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`Page 1 of 10
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`SENJU EXHIBIT 2139
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`LUPIN v. SENJU
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`Page 2 of 10
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`

`
`Surfactant Systems: Their Use in Drug Delivery
`
`M. Jayne Lawrence
`Department 0/ Pharmacy. King's College London, University of London. Manresa Road, London SW3 6LX
`
`1 Introduction
`Molecules or ions which are ampltiphilic. that is. contain both it
`hydrophobic and hydrophilic part. in aqueous solution fro-
`qucnlly assemble at interfaces and scll’-associate in an attempt to
`sequester their ttpolar regions from contact with the ztqueotts
`phase. This sclf-aasocitttion gives rise to it rich variety of phase
`structures (Figure l). Aggtcgation is not. ltowcvcr. just limited
`to aqueous solution; it is sometimes observed in non-aqueous
`polar solvents such as ethylene glycol and non~polttr solvents
`such as hexane (in the latter case giving rise to inverse
`structures).
`Over the years several of the phase structure: produced by
`surfactants have been of interest to the phartnttccutical scientist,
`either as drug vehicles/carriers or more recently as largetting
`systcms. in the former application the surfactant system takes
`no part in the biodistribution or tit’: drugit carries. acting purely
`as the vehicle. In the second case the surfactant system in some
`way ‘convt-ys' the drug to the desired (or target) site in the body
`and deposits it. Targctting can taltconc of two forms: namely
`‘p.-tssivc‘ targctting which relics on the natural biodistribulion of
`the carrier, or ‘active’ targctting in which the carrier is in some
`way directed to the desired site. frequently by tltt: use of
`targctting ligands expressed on Ihc surface of the carrier. Both
`types of targctting have the advantage of protecting the body
`from any tmw_antc_d sidc-cfl'ccts_ of the drug. )vh'ilc_ at the same
`tim‘c achieving the desired concentration or drug at 'thc‘tar3ct
`site’.
`By far thc majority of work cxaniining thc potential of
`surfactantsystems in drugdclivery hasexplorcd thciruséns drug
`carriers; for cxantplc non—ionic miccllcs have bccn widcly inves-
`tigated as a‘ rncnns of producing a clear’ sttiblc ‘solution of a
`poorly water-soluble drug suitablt: for intravenous or oral
`administration.‘-1 Howcvcr. during the past't\v<:nty year: or so.
`as the importance ofdrug targcttinghas bccnrcalizad. tt number
`ofsurfnctant systems. such as phospholipid or non-ionic surfac-
`tant vcsiclcs. have been extcnsivcly invcstigalcd as targctting
`systems.-'
`.
`Despite all the research into the potential use of surfactant
`phase structures for drug delivery. such plittsc struclurcs havc
`not made much ofan impact on the formulation sccnc; there are
`
`
`
`M. Jaymv Lmt-t-em-e grmltmretl
`.
`-
`
`
`
`in Plmrmat-_l' front Liverpool
`Polym/mic (-B.Sc-.)
`in I98]
`and qurtlflicd as (t member of
`the Royal Pharnmcettlical So-
`ciety Q/'Crt-at Britaitt in 1982.
`She _'rr.'t'cI'ved ltrr I'lt.D. rlegrtc
`iu /985 from the UuireI.st'I)- of
`.WtlIl(‘Ilt’.l‘l(I. Sittcc I984 S/It‘
`lmr been a Lt’Clm't'I‘
`in I/It’
`Pltarnmcy Departmcrtl. King '3'
`Callege’ Lonrluu. Ilcr I¢.\’l'lIl'(‘,l
`itttcrtrxts cover (he rlulgn, syn»
`tltcais.
`am! pitta-i4H'Itcrt1icrtI
`t‘Itarut.'lcI't':uH'wt of .vur_/ttrlrutl
`.ry:rmn.t
`and
`munI)rnn0
`Irrmsporl.
`
`only at low murkctcd prcpu rations that coukl hc considcrctl to he
`drug-containing sttrfactmtt systems in either the United King-
`dom or the United States. Consequently, the true potential of
`surfactant fomtulations. particularly of non-ionic surfactants.
`has perhaps not been fully realized. In order to appreciate the
`potential and also the lintitutiottsolsuch systcmsun understand-
`ing of tile phase bcltuviour of sttrfttctants is cssetttial. Thu
`fotlowittg account therefore describes the phasc behaviour of
`zsurlactants with reference to their pltysico-chcmical propcrtics
`relevant to their use as drug delivery systems. it also dctailssomc
`ofthcwork performed to date investigating the use ofsurfactnnt
`s_vstcms— in particular. those produced from the less toxic Hull-
`ionic surfactttnts — for drug delivery.’
`
`2 Phase Behaviour of Surfactants
`2.1 Equilibrium Phase Structures
`Although surfactzmtssclf-associate in a wide variety ofsolvcnts.
`their stale of aggregation varies considerably between ‘solvents
`(Tablet). As watcr or a- buffered ztqttcottssolution is the usual
`continuum for most drug delivery systems. it is important to
`understand ‘(and predict) the range of equilibrium phase struc-
`turcs commonly encountered in such solutions. Mention will be
`made of the phase structures encountered in othcr solvents
`where appropriate.
`When a surfactant is dispersed in watcrjust above the limit of
`its aqueous solubility (i.r. above its critical tniccllc concent-
`ration, crnc) it generally aggregates, depending upon its molecu-
`lar geometry.’ into one 01' four types of structure, namely the
`iso'tro'pic’ miocllar p'ha'sc.an<l the liquid crystalline hcitagottnl.
`l:tmellnr,nnd cubic phases. Thcnforcmcntioncd phases. with the
`cxccption of the lnmcllur phase, can either be in a normal or
`rcvcrsc-orientation. Rcccnlly, in addition to lh¢‘5t:' commonly
`encountered phase structures; there has been an increasing
`number of more unusual aggregates. such as helical bilaycrs°
`and_fi_b_rc gels’ rcportcd.
`Upon increasing the surfactant concentration well above the
`cntcthcrc arc gcncrally changes in aggregate or phase structure.
`' The ordcrofphnsc structures formed upon incrutsingsttrfactant
`concentration generally follows a well-dctincd scqucncc (Figure
`2) with a ‘mirror planc‘ through the lamcllar phase. such that
`normal phase structure: can be considered to be ‘oil-in-water‘,
`while rcvcrsc slructurcs can be thought of as-'tvntct~in~oi|'.’
`Most surfttctants. howcvcr. exhibit only a portion of this
`sequence. dependingupon the aggregate type initially formed at
`the cntc-and the resulting. intcraggrcgatc forces cxpcricnccd.’
`Although the samc~phasc structures are observed in other non-
`aqucous polarsolvcnts, the scqucnccof phases is sometimes very
`dillcrcnt and appears to dcpcnd both upon the molecular
`geometry and the nature ofthc polar hcad—soIvcnt interactions.
`
`2.] .1 lntpIIcrtIt‘mt.t/‘or Drug Delivt-r_t'
`An understanding of the phase behaviour of surfactants is
`essential for the cllicicnt use of surfztcc active systems in drug
`delivery. For example. after introduction into the body the
`surfactant system may. depending upon its route of administ-
`ration, undergo 3 large dilution.
`ll‘ the surfactant is diluted
`below itscmc, precipitation of transported drugmay occur. This
`precipitation may have very serious consequences. cspccially if
`
`til’?
`
`Page 3 of 10
`
`

`
`M3
`
`CHEMICAL SOCIETY RE\’lF,\VS. I9‘)-1
`
`
`
`
`iltttttuttt
`llttltlttttl
`ililiiiiiiilllllili
`
`Lnmellur Phase
`
`Ruvcrsc Hexztgonttl Phase
`
`Reverse Micelles
`
`Figure 1
`
`
`Tablet Sell‘-association in solvents
`
`‘
`Class or
`Type of Aggregate
`Exantblcnfclttss
`solvents
`Class A Wnter. glycerol. cthylerte’glycol' Normal
`Class B
`tlcxnne. benzene, eytrlohexane
`Reverse
`
`Class C Methanol. ethanol No aggregate formation
`
`the drug is being administered intravenously, ldtxtlly therefore
`the core should be a low as possible in order to avoid such
`problems. Surfactants thatlurm lamcllar phitses_-at-.1hci_r cine
`generally do so at much lower cortctmtrntionsthun those s_urfae~
`tants which initially form nticelles..Si‘n¢e non-ionic surfactants
`generally exhibit lower cmc‘s than ionic surl‘;tct:mts~ they are
`preferred for the purposes ofdrug delivery. especially when a
`miccllar solution is being ittvestigated as the __drug deliycry
`vehicle. In :1 similar vein, it',:t concentrated surfactant‘ solution is
`administered it may experience a sufiicicnt dilution to induce a
`phase change, suy for example-from yan hexagonal to ,1 micellar
`phase. As the drug-carryingvcapucity ofeaeh aggregate type may
`dilTcr. such a phase change "could have very serious implications
`
`such as dose dumping within the body. When considering using
`a surt':tctant system as‘ a drug delivery vehicle it_ should also be
`borne in mind that phase transitions cattyalso be induced by a
`change in temperature and that normal human body tempera-
`ture istypieally l2 degrees above ambient. Other problems to be
`aware of are hysteresis effects. These are pitrtleularily common
`in cubiephases and may have important consequences for drug
`delivery. For example. certain cu,l_:aic phases have been shown to
`be pseudo-stable for very long'perie‘ds’at temperatures at which
`some other lotm of aggregate would normally be l'o_rmed.°
`A knowledge of the various biological surface-act'ive agents
`which the surfactant aggregate may encounter in vitw is also
`essential as these may alter or even destroy the aggregate. For
`example the endogenous miccllc-forming bile snlts encountered
`in the small intestine have been shown to solubilizc orally
`adntiiiistcred liposomcs. thereby releasing any w':ttt:r'-.soluble
`solute trapped inside the carrier.
`
`2.3 Modified Phase Structures
`in addition to the cquilibritun phase structures mentioned
`above, there are a few non-equilibrium and modified surfactant
`phase structures that are currently finding npblimtion in‘ drug
`delivery.
`
`lricrcasingsttrfnctant concentration
`‘oil-in-water‘
`.
`‘water-in-oil‘
`‘mirror plrtnc‘
`
`I
`I
`r
`'
`.
`In
`1
`r
`H30 Micellc (L, ) <l-lexagonul (ll,)< Lamellnr (l.,)< Reversed Hexagonal (H ,)~f Reversed Mioelle (L1) Solid
`g
`I
`
`tI0
`
`Cubie tr.)
`
`Cuhil: tv.)
`
`cut>sc'tv..)
`
`Cubii: (1,)
`
`Figure 2 ldeulized phase st.-qucucc in surI'aelunt—watcr systems. (Modified from reference 6: terminology as in rel'crr:nee 7.)
`
`Page 4 of 10
`
`
`he
`
`Surfactant Molecules
`
`Spherical Micellcs
`
`Hexagonal Phase
`
`

`
`SUR FACTANT SYSTEMS: THEIR USE lN DRUG DELlVERY—M. J. LAWRENCE
`
`«M9
`
`2.3. I Ve.rit‘lc.t'
`
`Vesicles are generally formed bydispcrsing lamellarphnses in an
`excess of water" (or non-aqueous polar solvents such as ethy-
`lene glycol. dimethylfornmniide). or in the case of reversed
`vesicles in an excess of oil.” The resulting vesicles are approxi-
`mately spherical structures dispersed in a water or an oil
`continuum. Vesicles produced from phospholipids have been
`widely investigated as drug delivery vehicles. Unlike the phase
`structures mentioned earlier, however. these non-equilibrium
`structures are prepared using methods such as -soniention and
`will eventually rc-cquilibrate back into the tnmettarphascs from
`which they originate." This inhcrcnt
`instability has ‘caused
`considerable problems with the wide-spread commercial exploi-
`tation of vesicular delivery systems. For tt few surfactants.
`however. the vesicular phase is an equilibrium structure; for
`example, the ionic gangliosldc GM3, a glucosidic ttmphlphile of
`biological origin. forms vesicles spontaneously in water.‘ 5 while
`some combinat ions ofnon-ionicsurfactants have been shown to
`form reversed vesicles spontaneously."
`
`2.3.2 Pal)'mert':rdAggr:_gn!c{r
`Attempts have been made to use polymerization to stabilize
`various nascent phase. stmctures. for cxttmple micelles.‘ ‘ cubic
`phases.‘ 9 and vesicles." With the exception of micelles (which
`as yet it has not proven possible to polymerize) polymerization
`of these stntetures gives aggregates exhibiting the significant
`advantage that they do-not sulfcrbrealt down upon dilution in
`viva. However, because of their size (ranging from tens to
`hundreds of nm) these aggregates can cause problems as they are
`not readily ester-cred from the body; ltcriccsutzh systems will
`probably have limited clinical usepalthough they may have it use
`in oral adtnihistration. lnran ztttempt to overcotne the problem.
`biodegrada blc polymerized aggregates-are._presently being inves~
`ligated.“ When preparing drugcontdining polymerized aggre-
`gates it is irnponant to‘.ch‘o‘ose'.the_ approprittte stage fordrug
`addition; adding the-drug ‘b'el'ore polytnerizntiott may cause the
`drug to be irreversibly" bouird in ‘tlic aggregatc.'.\'vltilc‘additioii of
`the drug utter polymerization may lead ‘to low levels of
`entrapment.
`
`2.4 Drug Aggregates
`A number ot"drtt_gs are themselves amphiphilic and may aggre-
`gate into various structures. most frequently sm:ttl=mieellar type
`strnctur.cs.' In lheseeases the. drug nggregatefcoutd act as itsewn
`vehicle. if the drugdoading were not too high. It has been
`postulated that the’I'ormation ofvesicles consisting oi‘.pure drug
`(pharmttcosomes) should also bc—l'eusible.' " Unfortunately-most
`drugs-‘arc not lipophilic cnotigh to_f9r'm t/csielcsfcasily without
`derivatization with materials like fatty acids." However with
`certain drugs it may be" possible" to produce vesicles over a
`narrow pH range using the appropriatclrutio ofam phiphilic salt
`to freedrug. Tho tighteontrol over pH thatwould be necessary.
`however. means that such vesicles areunlikcly to provide useful
`drug delivery system. An alternative -approach to producing
`pharmneosomes has-recently been reported in which a'biode-
`gradnble niiccllc-forming drugzconjunct has been synthesized
`from the hydrophobic drug adriamyciu and a polymer‘ com-
`posed oi‘ polyoxyothylcnc glycol and polyasparlit: acicl." This
`approach has the benefit that whilcit may be possible to dilute
`out the micclle. thedrug will probably not precipitate becauscot‘
`the water solubility of the monomeric drug conjunct. since
`neither of these types 0|‘ dcrivatizcd drug structures consist of
`drug alone. they can therefore not be considered to be true drug
`aggregates.
`
`2.5 Influence oi Oil
`When oil is added to :1 binary mixture of surfactttnt and tvtttcrzt
`whole variety or phase structures may be formed. Several of
`these structures currently have a use in drug delivery. for
`
`example microcmutsions. macrocmulsions, and multiple emul-
`sions.‘ Others such as self~cmulsil'ying systems" and vesicles
`encapsulated in water-in-oil emulsions are at present under
`investi_o,atiort.=‘
`
`3 Choice of Phase structure for Drug Delivery
`Whctt chooslngu phase struct urc for drug delivery a number of
`factors need to be considered. in particular. how the physica-
`clicmiatl properties of the phase structure relate to the intended
`application. If. for example, it surfactant system is required for
`topical use the phase structure chosen should be of sutlieiently
`high viscosity to enable the prcparlttiort to be retained on the
`skin surface. while at
`tile same time allowing it to be spread
`readily over the surface of the skin. in contrast, if a system is
`intended for administration intravenously it should be ot‘sufi‘1-
`ciently low viscosity not to cause pain upon injection. Another
`importttnt factor to be considered is the capacity oftltc aggregate
`for the drug to be incorponttctl. M iccllar solutions, by virtue of
`low sttrfactant concentrations, generally exhibit
`the lowest
`Capacity for drug. while in contrast cubic and other liquid
`crystalline phases can frequently tolerate very high drug load-
`ings.’-"“ Recently it has been rcnlivctl that the toxicity of a
`particular surfactant may depend upon the nature of its aggre-
`gate. For example, the same surfactant has been shown to
`exhibit a significantly reduced toxicity when present in rt vesicu-
`lar as opposed to a miecllar solution.
`Table 2 gives some of the physico-chemical characteristics
`itttportrtnt for formulation purposes together with the possible
`pharmaceutical applications of each phase structure. it should
`be noted that while Table 2 gives the average properties of each
`pltosc, the variations in each case maybe quite significant. For
`example; while solutions containing .rpIterle'aImit:cllcs generally
`exhibit low viscosities, those containing lo_)tg rmlslmperi micelles
`frcquently exhibit very high visoositics. Similarly. cubic -phases
`cantdisplay a‘ widcrange ofstlilncss; sorncsamplcs nreashard as
`plexiglass, while in others the phases are suflicicntly flexible that
`they almost "flow."
`ltqis-important when considering the use of surfactant phase
`structures as delivery vehicles to remember that a surfactant
`aggregate cannot be considered an inert carrier. and that the
`drug and indeed other additives such as preservatives and
`llovourings" may (depending upon thettmount present) drtt~
`matically alter the en-tc and, in some cases. the type and range of
`aggregates fommcd. Unfortunately very little work has-been
`performed in this area and is difficult to predict the effect of a
`drug (or indeed any othcr__aclditivc)Aon a phase structure as it is
`expected to vary according to whether the additive'(a) is water
`soluble, (in) adsorbs at the aggregate surface. (c) coaggrcgtttcs
`with the surfltctnnt, or (d) resides in the intcriorof the aggregate.-
`Evidence suggests, however. that the phascstructure experiences
`themostdisrttption when the additive is itsc|l'surt‘aeeactive. For
`example, the presence of the drug lignocainc hydrochloride at
`concentrations greater than about 5 Wl% converts tltecubic
`structure formed from 10 wt% monoolein in water into it
`lamellarpltast:'°Theinilucnocoi’thc presenceofdrugis fttrthcr
`complicated becnusernost drugs are administered ussttlts, hence
`the ‘amount of amphipltilic Still to lipophilit: free drug varies
`according to pH. Consequently the etfcct oi‘ the drugon the
`plntse structure may vary with the pH of the surrounding
`environment. This circct is more likely to be significant if ionic
`surfactants are used. Yet another complicationis thutif the drug
`promotes ti phase transition. this transition may conceivably be
`reversed as the release ot'a surface~activc drug from the aggre-
`gate proceeds.” This phase reversal may lead to two ditfetcnt
`patterns of drug release.
`
`I-‘lavnurlngs are very important it’ surtnetants are to be given or-.rlt_r: min.
`'
`tartts do not taste very pleasant.
`.-\lsn. because at their elftct on trtclntrmzs.
`suit‘-ttcunts may numb the p.uticttt'x mouth.
`
`Page 5 of 10
`
`

`
`430
`
`
`CHF,MlC.«\L SOCIETY RF,VlE\‘\"S. 1994
`
`
`
`
`
`
`
`
`Miccllcs
`
`
`
`Ararat-ztrttttcl:
`
`Cluttf. ttun-bireftlttgc in
`
`
`
`\’i-.;cmtit3'
`
`Low
`
`Least \'l5l.'nl|S phase
`
`
`
`
`Staluhilimtion Capacity
`
`
`Low — ttlttphiphillc and non’
`
`
`polar solutes only
`
`
`
`
`
`
`Possible Use
`
`
`Solution for most routes of
`
`
`
`
`
`clelis-cry
`Protection ofluhilc
`
`
`compounds
`
`Viscous prertorrttiott for
`
`
`
`sustained release
`
`
`itttrnrnusculur.
`sithcutatncous. om] ‘a nd
`
`topical
`
`Protection oflahilc
`
`
`
`cornponncls
`
`Sustained release.
`Prohubly high - tmtphiphilic
`
`
`
`
`
`um! nmhpnlatr solutes
`pttrliculmly topical
`
`
`
`
`
`Low — \\':ill.'r-sohlbll: solutes
`
`
`Sttstnitted release,
`ilttlpltlpltilic
`Prnh'.thlyEtl_t;l1
`
`
`
`
`mid non-pt:tl:tT solltlcs
`pttrliculatzly topiutil
`
`
`
`
`
`Low - w;tlt:r-soluble Solutcis
`
`
`Most routes OF
`liiglt - amphipliilic and :1m:- FlIifl)‘l0W
`
`
`
`
`
`
`
`
`['lI‘Jl‘.ll' solutes’
`Generally less
`:tdmutt5lr:t[i_on except oral
`
`
`
`
`
`
`Low -. willCl'-5Dllll‘Ill.‘ solutes
`than I0 wt%
`
`Protecti'on'ul' irtbiit:
`
`
`
`
`
`
`compounds
`
`
`Not lcnnwn
`Solid dispersion Fnr oral use
`HID wt°.a‘g
`Still’
`W :13;3! solid
`Solid
`
`
`
`
`
`
`
`
`
`
`
`
`' The solubitiautiutt cur.-:n:it3: record ad here rel‘;-rs towresieles pruiltuml by no ts-t-qutlil-rittm I'l1IHl1D|‘]Si1l'|I)S\! formed :|1onI:mr¢ms|)r :I‘rc expocled to ex hiisil very low
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`('«'J[}2lI!ll}‘ I'IJr ntnrilliphille and non-pt:-Inr drug-r (see Section 5.4].
`
`
`
`
`
`
`
`
`
`Table 2 some ph}-sieo-cltemicatl properties and potential pltttrtn::ct::ttit::il ttpplicatiorts ol'sctrl‘:tt:u1nt phase structure
`
`
`
`
`
`
`
`
`
`
`
`SurJ‘:ict:mt
`Phnse
`
`
`structure
`Concctuxzt lion
`
`
`l'l—-25"!»
`
`
`
`
`
`Cubic Phttsc
`
`
`
`Clerir. non-hirclrisigcitt
`
`
`
`Very high
`
`
`Most viscous pltttse
`
`
`
`
`alltpltiphllic and min-
`High
`
`
`
`
`p0lill' solutes
`
`
`Law ~ \\r'llll.‘I‘-5(1ltll‘llT soltttcs
`
`
`
`Varies
`
`Generally greater
`
`
`llllln 30%
`
`
`
`Itlcxugunal
`
`
`CIcur.r'cIou:l_t-hirtfringertl
`
`
`
`
`\’i§cous
`
`
`Lztmellitr
`
`
`Vesicles
`
`
`Clt:ttr,.'C'!tJut.l 3'
`
`hirelringeltl
`
`
`Frtirly viscous
`
`
`
`Clenrjcloudy birefrittgettl Low viscosity
`
`
`
`
`
`\'r'ir.li: range possible
`
`
`
`
`Vltlltle rtIt‘l_E__C pnssihlc
`
`
`
`
`
`
`4 Choice of Surfactant
`
`
`
`
`'wl_de'raoge of biological,
`Surfactants are well known to exert at
`
`
`
`
`
`
`
`pltortnacologicztl, and 1oxicol_ogir:.-t_l t:J’l'ectti _0n_-titan.‘ Tliercfore
`
`
`
`
`
`
`
`the-single ntost.impo'rtttnt l‘ac_tor- lntltc choice are sttrfacltttil. or
`
`
`
`
`
`
`
`
`combination of -sur[:_1ct‘:1nts,
`is ‘toxicity. Unfortunately tltis
`
`
`
`
`
`
`
`property ishartl to assess. The reasons for this are many. not the
`
`
`
`
`
`
`
`
`
`
`
`least being the dillieully in finding trn-u;'>pro'priai_e' measure of
`
`
`
`
`
`
`
`
`
`toxicity,-especially when screening new su_r‘_[}tclan'ts. Generally‘.
`
`
`
`
`
`
`uctrte oral ,to:tl:_:olo_gical-studies are routinely perform'ed. on all
`
`
`
`
`
`
`
`
`new suI‘l'1cl:_tnts regardless of their intended 1:_ts_age. Altliough
`
`
`
`
`
`
`
`
`tltis'inl'ormt_t1iort is valuable it cannot. adequately predict cltronic
`
`
`
`
`
`
`
`
`
`toxicity.-A fttrther complication is the unjdcrstnurl:t_ble_-rr:lue-
`
`
`
`
`
`ttmce ofithc Pharmaceutical Companies to enter into the full
`
`
`
`
`
`
`
`
`
`scale chronic toxicity studies ucedert For as properasscssmcnt ofa
`
`
`
`
`
`
`
`
`
`new surfactant for drug delivery pup-poses;.:t
`toxicity stud);
`
`
`
`
`
`
`
`
`currently costsin the order oflllrnilliort GB pounds. Dnlya very
`
`
`
`
`
`
`
`
`
`
`
`
`limited number of su'rl'rt't:tu'nts -"uric" geiterelly considered for
`
`
`
`
`
`
`
`formulaliott purposes. Usually only those surfactants are usctl
`
`
`
`
`
`
`
`
`that have been used in pharmaceutical [orrrtulations for many
`
`
`
`
`
`
`
`
`
`
`yeursartd are therefore generally recognized as sal‘c,_even though
`
`
`
`
`
`
`
`
`
`some of these "surfactants may thentselves not havehcen tested
`
`
`
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`
`
`
`
`
`
`for cltronic toxicity!
`
`
`
`From -.1 toxi,colog_i<:al point of view, non—ionic surl‘ttct't1nt5,,:tre
`
`
`
`
`
`
`
`
`generally regarded as the most suitable for phamtaceutical
`
`
`
`
`
`
`
`
`formulation-. l -1 Even so the range of non-»ionit: surfacttttits used
`
`
`
`
`
`
`
`
`
`
`
`is very limited. Tweet: 80 [polyoxyerhylctte (21)) S0l‘l£}ll£'lJ1 mono-
`
`
`
`
`
`
`
`
`olejrl ether) and Crcmorpltor EL jpolyo:-tyelhylcne {till} castor
`
`
`
`
`
`
`
`oil] aI1:_-probably tho two most cornnton. There are, liowcvar, -:1
`
`
`
`
`
`
`
`
`
`large number of non-ionic surfactants commercially awttilabltr.
`
`
`
`
`
`
`Sotrte of the more common examples are shown in Table 2. A
`
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`
`
`sttrlztctnnt is.cotnposed oi'tl1'rcc distinct porlion_s:':t ityclrophilic
`
`
`
`
`
`
`
`littlter.
`:1
`ltydrophobic portion,
`ttnd ll
`.-icnti-polar
`segtttcttl,
`
`
`
`
`
`
`
`
`Consequently it is tlteoreticully possible to join together any
`
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`
`
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`
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`combination ol‘ segments to produce :1 surfttclant with the
`
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`
`
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`required properties: for example hiodegrtttlrthle sttrluclztnts can
`
`
`
`
`
`
`
`be rcztdily ztclric-red b;.- the‘ use olatn ester |irtl::igc_ while bll:1}'_{:r
`
`
`
`
`
`
`
`
`
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`(vesicle) and micellc l'orming s:url‘aet:mis can he prod uced from
`
`
`
`
`
`
`
`
`
`dialkyl and ntonottlltyi cltttin surfactants respectively. Despite
`
`
`
`
`
`
`
`the wide range ofsurfactanls potentially nvailalJle,mos_t workers
`
`
`
`
`
`
`
`
`
`tend to use surfactants that have been pr'eviousl3.- used in
`
`
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`
`
`
`
`
`
`
`lorrnttlutiott. thereby limiting themselves considerably. There is.
`
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`
`
`however-. at real need to produ_ce'nc'_w- surlhetants in ordcrjo
`
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`
`
`realizejtlte full potential of surfactant s}_rs_te_ms_ita drug delivery
`
`
`
`
`
`
`
`
`the number of surlaclanis that can bi: synlhesiitd is
`Yet
`
`
`
`
`
`
`
`
`
`enormous. In an attempt to address the. prc-_bl_em_ of eiesigzt and
`
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`
`
`
`
`S)'[1l.l)C5lS of new l_:t’.oco:npet_il:tlo surfaclanls,
`a phagrtim
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`
`
`
`
`
`
`VES1CA3’ has been developed with. a View to predicting which
`
`
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`
`
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`potential surfatctttnts would prefetentittlly form a particttlair
`
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`aggregate type. In this way the n1ttnber'_ol"sttrf:_1cl‘:tnts that need
`
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`
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`to be synthesized could he gn‘:atl:,- reduced.
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`
`
`5 Phase Structures in Drug Delivery
`
`
`
`
`
`5.1 Normal Mlcellcs
`
`
`
`The increased solubility in n miccllar solution of on organic
`
`
`
`
`
`
`
`
`
`
`substance-._ insoluble or sparingly soluble in water,
`is _t_t well
`
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`
`
`
`
`
`
`established phenomenon. Indeed the soluhiiization of w;t'tt:r-
`
`
`
`
`
`
`insoluble drugs by nticellcshaslong been i_mrcstig‘ated as it mcatts
`
`
`
`
`
`
`
`
`
`
`of improving solubility for drug delivery,
`in particular" for
`
`
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`
`
`
`
`
`
`parenteral or oral admittlstration, but also for opltthalmic,
`
`
`
`
`
`
`
`
`topical, rectal, and nasal delivery.‘-1 The protection oflabilc
`
`
`
`
`
`
`
`
`drugs from the environment
`tltrouglt soluhilizatioh within
`
`
`
`
`
`
`
`micelles has also been examined. Consttqucntlgr an enormous
`
`
`
`
`
`
`
`
`nuntberolpapcrs cxaminethc incorporation ofa wide variety oi‘
`
`
`
`
`
`
`
`
`drugs into micelles-Tonned from :t largc'wtrie_t3r ol‘. surfajctants,
`
`
`
`
`
`
`and in prtrticttlar non-ionic sttrlfactantsol the type shown in
`
`
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`
`
`
`
`
`
`Table 3.‘-’ There are. howtztrct‘. only a_ few products '01!" ll!!!
`
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`
`
`
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`market that can be-considered to he miccllar systems. This is
`
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`
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`mainly because solubilization capacity is usually too l_on- to be
`
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`
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`of practical use. with only :1 Few mg ofdrug solutrilizcd per g of
`
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`
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`sorFact:tnt. fits the average doseof a drugis in the order ohens of
`
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`
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`mg and. as the concentration of the mieel]at'-solution-is never-
`
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`
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`more than 20 wt‘?-'3 surfactant. this means that solubilization is
`
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`
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`not feasible except in :1 I'ewlnstanceswl1erc'very potent lipophilic
`
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`drugs, rag. testosterone. are incorporalcd.
`
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`Atlcmpis lmve been mtuic to design non-ionic —surFnclzints
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`
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`with :13’: improverl trolubiliztttion capacity. An early approach
`
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`
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`involved the rtrodttction ollarger micelles. Despite an increnw
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`miccllc size. sol ubilizution decreased upon lengthening the hyd—
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`ropltobic chain;
`this decrease was attributed to deleterious
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`Page 6 of 10
`
`

`
`SURF/\(.'T+\l’~."l’ SYSTEMS: Tl-lEl_R USE IN DRUG DELlVlZRY—~M. J. LAWRENCE
`
`-l2l
`
`ing to the limited cvitlcttcc ttvttilttblc. micellttr sohtbilizittion
`reduces the rate of mass tnmsfer of most drugs across inert
`membranes.‘-3 In the body this ellect appears to be counter-
`balanced by the fact that the surl‘-.tctnnt can frequently incrcnse
`ntembranc pcrtnenhility.
`
`5.2 Cubic Phases
`Cubic phases have received a considerable attnottnt of ttttention
`as puttttive drug delivery s_vstcms.'°-3’-W V3’ One interesting
`cubic phase is that formed by the polyoxycthylenc-polyoxypro-
`pylcnc co-block polymer. pluronic F I37. This pnrticttlurly
`tttlraclive system has at high solubilizing ertpttcityttnd isgenerally
`considered to be relatively non-toxic. in aqueous solution. all
`cottcetttrtttiotts grcttter than 20 wt%, F127 is truusfomtetl upon
`treating from a low viscosity trttnspttrent (mioellur) solution lll
`room tcmpcrttture to it solid clear gel (cubic phase) at body
`tctttpcmtttrc. Other members oI‘the plllI‘0l1lCSl!l'lCS also undergo
`a liquid to gel transformation ttt around body tern pcroturc. but
`only all higher surfactant concentration: (namely 30 wt% and
`:tbovc).’~‘ This thermal gclzttion, which irreversible upon cool-
`ing. has it number of important ttpplictttio'ns.in drug delivery.
`Forexztmple. at solution poured onto the sltin orinjcctctl into the-
`body will gel to form it solid sustained release depot. Further-
`more. since the gelation is reversible, removal from the skin is
`fztcilitzttcd by simply inuncrsing. or irrigating the skin with cool
`tvntcr. Removal from :1 body crt