of /3CD in a saturated aqueous solution of carbamuzepine was determined to be 28.4 mgfml but 53.3 mgiml when
`0.25% (wiv) hydroxypropyl methylcellulose (HPMC) was present in the solutions. The total solubility of /3 CD in such
`aqueous systems appeared to be the sum of the intrinsic solubility of /3CD and the solubility of the various /)’CD
`complexes, Be. the drugw/lCD complexes and the complexes of [ICD and drug /{CD complexes with the water-sol«
`uble polymers. Not only did the polymer solubilize (5 CD and its complexes. but was also able to enhance drug~ /ICD
`complex Fonnalion.
`1998 Elsevier Science B.V. All rights reserved,
`
`K't‘j?l\'0rd€I Cyclodcxtrin; Complcxation: Drug delivery: Drug formulations; Polymers; Solubility
` o......t........t..........M.a..»...........,........\...........-.M.-~,.....»..,.....»..~.,,.~._,....“....m._~,,,mw,,.,~...,..,.
`w W-»»«~«»..«..n.;,. /.—.......~..t.,.........».............».....u m.m........a.,.......ut-st
`
`I. Introduction
`
`Cyciodextrins (CDs) are a group of structurally
`related cyclic oligosaccharicles that are formed by
`enzymatic cyclization of starch. The three most
`common naturally occurring CD3 are a:acyclodcx—
`trin (a:CD),
`/Jwyclodcxtrin (/ICD) and y-cy-
`
`‘Correspondtng author. Fax
`thorstlo@lu IS
`
`%354 5254071’.
`
`c»mutlI
`
`clodextrin (*yCD) consisting of six. seven and eight
`(a:~l,4)-linked a-tyglucopyranosc units,
`respec-
`tively. The CD molecules are cont:-shaped with a
`somewhat hydrophobic central cavity and by
`drophilic outer surface They are capable of form«
`ing inclusion complexes with many drugs by
`taking up a whole drug molecule. or more fre-
`quently some hydrophobic part of it,
`into the
`cavity. The complcxation will affect many of the
`physicochcmical properties of the drugs without
`
`0378-5l73»'9li:Sl9.00 O 1998 Elscvter Science B.Vi All rights reserved,
`PH S0378-5173(97)00371-2
`
`APOTEX EX1 044
`
`Page 1
`
`APOTEX EX1044
`
`Page 1
`
`

`
`H6
`
`7‘. Luflmin, H. Frioriksrlxltiirz [rm-rnrriiunui Journal of t°imrIml(‘L‘ttIi£.l‘ I63 (I998) H5 ~ [21
`
`affecting their intrinsic lipophilicity or pharmaco-
`logical properties (Frtlmming and Szejtli, 1994;
`Duchéne and Wouessidjcwe, 1996; Loftsson and
`Brewster,
`I996; Rajewski and Stella, 1996;
`Inc
`and Uckama,
`l997).
`The natural CDs, in particular /ICD, have lim-
`ited solubility in water and their complexes with
`lipophilie water-insoluble drugs often result
`in
`precipitation of solid drug- CD complexes (Szejtli,
`i988). Thereforc various CD derivatives possess-
`ing very high solubility in water have been synthe-
`sized. These
`derivatives
`include
`the
`/{CD
`derivatives which presently are the most common
`CD5 used in experimental drug formulations,
`i.e.
`2-hydroxypropyl-/i-cyclodextrin (HP/ICD).
`ran-
`domly methylated
`/I-cyclodextrin,
`sulfobu-
`tylether-/1-cyclodextrin
`and maltosyl—/i-cyclo-
`dextrin. Little attention has been focused on the
`
`usage of third component, such as water-soluble
`polymers,
`to enhance the aqueous solubility of
`/J’ CD and its complexes. The purpose of this study
`was to investigate the effect of water-soluble poly-
`mers on the aqueous solubility and complexing
`abilities of /!CD.
`Polymers are known to interact with CD5, al-
`though the exact nature of the polymer-»CD inter-
`actions is still not known. Hladon and Cwiertinia
`
`/{CD interacts with a
`(1994) have shown that
`number of water-soluble cellulose derivatives.
`
`Other investigators have shown that at low con-
`centrations, polymers
`increase the complexing
`abilities of CD5 (Loftsson ct ah, 1994; Ganzerli et
`al.. 1996) and that
`the polymers enhance the
`availability of drugs in aqueous CD solutions
`(siguroardottir and Loftsson, 1995). This indi-
`cates that these interactions between water-soluble
`
`polymers and CD5 are different from those ob-
`served in, for example, polyrotaxanes where many
`CD molecules are threaded onto a linear polymer
`(sec for example Fujita et al.,
`i996). Such inclu-
`sion complex formation between CD5 and poly-
`mers will reduce the abilities of the CDs to form
`
`complexes with other molecules. Polyrotaxancs
`are prepared at room temperature by gently stir-
`ring an aqueous solution containing both the
`polymer and the CD. Enhancements of the com-
`plexation efficacy and increased drug availability
`in CD solutions are usually obtained by heating
`
`aqueous solutions containing polymer, CD and
`drug in an autoclave (120-l40“C for 20-40 min).
`Simply adding the polymers to the solutions with-
`out heating docs not enhance the complexation or
`the drug availability (Loftsson and Siguréardottir.
`1996).
`
`2. Materials and methods
`
`2.1.
`
`IW(IlL'l'lll’.S'
`
`/3-Cyclodextrin (/XCD) was obtained from
`Celedex (Japan), Lhydrexypropyl-[3~cyclodextrin
`MS 0.6 (HP/ICD) and it-cyclodcxtrin ()vC'D) from
`Wacker
`(Germany).
`carboxymethylcellulose
`sodium salt of medium viscosity (CMC)
`from
`Norsk Medisinaldepot (Norway), hydroxypropyl
`methylcellulose
`4000
`(HPMC)
`and
`poly-
`vinylpyrrolidone of molecular weight 40000
`(PVP) from Mecobenzon (Denmark), sodium sali-
`cylate and sulfamethoxazole from Icelandic Phar-
`maceuticals (Iceland), acetazolamide from Agar
`(Italy), earbamazepinc from Aldrich (USA), and
`alprazolam. dexamethasone, econazole. ethoxyzo-
`lamide and methazolamide from Sigma (USA),
`All other chemicals used were of pharmaceutical
`or special analytical grade.
`
`22. Quantitative deternifnation
`
`The quantitative determination of /JCD was
`performed on a high—pcrformance liquid chro-
`matographic (HPLC) system composed of a Wa-
`ters Model 501 pump operated at 1.0 mlfmin flow
`rate, a Rheodyne 7125 injector and PAD-2 pulsed
`amperomctric detector from Dionex (USA) with a
`gold working electrode and a silver-«silver chlo-
`ride reference electrode. The column was a Carbo-
`
`Pae PAI Analytical Column (4 x 250 mm) from
`Dioncx. The cluent consisted of ISO mM sodium
`
`hydroxide and 300 mM sodium acetate in water.
`Duration times for detection were: 15, = 100 mV
`(1.m=l20 ms). E,rm600 mV (:32--"I20 ms) and
`E; m -«~ 800 mV ((3 w 300 ms). The PAD response
`time was set at 1 s. Quantitative determinations of
`the drugs were performed on a reversed-phase
`HPLC component system consisting of a Milton
`
`Page 2
`
`Page 2
`
`

`
`T. Loflsson, Ht Fridriksr/dllirfInternational Jmrrnul of P/mmmcctm'c.t' I63 (£998) H5» 12!
`
`H7
`
`Table 3
`
`Conditions of quantitative drug determination by HPLC
`
`Drug
`
`Mobile phase
`
` ~......«,.u......»y»~».~<.9«m«»\ssm.\.e.ws.».s4«+vw’avw
`
`Flow rate
`(mlfmin)
`
`Wavelength
`(nm)
`
`Retention time
`(mm)
`
`Acctazolumide
`
`Carbamuzepinc
`Hydrocorusone
`Econuzole
`
`Methazolurnide
`-vwwmv?
`
`L5
`
`2.0
`L5
`l 5
`
`Acctomtrile. acetic acid. water ( l0‘2:88) containing
`{).0l5‘?’~. hoctunesulfonute
`Acelonitrile. tetrahydrofurun. wutcr (3S‘| 64)
`Acetomtrile, tetrzlhydrofurun. water (30 l 69)
`Methanol. 0.01 M aqueous potassium phosphate solu«
`lion (pH 4.5) (90:l0)
`254
`2.0
`Aeetonitrile, acetic acid. water ( l2 2 86) containing
`0.0l5‘:»tt (wiv) l-roctanesulforttttt:
`.0.“ M.140%:-v«an>«\¢-p-xv’-‘»....»,,.....,..w...;e...ec....t-..t....i. ....s..............\.........-.ss..
`o-mxu¢vvx‘~1,'»vr\-Mmr-rvvtmvnnaV»~»o>9-ww~om-rvrwmwawov
`
`263
`
`278
`254
`226
`
`4 0
`
`2 8
`2 6
`2.0
`
`2 5
`.............t..................._........u........_.
`
`Roy Constalvletric 3200 solvent delivery system
`(USA), a Spectra Monitor 3200 UV,t"Vis variable-
`wavelength detector, AS-2000A Hitachi Merck
`3200 autosamplcr (Japan-Germany), and El Beck»
`man Ultraspere ODS 5 tr, 4.6 x l50 mm column
`(USA). For other HPLC conditions. see Table l.
`
`3.3. Eva/tralfon of /3’ CD stability during
`cmloclcwing
`
`Stability of the /1CD was determined by heating
`pure unbuffered aqueous IICD (0.5% w;‘v) solu-
`tions, at it pH of about 5, to l20°C in an auto-
`clave (M7 Speed Clove from Midrnark, USA) for
`0 to 80 min (0«~4 heating cycles). The solution was
`heated in closed vials and one vial removed from
`
`the autoclave after each heating cycle. After cool-
`ing the samples to room temperature,
`the /ICD
`concentration was determined by HPLC. The ex-
`periment was repeated two times. No degradation
`of /ICD could be observed in the three indepen-
`dent experiments.
`
`2.4. Solubflity stmiies
`
`An excess amount of /XCD andior the drug to
`be tested was added to water or aqueous polymer
`solution. The suspension formed was heated in an
`autoclave in sealed containers (l20°C for 20 min).
`After equilibration at room temperature (23°C)
`for 4~ 7 days, the suspension was filtered through
`a 0.45-hm membrane filter (Nylon Acrodisc from
`Gelman. USA), diluted with water (when the sol-
`ubility of
`JECD was
`to be determined) or
`
`methanolwwatcr (7:3) solution (when the solubil-
`ity of the drug was to be determined) and the
`/}CD and drug concentrations determined by
`HPLC. The apparent stability constants (Kc) of
`the drugw/ICD (lzl) complexes were determined
`from the phase-solubility diagrams according to
`the method of Higuchi and Connors (i965).
`
`2.5. Diffusion tftrottglz Ce!/opitarze membrane
`
`The effect of heating the polymer /{CD solu-
`tions on the diffusion of M31) through cellophane
`membrane (Spectropore membrane tubing, m.w.
`cut off l2000-~ 14000) was investigated in Franz
`diffusion cells (Vangard, USA). The aqueous so-
`lution to be tested contained l% (wfv) /}CD and
`0.25% (wiv) water-soluble polymer. Half of each
`solution was heated in an autoclave as described
`
`in Section 2.4 (the heating promotes the polymer~-
`/JCD interaction) and the other half was not
`heated {minimal polymers/J CD interaction). Wa-
`ter was used as a receptor phase. Samples (200 pl)
`were withdrawn from the receptor phase every 15
`min for 90 min. The ,{1’CD concentration was
`determined by HPLC. Each experiment was re-
`peated at least three times and the results reported
`are mean values 1 standard error of the mean.
`
`3. Results and discussions
`
`3.]. Polymer» /1 CD interaction
`
`it is possible to enhance aqueous solubility of
`/3CD by forming complexes with water-soluble
`
`Page 3
`
`Page 3
`
`

`
`H8
`
`7‘. Liiflssun. H. Fribrilrsr/élltr Unrernalionrrl Journal of Pizttrtitacciitlcur I63 (I998) H5~»!2l
`
`the
`drugs like sodium salicylate. For example,
`solubility of fi'CD was determined to be l8.6
`mgiml
`in pure water but
`it
`increased to about
`200 mgfml when the solution contained 5% (wt
`v)
`sodium salieylate. The
`apparent
`stability
`constant
`(Ku) of the salicylate~,8CD complex
`was determined from the linear phase-solubility
`diagram to be Si M“ in pure aqueous ,6’CD
`solutions but it
`increased to 64, 87 or 80 M”
`when 0.25% (wiv) CMC, PVP or HPMC,
`rc-
`spectivcly, were added to the solution. How-
`ever.
`solubilization
`of
`/1CD
`through
`complexation with watensoluble drugs
`is of
`limited value to the pharmaceutical
`industry
`The observed enhancement of Kc upon addition
`of the polymers shows that
`the polymers are
`able to interact with the anionic salicylate»
`/ICD complex. The polymers»/ICD interaction
`could also be observed by measuring the flux
`of
`/JCD from aqueous
`polymer
`solutions
`through a semi-permeable membrane which was
`impermeable to the polymers. Thus the fluxes
`of
`/}CD from aqueous PVP solutions were
`56;l:4><l0“‘
`and
`46i4>~.: l0” M min”
`cm” from unheated and heated solutions.
`rev
`
`spcctivcly. From a CMC-montaining solution,
`the fluxes were determined to be
`I003; 18x
`10”’ and 53;t;7x 10*“? M min“ em” from
`an unheated and heated solution,
`respectively.
`This indicates that heating in an autoclave en~
`hanced the polymerw CD interaction resulting in
`slower CD permeability through the membrane.
`Finally,
`the polymer/ICD interaction can be
`observed by measuring the effect of the poly»
`mer on the aqueous solubility of /ICD itself.
`For example, addition of a small amount of
`PVP and heating in an autoclave resulted in
`notable enhancement of the aqueous solubility
`of
`/)’CD (Fig.
`l). The
`solubility
`decreases
`somewhat
`at higher polymer
`concentrations,
`possibly due to formation of water-insoluble
`inclusion complexes between the polymer and
`several
`/ICD molecules. Such precipitates are
`commonly
`observed when
`polyrotaxanes of
`/3CD are formed in aqueous solutions (Fujita
`at £11., 1996).
`
`3.2. Ejfect of Iipop/zilic drugs and polymers on
`the 501ubift'!_tr of /1'CD
`
`In general, lipophilic drugs possess low intrinsic
`aqueous solubility and,
`thus, one would expect
`that addition of such drugs to aqueous /3CD
`solutions should lower
`the solubility of ;b’CD.
`However, the solubility of /iCD in such systems
`should be the sum of the intrinsic solubility of
`/3CD and the solubility of the drug~flCD com
`plex. The solubility of /}CD was determined in
`water and several aqueous polymer solutions and
`the effect of complex formation between drug and
`/JCD on the solubility investigated (Table 2).
`Addition of the polymers results in a 3»«l0‘V.t
`increase in the total aqueous solubility of IICD
`but the drug~fiCD complexation results in a ca
`40% to > l00'i’u increase in solubility (the solubil«
`ity ratio in Table 2 is l.4—-2.l). Further solubiliza-
`tion was obtained when a water-soluble polymer
`was present
`in the aqueous complexation media
`resulting in an additional .'Z~sl00“i»’:t increase in the
`total aqueous solubility of /1CD. The total
`in»
`crease in the /1 CD solubility was in some cases as
`high as 190% (solubility ratio was up to 2"9)X It
`appears that the total solubility of /ICD in such
`aqueous compositions is the sum of the individual
`contributions. For example. the total solubility of
`
`N N
`
`N O
`
`3-4InnoasUsno
`
`
`
`B«Cyclodcxtrlnsolubility(mghnl)
`
`0
`
`5
`4
`3
`2
`1
`PVP concentration (% w/v)
`
`6
`
`l. The effect of increasing PVP concentration on the
`Fig.
`solubility of_,t3’CD in water at room temperature (23"C) The
`mean :3; standard error of the mean of three experiments
`
`Page 4
`
`Page 4
`
`

`
`T. Loflmrn, Ii. Frit’Jn'k.i'¢l:3m‘r.:’lnlcrnutiomI/ Journal of Phc:r:nztc'eml'c.i' I63 (1995) H5 42!
`
`H9
`
`Table 2
`
`The solubility of /ICD in water. in aqueous 0«2S°»"i1(W.’Y) polymer solution, in water saturated with both 19C!) and the drug. or in
`-
`......i........
`cits.»
`aqueous 0.25% (W/Y) polymer solution saturated with both /i'CD and the drug
` ¢..,,...............
`
`Drug (sol. mg/ml)"
`
`Polymer
`
`Solubiiityj: standard deviation (mgfmll
`
`Solubility ratio"
`
`Acetazolumidc
`(0.70)
`
`Alprazolam
`(0.07)
`
`Cttrbamuzcpinc
`(0. l l)
`
`Dcxamcthasonc
`(U l I)
`
`Ethmtyzolamide
`(004)
`
`Mcthazolamide
`(0.05)
`
`~» “
`PVP
`HPMC
`CMC
`
`PVP
`HPMC
`CMC
`
`-
`PVP
`HPMC
`CMC
`
`PVP
`HPMC
`CMC
`
`~~
`PVP
`HPMC
`CMC
`
`-—
`PVP
`HPMC
`CMC
`
`Polymer
`
`18.6 i 0.4
`20.5 :1: 0.8
`20,2 $1.5
`l9.l i 0.!
`
`20.5 i 0.8
`20.2 1 l.S
`l9.| i0.l
`
`18.6 ¢ 0.4
`20.5 3: 0.8
`20.2 3; LS
`19.! $0.!
`
`20.5 ;+_ 0.8
`20.2 i L5
`l9.l 10,!
`
`l8 6 1 0 4
`20.5108
`20.21 |.5
`I91 1- (H
`
`I8 6 1 D 4
`20.5 1; 0.8
`20.2 :1: L5
`l9.li{l,l
`
`Sulfamethoxazole
`(0.36)
`
`l8.6 t 0 4
`-
`20.5 1 0.8
`PVP
`20.2 351.5
`HPMC
`I9 I :0 l
`CMC
`wm WN~
`
`Both polymer and drug
`
`26.01: 0.6
`26.6 3 2.8
`36.8 3‘; 68
`26.8 31.9
`
`24.9 3 0.4
`212 3; (L2
`244};0t4
`
`2841 3; 0.0
`48.4 is 0.1
`53.3 :§- 2.5
`38.25240
`
`24.9 3%; 0.4
`25.2 :1 0.2
`24.4 2 0.4
`
`25.5 3, 3.5
`28.52: 0.5
`350326
`370.: 3.0
`
`360g 0.7
`29.0 '3; 2.2
`323
`3.2
`5l.l:§0.3
`
`38.8 gt; 0.3
`48 0 1?; 2.8
`53.0 3 2.0
`4193.28
`
`L4
`1.4
`2.0
`3.4
`
`1.3
`L4
`L3
`
`1.5
`2.6
`2.9
`2.1
`
`1.3
`1.4
`1.3
`
`L4
`L5
`L9
`2.0
`
`M
`3.6
`l.7
`2.8
`
`2.1
`2.6
`2.9
`2.3
`
`The solubility is the mean of at least three determinations 1 standard deviation,
`“ Solubility (in mgsrnli of the drug In pure water at room temperature.
`" Solubility of /!CD in aqueous solution saturated with both drug and /{CD divided by the intrinsic solubility of [ICU in pure water
`“ No polymer.
`
`flCD in aqueous 0.25% HPMC solution which
`has been saturated with carbamazcpinc was deter-
`mined to be 53.3 mgiml. The individual contribu-
`tions calculated from Table 2 are as follows: (a)
`the intrinsic solubility of {JCD contributes l8.6
`mgfml.
`(b)
`the HPMC~- ,11CD interactions con-
`tribute 1.6 mgiml. (c) the carbamazcpinc-flCD
`interactions contribute 8.2 mgfml. and (d)
`the
`HPMC carbamazcpine « /3 CD interactions con-
`tribute 24.9 mgfml. Only a very small amount of
`HPMC had to be added to the system to obtain
`this solubilizing effect (Fig. 2).
`
`3.3. C0nzple»\’atz'on eflcacy
`
`The polymers increase the aqueous solubility of
`/} CD without decreasing its ability to form inclu~
`sion complexes. Actually, in most cases, the poly»
`mers increase the complexing abilities of /ICD.
`For example, Fig. 3 shows the effect of CMC and
`HPMC concentrations on the carbamazepinc in-
`corporation into /JCD, i.e. how many milligrams
`of carbamazepine forms a complex with one gram
`of /JCD. It can be seen that addition of a small
`amount of the polymers dramatically increases the
`
`Page 5
`
`

`
`120
`
`T. Luflsson. H. Frl€lrik.rcIzlm‘r,"Imermnlonui
`
`./oumul of Plmrnmccimn [63 (I998) 11313131
`
`%é A
`
`ceuxohmidc Hemuohmfle Bcunuolo
`
`h %
`*5.
`
`*-J G
`
`9\ O
`
`U‘! 3
`
`It 9
`
`biLicac
`
`
`
`B-Cyclodcxtrinsolubility(mglml)
`
`0
`
`0.1
`
`0.2
`
`0.3
`
`HPMC concentration (‘fa wlv)
`
`use
`
`140
`5
`120
`._—_.
`3 '3 mo
`Ha
`§t2 "
`«-3 so
`Drug
`mi.56
`
`Fig. 2. The effect of HPMC concentration on the solubility of
`/ICD in an aqueous solution which is saturated with both
`/t’CD untl curbamazcpine.
`
`incorporation. Maximum incorporation was
`about
`IOO mg earbamzizepine per gram /}CD.
`which was obtained in 0.075~~0.25% (wfv) HPMC
`solution. HPMC significantly increased the incor-
`poration of acctazolamide into /.?CD but PVP was
`better
`for both mcthazolamide and cconazole
`
`In our study /XCD was a much better
`(Fig. 4).
`complczting agent
`than HP/1CD (Fig. 4). The
`polymers were also able to enhance drug incorpo-
`ration into ;'CD (Fig. 5). Thus, this effect on drug
`incorporation appears to be a general effect of the
`polymers on CD cornplexation. as previously
`shown in the case of HP/1CD (Loftsson et
`‘.11.,
`I994).
`
`Fig. 4. Drug incorporation into HP;?CD and fiCD and the
`effect of addition of 0.25% {aw-v) PVP or HFM-C on drug
`Incorporation into /3CD.
`
`4. Conclusions
`
`The aqueous solubility of/ICD in pure water is
`only l8.6 mg,-‘rnlt However,
`its
`solubility in
`aqueous drug formulations will
`increase signifi»
`cnntly upon formation of inclusion complexes
`with drugs or complex formation with water-solo»
`ble polymers. The polymers not only solubilize
`/1CD and its complexes, but they are also able to
`enhance formation of complexes between drugs
`and /JCDI Thus,
`it should be possible to form
`aqueous drug formulations containing a water-
`soluble polymer and up to 5 or 6% ;9CD in
`solution.
`In such solutions, [fCD could be as
`effective a solubilizer as l0»~15% solution of some
`
`120
`
`200
`
`I-l 6 6
`
`
`
`Incorporation(mglgIl—cyclodextrin)
`
`% 5
`
`v
`__,,.....----- I]
`
`‘BOD
`
`0
`
`0.2
`0.1
`Polymer concentration (% W/V}
`
`0.3
`
`
`Drug
`
`incorporation_(mgdruglgcyciodexlnn)
`
`I-D U! §
`
`u:8QG
`
`Fig‘ 3. The effect of CMC I_§«1.;?) and HPMC (6) concentration
`on carbumazcpinc incorporation into BCD.
`
`Fig. 5. E|Tccl of nddition of 0.25% (wjv) CMC. 0.25% (wiv)
`PVP, or 0.10% wiv HPMC on the incorporation of carbu-
`mnzcpinc and hydrocortlsenc in n lyophiltzed yCD complex.
`
`Page 6
`
`

`
`'1'. Lrzflxsan. ll. Fribrikwltirtir International ./uurnul of I’l1arnmcc'm'ic.x' /63 (I998) II5~/ I21
`
`l2i
`
`of the more water-soluble /ICD derivatives. Fl»
`nally. addition of a watcr—solublc polymer could
`also enhance the efficiency of the complexation
`when solid /{CD complex powder is produced by
`kneading or co~grinding at elevated temperatures
`(Loftsson and Brewster, I997}.
`
`Acknowledgements
`
`for this investigation from
`Financial support
`the lcclzmdic Research Council
`is gratefully ac-
`knowlcdgeci.
`
`References
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`Page 7
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`Page 7