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`Page 1 of 10
`
`SENJU EXHIBIT 2139
`INNOPHARMA v SENJU
`IPR2015-00903
`
`

`
`Chemical Society Reviews
`
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`
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`Page 2 of 10
`
`

`
`Surfactant Systems: Their Use in Drug Delivery
`
`M. Jayne lawrence
`Department of Pharmacy, King's College London, University of London, Manresa Road, London SW3 6LX
`
`1 Introduction
`Molecules or ions which are amphiphilic, that is, contain both a
`hydrophobic and hydrophilic part, in aqueous solution fl'c(cid:173)
`qucntly assemble at interfaces and self-associate in an allempt to
`sequester their apolar regions from contact with the aqueous
`phase. This self-association gives rise 10 11 rich variety of phase
`structures (Figure I). Aggregation is not. however, just limited
`to aqueous solution; it is sometimes observed in non-aqueous
`polar solvents such as ethylene glycol nnd non-polar solvents
`such as hexane (in the IaUer case giving rise to invcr~c
`structures).
`Over the years several of the phase strucLUres produced by
`surfactants have been of interest to the pharmaceutical scientist,
`either as drug vehicles/carriers or more recen1ly as tar.geitilig
`systems. In the former application the surfa~tant system takes
`no part in the biodistribution of ihe drug it cartics. acting purely
`a;; the v.chicle. In the second case the surfactant system in some
`way ·conveys' the drug tqlhe desired (or target) site in the b~dy
`and deposits it. Targetting can take.oJic of two forms; narne.ly
`·passive' targettingwhich relies on the natural biodisttibution of
`the carrier, or 'active' targelting in which .the carrier is in some
`way directed to the desired site, frequently hy the usc or
`targelling lisands expressed on the surface of the carrier. Both
`types of targetting have the advant<:~ge pfpro.tecting th.e body
`from any unwanted side-effects ofthc drug, while at the ~ame
`time achieving the desired concetHraiiOil of drug at the tin· get
`sitec.
`By far the maj()rily of work exatnining the potential of
`surfaCtant systems in drug delivery has explored their useiis drug
`carriers; for example non-ionic micelles have been widely inves(cid:173)
`tigated as a moans of producing a dear suiblc sohitiori of a
`poorly water~soluble drug suitable for Jnwavcnous or oral
`adniinistiaticm.'·2 However, during the past twenty years or so,
`as the importance of drug tar getting has been realized, a number
`of surfactant systems, such as phospholipid or non-ionic surfac(cid:173)
`tant vesicles, have been extensively investigated as targetiing
`systems.J
`.
`.
`.
`.
`Despite all the research· into the ·potential usc of surfaciani
`phase structures for drug delivery. such phase structures have
`not made much of an impact on the formulation scene; there arc
`
`1\l. Jayne Ltm(ence gmdlltlletl In Pharmacy front Liverpool
`Polytechnic (B.Sc-,J in 1981
`and quiilifted as a illember of
`the Raval Pharmaceutical So(cid:173)
`cil!tl• of Great Briiain inl982.
`She i·e~·eil•ed her Ph.D. degree
`in 1985 from 1/le Unil•ersiry of
`Manchester. Sini:e 1984 she
`has been a U!cfw·er in the
`Pliarmacy Department, Ki11g's
`College London. Her research
`· iiueresls co\'er the design, syn(cid:173)
`thesis. a/Ill plr.l'sio-d~e~nical
`charm:teri::ati0/1 of swf(tc/a/1/
`systems
`and membrane
`transport.
`
`only a few marketed preparations that could be considered to be
`drug-containing surfactant systems in either the United King(cid:173)
`dom or the United States. Consequently, the true potential of
`surfactant formulations, particularly of non-ionic snrfaclants.
`has perhaps not been fully realized. In order to appreciate the
`potential and also the limitations ofsueh systems an understand(cid:173)
`ing of the phase behaviour of surfactants is essential. The
`following account therefore describes the phase behaviour of
`surfactants with reference to their pbysico·chemical properties
`relevant to their usc as drug delivery systems. It also details some
`ofthc·Workpcrformcd to date investigating the use ofsurfaetant
`systems- in particular. those produced from the less toxic non(cid:173)
`ionic surfactants- for drug dclivery. 1
`
`2 Phase Behaviour of Surfactants
`2.1 Equilibrium Phase Structures
`Although surf.:lc!anL~sCif-associ:Hc in a wide variety of solvents,
`their stale of uggrcgation varies considerably between ·solvents
`(Table 1). As water or a buffered aqueous solution is the usual
`continuum fot ino.st drug delivery systems, it is important to
`understand (and predict) the range of equilibrium phase stwc·
`tures commonly encountered in such solutions. Mention will be
`made of the ph&sc structures encountered in other solvents
`wl1cre appropriate.
`·
`Whe.n a sur(actant is dispersed in water just above the limit of
`Its aqueous solubility {i.e. above its critical micelle .concent(cid:173)
`ration; ctnc) it gcilerally aggregates, depending upon its molecu(cid:173)
`l:ar geomct~y, 5into one of fpur types of structure. namely the
`is(itro-piC miCellar phase and the liquid crystalline hexagonal,
`lamcUni',Und cubic phases. The aforcn1cnti6.ned phases, with the
`exception of the lamellar phase, can either be in a normal or
`reverse oriehtl!tion. Recently, ill addition to these commonly
`encountered phase structures, there has been an increasing
`number of more unusual ,aggregates. such as helical bilaycrs6
`and fibre gels7 reported.
`Upon increasing the siirfaetant concentration well above the
`cmc thcr<; arc gcnenilly .changes in aggregate or ppase structure.
`The order of phase structures formed upon increasing surfactant
`conccntnition generally follows a well-defined sequence (Figure
`2) with a 'mirror plane' through the. lamellar phase, such that
`normal phase structures can be considered to be 'oil-in·watcr',
`while reverse structures can be thought of as· 'water-in-oil'. s
`Most sut;factanis·, ho\vcver, exhibit only a portion of this
`sequence. depending upon the aggregate type initially formed at
`the cmc and the rcsu}(ing intcraggregate forces cxperienccd.9
`Although the same phase structures are observed in other non(cid:173)
`aqueouspolar solvents, the sequence of phases is sometimes very
`ditfercnt· and appears to depend both upon the molecular
`geometry and the nature oft he polar head-solvent interactions.
`
`2.1.1 lllip/fa!iionsfor Dmg Deli1•ery
`An understanding of the phase behaviour of surfactants is
`essential for the cnicicnt use of ourface active systems in drug
`delivery. For example, after introduction into the body the
`surfactant system may, depending upon its route of administ(cid:173)
`ration, undergo a large dilution. If the surfactant is diluted
`below its erne, precipitation of transported drug may occur. This
`precipitation may have very serious consequences. especially if
`
`417
`
`Page 3 of 10
`
`

`
`418
`
`CHEMICAL SOCI.ETY REVIEWS. 1994
`
`,{
`
`iJ
`//
`; !
`
`Surfactant Molecules
`
`Spherical Micelles
`
`Rod-shaped Micelles
`
`Hexagom1l Phase
`
`1mmmmnrr ..
`
`rmmmmmmu
`
`l..<tmellar Phase
`
`Reverse 1-lcxngonul Phase
`
`Reverse Micelles
`
`Figurt! 1
`
`Table 1 Self-association in.solvents
`Class of
`solvents
`Class A
`ClassB
`ClassC
`
`a~amplc .of dass
`Water, glycerol .. ethylene glycol
`H~xaiu:, bcm~eiic, cyClohcxane
`Me! hanoi, cihaiiol
`
`Type of Aggr~ga(e
`Norri1;tl
`Reverse
`No aggregate formation
`
`the drug is being administered intravenously. ideally therefore
`the cmc should be a low as poss.ible in order to: avoid soch
`problems. Surfacranis that form lamellar phases atJhcir cmc
`generally do so at much lower concentrations Jhan those surfac(cid:173)
`tants which initially form micelles. Si·nce non:Cionic surfaclants
`generally exhibit lower erne's than ionic Sur(actanis they arc
`preferred for the purposes ofdiug delivery, especially \Vhen a
`micellar solution is being invesiigated as ihe drug d~livcry
`vehicle. In a similar vein, i(a concentrated surfactant soiution is
`administered it may experience a sulficien( diiution to induce a
`phase dJUnge, say for exampleTrom an hexagonal to a micellar ·
`phase. As the drug-carrying,capacily of each aggregate type may
`differ, such a phase change could have very serious implications
`
`such. as dose dumping within the body. Wbcn considering using
`a sur(actant system as n d~;ug delivery vehicle it should also be
`borne in mind that phase trl\nsitions can also be induced by a
`ch;mge in temperature and that normal human body tempera(cid:173)
`ture is typically 12degrees above ambient. Other problems to be
`aware ofare hysteresis effects. These are particularily common
`in cubic phases and may have important eon~equences ford rug
`delivery. forexample, ccrtaij) cu.bic phases have been shown to
`be.pscud()·stable for very long periods at temperatures at which
`some other form .of aggregate would normally be fom1cd. 0
`A kn(jWiedgc. of .the various biological sorface-adivc agents
`wbi.ch. the surfactant aggregate may encounter ill vivo is also
`essential as these may alter or even destroy the aggrcgaie. For
`example the endogenous micelle-forming bile 56.ltS encountered
`in .the smitll intestine have been shown to solubilize orally
`administered Iiposomes. thereby releasing any ,vater-solublc
`solute trapped inside the carrier.
`
`2.3 Modified Phase Structures
`In addition to the equilibrium phase structures mentioned
`above, there .are a few non-equilibrium and modified surfactant
`phase structures that are currently finding application in: drug
`delivery.
`
`1ncteasing surfactant conccntrntlon ,
`'oil-in-water'
`·mirrof phmc·
`·water-in-oil'
`
`.
`
`H!O Micelle (L,)< Hexagonal (B,)< Lamellar (L,) <Reversed Hexagonal (H 2)< Reversed Micelle (L1 ) Solid
`
`t
`1
`
`..
`
`I
`I
`
`:
`Cubic(l;)
`
`:
`:
`, Cubic(V2 )
`1
`Figure 2. Idealized phase ~cquence in surfaciant-\vatcr syslcms. (Modified from reference 6: terminology as in reference 7.)
`
`t
`I
`
`!
`Cubic(!,)
`
`I
`1
`
`~
`t
`
`;
`Cubic(V 1)
`
`Page 4 of 10
`
`

`
`SURFACTANT SYSTEMS: THEl R USE IN DRUG DELIVERY -M. 1. LAWRENCE
`
`419
`
`2.3.1 Vesicles
`Vesicles arc generally formed by dispersing lamellar phases in an
`excess of water 11 (or non-aqueous polar solvents such as ethy(cid:173)
`lene glycol, dimethylformamidc), or in the case of reversed
`vesicles in an excess of oiL 1 ~ The resulting vesicles nrc approxi(cid:173)
`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, ihese non-equilibrium
`structures are prepared using methods such as sonication and
`will eventually re-equilibrate back into the lamellar phases from
`which they originate. 11 This inherent instability has caused
`considerable problems with the wide-spread commercial exploi(cid:173)
`tation of vesicular delivery systems. For a fc\v surfactants,
`however, the vesicular phase is an equilibrium stnlcture; for
`example, the ionic ganglioside GM3, a glucosidic amphiphile of
`biological origin, forms vesicles spontaneously in water,-' 3 1vhile
`some combinations of non-ionicsurfactants have been shown to
`form revcrscdvcsitlcs spontaneously. H
`
`2.3.2 Polymeri::ed Aggregates
`Attempts have been made to use polymerization to stabilize
`various nascent phase_structur.es. for example miceHcs, 1 s cubic
`phascs, 1 ~·and vesicles.l7 With the exception of micelles (which
`as yet it has nor proven possible to polymerize} polymerization
`of these structures gives aggregates exhibiting the sigpificant
`advantage that they do.not.suffcrbrcak down upon dilution in
`vivo. However; because .Qf th~:;ir size (ranging from tens to
`hundreds of nm) thes.e aggregates can cause problems as they arc
`not readily excreted from tile body; hence .such systems will
`probably have limited clinlcl\1 use,,although.thcymay have a u~c
`in oral admiilistratidrt. In:an littempl to .overcome the problem,
`biodegradable polymerized aggresatesarcpresently bcinginves(cid:173)
`tigilJcd:1" Whenprcjniri11g di:ug~coritainirig pi1lymrirized afigre(cid:173)
`gaies h is important to choose the appropriate stage· for drug
`addition; addin~ the drug ·b¢forc polymerization may cause the
`drug to be irrevcrslblYbouild hi tlic aggrcgate;whilc addition of
`the drug al}er polymerizatiotl :may lead to low levels of
`entrapment.
`
`2.4 Drug Aggregates
`A number ofdrttgs arc themselves mnphip}]i!lc and may aggre(cid:173)
`gate into various strtictures, most frequently small micellar type
`s.tructurcs. 1 J:tl tb.ese cases th~ drllg aggregat¢could aetas its own
`veliicle, if the drug loading were not too high. Jt has been
`postulated that the formation of veskles consisting 6f pure drug
`(pharmacosomes) should aJso be feasible. 19.Urifortunatelymo~t
`drugs :ne not lipophilic enough to f.;>im vesicles easily without
`derivatization wHh materials like fatty acids. 19 However with
`certain drugs ii may be possible: to produce vesiCles over a
`narrow pH range using theapprop:riate ratio ofamphiphilicsalt
`to free drug. The tight control over pH that. would be necessary.
`however, means that such vesicles:are unlikely 19 provide useful
`drug delivery systems; An alternative approach tq producing
`pharmacosomcs has· recently. been reported in which a' biodc·
`grad able micelle-forming drug. conjunct has been synthesized
`from the hydrophobic drtig adriamycin and a polymer com(cid:173)
`posed of polyoxyethylene glycol and polyaspartic acid. zo This
`approach has the benefit tl1at while it may be possible to dilute
`out the micelle, the drugwill probably notprccipitate because of
`the water solubility of the monomeric drug conjuocL Since
`neither of these types of derivatized drug s(ructures consist of
`drug alone, they can therefore nor be considered to be true drug
`aggrcga tes.
`
`2.5 Influence of Oil
`When oil is added ton hi nary mixture of surfactant and water a
`whole variety of phase structures may be formed. Several of
`these structures currently have a ~1se in drug delivery, for
`
`example microemulsions. macrocmulsions, and multiple emul(cid:173)
`sions.' Others such as self-emulsifying systcms21 and vesicles
`encapsulated in water-in-oil emulsions are at present under
`investigation. n
`
`3 Choice of Phase Structure for Drug Delivery
`When choosing a phase structure for drug delivery a numbl:rof
`!'actors need to be considered, in particular, how the physico(cid:173)
`chemical properties of the phase structure relate to the intended
`application. If, for example, a surfactant system is required for
`topical usc the phase structure chosen shonld be of sufficiently
`high viscosity to enable the preparation to be retained on the
`skin surface. while ar the same time allowing it to be spread
`readily over the surface of the skin. In contrast, if a system is
`intended for administration in!ravenously it should be of suffi(cid:173)
`ciently low viscosity not to cause pain upon injection. Another
`import<lnl !actor to be considered is the capacity of the aggregate
`for ihc drug to be incorporated. Micellar solutions, by virttlc of
`low surfactant concentrations, generally exhibit the lowest
`capacily for drug, while in contrast cubic and other liquid
`crystalline phases can frequently tolerate very high drug load"
`ings. ~~·14 Recently it has been realb;cd that the toxicity of a
`particular surfactant may depend upon the nature of its aggre·
`gate. For example, the same surfactant has been shown io
`exhibit a significantly reduced toxicity when present in a vesicu(cid:173)
`lar as opposed to a micellar solution.
`Table. 2 gives some of the physico-chemical characteristics
`import:l}lt for formulation pllrposcs together with the possible
`pharmaceutical applications of each phase structure. It should
`qe noted that while Table 2 gives the average properties of each
`plwse, the. variations in each case maybe quite significant, For
`example; white-solutions containing spheriml miccllc.s generally
`exhibit h:nv viscosiiics, those containing long rod shaped micelles
`frequently exhibit very high viscosities. Similarly, cubic phases
`can disp)ay a· wide range ol stifl'n'ess; son1c samples are as hard as
`p1exiglass, while in others the phases ate sufficiently flexible that
`thev ~ilinosi. flow. 6
`Ii is ipiportant when considering the usc of surfactant phase
`structures as delivery vehicles to remember that-a surfactant
`aggregate cannot be considered an iner1 carrier, and thoit !lui
`drug and indeed pthcr additives SlJch as preservatives .and
`flavourings* may (depending upon the amount present) dra(cid:173)
`matically alter the. erne and, in some.cases, the type and range of
`aggre_gates formed. Unfortunately very li.ttle work h.as been
`performed in this area and is difficult to predict the effect of a
`drug {or indeed any otbcradditive) on a phase $trUcl\lre as it is
`expeCted to vary according io whether the additive (a) is water
`soluble, (b) adsorbs ill the aggregate surface, (c) co-aggregates
`with the surfactant, or (d) resides in the interior oft he aggregate.
`Evidence svggcsts, however, that the phase structure experiences
`the most disruption when the additive is itself surface active. For
`example, the presence .of the drug lignocaine hydrochloride a(
`CO.ltccntrations greater than about 5 wt% converts the. cubic
`struCture formed from l{) wt% monoolein in water into a
`lameUarphase. 1·0 The influence of the presence of drugisfurthcr
`complicated because most drugs are administered as salts, hence
`the amount of amphiphilic salt to lipophilic free drug varies
`according to pH. Consequently the effect of the drug on the
`phase structure nmy vary with the pH of the surrounding
`environment. This effect is more likely to. be significant if ionic
`surfacianis are used. Y cl another complication is that if the drug
`promotes a phase transition. this tmnsition may conceivably be
`reversed as the release of a surface-active drug from the aggre(cid:173)
`gate procecds. 10 This phase reversal may lead to two different
`patterns of drug release.
`
`• F,l\1\·ourings U..Tl!" very important if s:urfuc\anls me to be gh•cn omtly; surfnc.
`t;mts do not taste very plci1sant. Also. because of their dfcct on mcn'tbrancs,
`surfitctanl:s may numb the p~\tlcnfs_ mouth.
`
`Page 5 of 10
`
`

`
`420
`
`CHEMICAL SOCIETY REVIEWS. !994
`
`Table 2 Some physico-chemical properties and potential phannaccutical applications of surfactant phase structure
`Surf:Jctant
`Phase
`Concentration
`StruciUrc
`
`Appearance
`
`Viscosity
`
`Solubilization Capacity
`
`Possible Usc
`
`Micelles
`
`Clear. non-birefringent
`
`Low
`Least viscQus phase
`
`low- amphiphilic~nd non-
`polar St)lutcs only
`
`tlmphiphilic and non- Varies
`High
`polar solutes
`Generally greater
`Low- watcr-soluhk solutes
`than 30%
`
`(}-25%
`
`Solution for most routes of
`de liven•
`Protcctioit oflabilc
`compounds
`Viscous preparation for
`sustained release
`intramuscular,
`subcutaneous. oral ·and
`topic;1l
`Protection of labile
`compounds
`Wide range possible Sustained release.
`pnrticularly 1\lpicul
`
`Wide range possible Susntincd r.clcase,
`par1icularly topical
`
`Fairly low
`Gencrallv less
`than !Owl%
`
`Cubic Phase Clear. non-bircfringctll
`
`Vcrv high
`Mo~t vi;cous phase
`
`Hexagonal Clcaridoudy birefringent Viscous
`
`Lamellar
`
`Clcar,'Cloudy
`birefringent
`
`Fairly viscous
`
`Vcsidcs
`
`Clcarfcloudy birefringent Low viscosity
`
`Probably high - amphiphi!ic
`and non-polar solutes
`low- water-soluble solutes
`Probably high
`amphiphilic
`and non-polar solutes
`Low- water-soluble solutes
`High · :tmphiphilic und non(cid:173)
`pnlar ~olutcs"
`Lnw- water-soluble solutes
`
`Most routes of
`admini~tnuion except oral
`Protection ·11r labile
`~ompounds
`Solid dispersion f11r oral usc
`Not known
`StilT
`Waxy solid
`Solid
`IOOwi%
`• Th<; solubilitntion capacity recortfctf here refers to vc;idcs produced by non·cqudihrium methods; those formed >POnl:mctmsly arc expected to exhibit very low
`~apacity for amphiphilic und non-polar druss (sec Se<iion 5.4).
`
`4 Choice of Surfactant
`Surfactants arc well known to exert a wide range of biological,
`pharmacological, and toxi(:o)ogicill c.ffccts on mnn. 1 Therefore
`the single mo~timpo:rtant factor in the choice of a surfactant, or
`combination of surfacrants, is toxicity. Unfortunately this
`property is hard to assess. The reusons for this arc many, not the
`leust being the difficulty in finding an appropriate measure of
`toxicity, especially When screening new surfitctants. Generally,
`acute oral toxicological studies are routinely performed on all
`new surfacllmts regardless of their intended usage. Althollgh
`this information is valuable it cannot adequately predict chronic
`toxicity. A f\trihcr i:omplil;ation is the understandable reluc(cid:173)
`tance· ohhe Pharmaceutical Companies to enter into the full
`seale chronic toxicity studies needed for 1i proper assessment of a
`new surfactant for drug delivery purposes; a toxicity study
`currently costs in the oroer ofl 0 million dB pounds. Only a very
`limited number of surfactiints are generally considered for
`formulation purposes. Usually only those S!lrf~ctants arc used
`!hal have been used iil pharmaceutiCal formulations for imtny
`years and are therefore.generaUy recognizedassafc,evcn though
`some of these surfac!ants may themselVes riot have been tested
`for chronic toxicity!
`From a toxicological point of view, non-ionic surfaciants,are
`generally regarded as the most suitable for pham1aceutical
`fot'mulation.t .. ~ Even so the range of non-ionic surfactants used
`is very limited. Tween 80 [polyoxyethylcne (20) sorbitan mono(cid:173)
`oleyl ether] and Crcmorphor EL [polyoxyethylcnc (40) castor
`oil) arc probably the two most common. There arc, however, a
`large number of non-ionic surfactants commercially available.
`Some of the more common ex:.unplcs arc shown in Table 2. A
`surfactant is .composed of three distinct portions: a hydrophilic
`segment, ;1 hydrophobic portion, and a semi-polar linker.
`Conscquemly it is theoretically possib!C to join together any
`combination of segments to prodi1ce a surfitctant with the
`required properties; for example biodegradable :mrfactants can
`be rcadilv achieved bv the usc of an .ester linkace. while bilavpr
`(vesicle) ;md micelle t=orming surfactanis can b; produced fr~m
`dialkyl and monoalkyl chain surfactants respectively. Despite
`the wide range of surfactants potentially available, most workers
`tend to usc surfactants that have been previously used in
`
`formulation. ihcrcby limiting themselves considerably, There is,
`however; a real need 'to produGe ne)v surfactartfs hi order to
`realize the full pou:ntial of $Urfaclant systems in drug delivery.
`Yet the number of s'urfactanis thin cari b¢ synthesi~eQ, is
`enormous. In an attempt to address the pr<>blem of design and
`.of new biocompatible surfactants, a program
`synthesis
`VESICA 2 ~ has been developed \vith. a view to Predicting \vhich
`potential s.urfactants wo.uld prcferentiu!ly form a particular
`aggregate type. In this way the n\nnbcfofsurfacthnts that need
`to be synthesized could be greatly reduced.
`
`5 Phase Structures in Drug Delivery
`5.1 Normal Micelles
`The increased solubility in a micellar solution of ail organic
`substance, ittsoluble or sparingly sol.uble in Wl\lcr, is .a well
`established phenomenon. Indeed the solubilization of Willer·
`insoluble drugs by micelles has long been investigated aS!\ means
`of improving solubility for drug delivery, in particular for
`parenteral or oral administration, but also for ophthalmic,
`topical, rectal, and nasal delivery.1 •2 The protection of labile
`drugs from the environment through solubiliirilloit wi\hlri
`micdlcs has also been examined. Consequently an .enom1ous.
`number of papers examine the incorporation ol"awidevariety of
`drugs into micelles.formcd from a large variety of surfactants,
`and in particular non-ionic sur(actants.of the type shown in
`Table 3.1•2 There arc, however, only a fcw·produe(s.on the
`market that can be considered to be micellar systems. This is
`mainly because solubilization capacity is usually toQ l.ow to be
`of practical use, with only R few rrig of drug solubilized per g of
`surfactant. As thcavcragcdose of a drug is in the order of tens of
`mg and, as the concentration of the micellar solution is never
`more than 20 wt% surfactant, this means that solubilization is
`not feasible except in a few instances where very potent lipophilic
`drugs, e.g. testosterone, arc incorporated.
`Attempts hnvc been made to design non-ionic surfactants
`wiih an improved solubilization capacity. An early approach
`involved the production of larger micelles. Dcspiie an increased
`micelle size. solubilization decreased upon lengthening the hyd(cid:173)
`rophobic chain; this decrease was attributed to deleterious
`
`Page 6 of 10
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`

`
`SURFACTANT SYSTEMS: THEIR USE IN DRUG DELIVERY-M. J. LAWRENCE
`
`421
`
`Table 3 Commonly encountered non-ionic surfactants
`
`Common
`Hydrophilic Group Hydrophobic Group Linker Moeity Name
`
`Polyoxycthylcnc
`
`Cholesterol
`Ether
`Long chain alcohol Ether
`Long chain acid
`Ester
`Long chuin acid
`Sorbitan ring
`Alkyl phenpJ
`Ether
`Alkyl amide
`Amide
`Alkyl amine
`Amine
`Polyoxypropylenc
`Ether
`Long chain
`Ester
`triglyceride$
`
`Solulan
`Brij
`Myrij
`TWI!I.!J)
`Triton
`
`Pluronic
`
`Sugar
`
`Sorbit;m ring
`Crown ether
`
`Long chain alcohol Ether
`Long. chain acid
`Ester
`Ester
`Long chain acid
`Ether
`
`Long chain acid.
`
`Tertiary amine oxide Long alkyl chain
`
`Span
`
`changes in tiN polyoxyethylenc chain$ neare~t to the core, the
`main locus. ofsolubilizationfor most drugs. 26 As the am(lunt of
`drug solubilized in the cote is usually Jess than a few percent of
`the total drug incorporated in the micelle, the same group
`attempted to promote solubilization in this region by the
`introduction of a semi-polar group into the hydrophobic chain.
`Incorporating a single ethcrlinkagein the hydrophobe resulled
`in a marked rcduetiOJ.l in the tendency to aggregate and, as a
`consequence. a sigriifii::nil reduction in solubilization.27 This
`modificlltion wasobviously counter~proc:luctive and suggests
`iha.f SOit!bilizaHon c,tinO:ot be improVed byaltci"lng the nature of
`the hydrophobic'i·.egion and that it maybe pctter to ~;:onsidcr
`replacing th~:usualpo)yoxyqthyl~:nc ]Jcad groliP· Data d.o sug(cid:173)
`gesf that i( may be feasible ·1.0 richiev~ s)griifk:mt increases hi
`solub.llir,ation by using alternative he:id groups su<;h as the
`amine oxides.2 "
`Even if it is possible Jo increase solubilization to a sufficient
`degree (ideally to about a I 00 mg per g ofsurfactani) there arc
`still a n(m1bcr of problems with the use of micellar solutions for
`drug delivery.9nc ofthemajor problems ,is thclurgcdilution the
`systenlexpcfienl::es upon admiliis'tratlon. Thls dilution is pat'(cid:173)
`ticuhlrlY hp·ge ;tfier oml and intravenous administration, and
`cancalisc ihc unwanted predpitatioi1 of drog.ln ihc c1isc of oral
`delivery this may lead to irritation of the gils\roinlcstinal traCI,
`while in the case of intravenous admiliistration, pain may be
`.
`experienced up-on injection.
`Other complic;~(ingfactors experienced when using micellar
`solutions include the concomitant solubilization of other addi(cid:173)
`tives such as preservatives and sweetening agents: some surfac(cid:173)
`tants taste fouLcspcdallyif administered as a solution. Depend(cid:173)
`ing upon their relative sites of incbipor;~tion in the micelles this
`co-solubilizmion can either lead to adecrea·seor increase in drug
`solubilizaiion. 1 This poteiltlal problem ofcontomitant solubili(cid:173)
`zation of additives is not just limited to micellar systems and is
`encountered wiih ;111 surfactant systems.
`Owing t() their labile nature, micelles can only be used as drug
`carriers and not.as targ_ctting systems, alth()ugh there is a small
`amount. of evidence that suggests it niay be possible to alter the
`biodistribution of a drug bY administering it in a micellar
`solution. 29 This alteration bas, however, been attributed (at
`least in part) to ;1 direct clfect of the surfuetant (in this cuse, the
`non-ionic surfactant Tween 8Q) on biomembmne permeability:
`most micelle-forming !;urfactanls are known to influence the
`pem1eability of biomembranes. 1•2 Furthermore. as most of the
`surfactants_ used for drug delivery arc not readily biodegradable.
`their activity is retained for long periods in the body.
`Although drug solubilization in micelles has been extensively
`investigated. much less work has been performed examining the
`influence on drug transfer of solubilization in micelles. Accord-
`
`ing to the limited evidence available. micellar solubilizillioh
`reduces the ra tc of mass transfer of most drugs across inert
`membranes.'·" In the body this effect appears to be counter(cid:173)
`balanced by the fact that the surlaciant can frequently increase
`membrane permeability.
`
`5.2 Cubic Phases
`Cubic phases have received a considerable amount of a,itention
`as putative drug delivery systcms. 1 o.n.Jo H One interesting
`cubic phase is that formed by .the polyoxycthylcnc-polyoxypro(cid:173)
`pylcne co-block polymer, pluronic F