SENJU EXHIBIT 2139
`LUPIN v SENJU
`IPR2015-01105
`
`PAGE 1 OF 10
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`Chemical Society Reviews
`
`Edftoriaf Board
`
`Professor H. W. Kroto FRS
`(Chairmen)
`Professor M. J. Blandamer
`Dr. A. R. Butler
`Professor E. C. Constable
`Dr. T. C. Gallagher
`Professor D. M. _P. Mingus FRS
`Professor .1. F. Stoddart FRS
`
`University" of Sussex
`
`.
`
`-»- .
`
`University of Leicester
`University of St. Andrews
`University of Basel, Switzerland
`University of Bristol
`lmpe_ri_al College London
`University of Birmingham
`
`Consulting Editors
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`Dr. G; G. Balint-_l<t1rti
`Professor S. A. Benner
`
`Dr-. _J'. M.’ Brown
`Dr. J_.- B‘urges's
`Dr‘. N. Cape
`P_rofessor' B. T. Golding
`Prof_e_s.sor M. Green
`Professor A. H.a"m'_rtet_t
`Dr. T._M. Herr.ingtoi'I_
`Prof_'essor R. Hillman
`Profe'sso'r Ft. Keese
`Dr. T. H. Lilley
`_
`_
`Dr,._'HL_ Maskill
`P_r_ofes_'sor A. ,de ‘M eijere
`Pro'fe_s_s'o_r.J. N. .M_ille_r'
`Pro tease it St M.-B c.be_'r't_s
`Professo? B. -H-. Roliinson
`Professor M. R. Srnyth
`
`Dr. A, J. Stace
`
`Staff Editor
`
`Mr". ‘K. J. Wilkinson
`
`University of Bristol
`Swiss Federal Institute of Technology,
`Zijrich, Switzerland
`University of Oxford
`University of Leicester _
`institute of Terrestrial Ecology, Lothian
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`Lo_ughboro_ugh l-Jniv_e'r_si_t'y'ot Technology
`Un’ive.r'sity of Exeter
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`University "of East Anglia
`Dublin City University. Republic "of
`Ireland
`University of Sussex
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`Fioyal Sociezyof Chemistry, Cambridge‘
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`PAGE 2 OF 10
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`Surfactant Systems: Their Use in Drug Delivery
`
`M". Jeiyne Lawrence
`Department of Pharmacy, King's College London, University or London, Menresa Flood, London SW3 6LX
`
`1 Introduction
`M olceules or ions which are nniphiphilic. that is, contain both a
`hydrophobic and hydrophilic part. in aqueous solution fre-
`quently assemble at interfaces and selfqrssociale in an attempt to
`sequester their apolttr regions from contact with the aqueous
`phase. This self-assoeituiort gives rise to 1!. rich variety of phase
`structures (Ftgure I). Aggregation is not.'ho'wever. just limited
`to aqueous solution: it is somet_imcs 0_l')SCl"'C(l in -non-at] ueotrs
`polar solvents such as ethylene glycol and non-polar solvents
`such as hexane .(in the latter case giving rise to §!1¥{cl'SG
`structures).
`Over the yea rs several of the phase structures produced by
`surltictti nts have been ofintcrcst to the phatrmnceutical scientist,
`either as drug veltieleslcarriers or more recently as targettirtg,
`systems. in the former i_1ppllC3ll_Dll _tl_tt: $I.tt'fu_tE1n_nt system tttkes
`no pa rt in the biodistrilnttion of the drug it carries. acting purely
`as the vehicle. In the second catse the surfactant system in some
`way ‘conveys‘ the drug to the" desired (or target) site in the body
`and ‘deposits it. Targetting can t:rl<e.ot_:'e :of- two Fdrnts; namely
`‘p:!ssiVc' targetting which relies on the n':.ttural_ biodistribution of
`the carrier. or ‘:1etive‘ tztrgetting in which‘ the carrier is in some
`may directed to the desired site,
`frcquer.1t_iy by the use of
`utrgettiug ligands expressed on the surface of the carrier. Both
`types of tergctting have the advantage of pi*'o.te_c._ting the body
`from any _unw__ante_d side—eFl'_cels o_f_Ihe._'t:lrug, while at the some
`time achieving the desired coneentr'etton' o't‘-drug at "the-‘target
`site‘.
`By far the ntnjor-ity of ‘work eitninirting the potential of
`surfact_ant systerns in drug delivery hits explored their useais drug
`ertr.ri_cr5;_I'or example n_oo-ionic micelles hav_e been -tvidcly inves-
`tigated as n"-rneansol‘ producing a clear" st2ible"so'lttlior': ol’ :1
`poorly W3_._l¢i‘-_S0lllbl_e d_rug- suitable for :_in_t‘ra\_re_notts or oral
`a£:ln1'ini'strntion."-’ However, during-the past'u.ttent;,r years or so,
`as the importance. ofdrug targetling has-be_et't ‘realized. it number
`ol'st'trl‘eetant s'ystc'ms. such as phospholipid or non-ionic sttrlac-
`tent vesicles-, have been c.‘<tc't15ivt:ly" investigated as targétiing
`systenasfl
`_
`_
`_
`_
`Despite all the tfeseerchinto thepotential use of surfactant"
`phase structures For drug delivery. such plirtsemructures have
`not made much ol':tn impact on the formulation scene; there are
`
`M. Jrryrrrt Lmi'a'.'cm'e grnrlrrnrgrrl -in PlI(!J'i'.l1(l't‘_l' ji-out Litvcirpool
`-
`-
`Pol'yret:llJtic f-B._St:',_)
`in I98}
`and quttlflfed as :1 member of
`the Rrrya! Pltn_rr:rnc_etrtr'cvrl' So-
`t'=t‘e.l}' -‘if Great Brr'r(rr?t in I982.
`S!:e_'ret'er'ved her PIt_.D. degree
`in t'935fr;mt the Urrfi'er.rity of
`M:rttc!te.rrer.
`-St‘rrrt= 1984 site
`hr.-.r been (I Lecturer‘
`in the
`PF|'nr:rtae)' Departmertt, Kt'rrg'.r
`College L.-mdtm. Her re.rerrr'c!t
`'r'trrerc.'.'rs cover the _rlr.’.rr'grt, syn-
`rIre.sr'.r.
`arm‘
`p}r_t=.sfo-clrertricol
`c!terr:c'!e:'i:art'rJrr of .\‘trr(Ett'trt.tr.f
`:_t'.rrr-ms
`and
`mcmbrrme
`rmrtsport.
`
`
`
`only it few marketed pr,-":p:.t rations that cottlti he consitlerecl to be
`drug-containing surfactant systems in either the United King»
`dom or the United States. Consequently, the true potential of
`surfaetttnt formulations. purtiettlarly of non-ionic sttrfnetants.
`has perhaps not been fully realized. In order to appreciate the
`potential and alsotltc limitations ofsuch S)-'SIt:I11.‘S«'ttt1 un<lcrsta:td-
`lug of the phase behaviour ol‘ stirhtct-ants is essential. The
`fotlowiug account tlteretorc describes the phase hehzwiour of
`Burl"ttetun ts with reference to their physico-chemical properties
`relevant to their use as drug delivery systems. It also details some
`ofthc-tvorit-perlornted to date ln\*¢Slig;1l,ittg the use ofsurfatctttnt
`s}.'steI't1s -in particular, those produced from the less toxic non-
`ionic surl'ae'1nn.ts — for drug delivery.’
`
`2 Phase Behaviour of Surfactants
`2.1 Equilibrium Phase Structures
`Although surfnetait ts self-‘associate in a wide vitrietyelsolvcnts.
`their state cl‘ aggregation _varies considerably between ‘solvents
`(Table 1). As w-.tter'-or a buffered aqueous solution is the usual
`t:o_n_tint._ttnn for most drug delivery systems. it is important to
`un'der'stnnd "(and predict) the range of equilibrium phase slru'c—
`lurcs'cornt_no't1ly encountered in such solutions. Mention will be
`made of the phase -st_ruet_urcs encountered in other solvents
`where appropriate. .
`When ti surl"nctant_is_diSperscd in wttterjust above the limit of
`its aqueous solubility {i'.e. above its critieui rnicelle—.conccnt-
`r:ttion,"c_mc) it generally aggregates-. depending upon its molecu-
`lur.gcomctry._".into one 01' four types of structure. namely the‘
`iso't'ro'pie' mi.ecl_lttr f5has_e-and the liquid crystalline itcxagonttl,
`le_'ntel_lor,t_1nd cubic phases. The uforcnientioncd phases, with the
`exception of 'tl1e'l:tmell_u'r phase, can either he in :1 normal or
`t'.t:Vcr5¢.-orien_t1,tlion. Recentty, in addition to these "commonly
`encountered phase -structures; there has been an increasing
`munber of 'm_.o're unusual -_aggr<:g:ttcs. such as helical bilayers°
`and.fi_b_re gels’ repo1_'tcd_.
`Upon in'erc:t'sin'g'the stirfaetant concentration well above the
`cntejtltere are'gener_:'1l|y _cha'nges in aggregate or phase structure.
`' The ordcrofphnse structures fo rmed upon increasing surfactant
`concentration generally follows :1 well-delined sequence (Figure
`2) with at ‘mirror plane‘ through the. lanteilar phase. such that
`normal phe'se"strut5t'ttrcs eeubc considered to be ‘oil-in-water‘,
`while reverse structures can be thought of as -'wutcr—in-oil'.°
`Most
`sut-l':.tcttints'. however. cxltibit only 1! portion of this
`sequence. depending-upon the aggregate type initially formed at
`the cmc-and the resulting irtteraggregate forces experienced.”-
`Although the slime-'pl1ase"structures are observed in other non-
`aquco us polarsolvcnts, the sequence ol'phascs.is sometimes very
`dill‘erent' and appears‘ to depend both upon the molecular
`geometry and the nature cl’ the polar head-solvent interactions.
`
`2.)'J Irntplirrtlliurtsfor Drug Del?!-t-r_t'
`An understanding of the phase behaviour of surfactants is
`essential for the eflicient use of surface active systems in drug
`delivery. For example. after introduction into the body the
`sttrfactnnt system rnay, depending upon its route cl‘ -.td_minist-
`ration. undergo a large dilution.
`ll‘ the surfactant is diluted
`below its ernc. precipitation of t mnsporterl drug may occur. This
`precipitation may have very serious consequences. especially if
`
`4%‘?
`
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`M3
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`C|‘ll3MiCAL SOCIETY RE\-"]EWS. I99-1
`
`Surfactant Mculeculcs
`
`Spherical Micclles
`
`
`
`
`Hexagonal Phase
`
`lxintelltsr I’h:I.-it:
`
`Reverse Hexagonal Phase
`
`Reverse Micelles
`
`Figure I
`
`
`
`Table" l Self-association in.soivcn'ts
`
`_
`Class of
`Tjfpc of Aggrggzite.
`Examolc .ofi:lnss
`solvents
`Class A Writer. glycerol, .c:hylcne'gly&o1' Noirriitil
`Class B
`i'l_,r:xati1::‘. bcngcnc, cyttohcygntc
`Rcyursc
`Class .C Methanol.-ethaiiol
`No aggregate ‘formation
`
`the drugjs being administered intravenously. 1__dc_:_1l_ly lhcrgforc
`the cnfc should be gt low as posgiblc ‘in order .1'o;a~iui-id Such
`problems. Surfactants that-—I'onn Iamcllzgr phétscsgat.-their c_mo
`generally do so at much lowerco:1ct:I1!rali_ons_lhan thosc st.frI'ac-
`tants which initially form nticclles.=Sinoc no_n¢i0nic §‘.u_rl':sr:tants
`generally exhibit lower cm't:‘s than -ionio'sur!_'§1§:t_rlnts-they are
`preferred for the pu,,fP_oses o_f'-._d1‘ug ._dc!i\e'ery_. _r:.spei:i£1lly when a
`micellar solution is being investigated as the drug _r_;lg;lix_._rcry
`vehicle. In a similar vein, il'.:1 cone:ntratcd.s1.;r['aclant'-s'oItztion is
`administered it may experience a suflicicnl diluiion 1'0 induce a
`phase change. say for example-from _a_n Hexagonal to _a ;~_n_ic_cllar -
`pluasc. As the drug-ca rryi_ng_ca pacity ofcacl1 aggrqga't_e Iype may
`differ, such a phase changtrcould have very serious implications
`
`sucltias Idosc dumping _w_itl1it1 the body. When co'nsLidcrin_g using
`a.?_:mjl_';:c_t:1nt' system as“ it drug dclivéry vehicle it_s'hot1ld-also be
`bornii in mind that phase transitions can_also be induced by a
`cl1__an_g_e in temper:1tu._rc'8l1d that normal human body tempera-
`uiré is ‘typically '12.dc'g'recs nbpvt: '.1mbionI.Other_probIcms _to be
`aware of._an:_l1ysIcrcsis cfibcts. These are particularity common
`in cu_bic"phase.'s and may have important consequcnqcg l'ordr_u_g
`clc_livcr§rg__Fpr_§:_xatnpl!=,. certain cu_bic_ phases l_:aw:'been éhown to
`by; pSCt_1_d(_J*S_l€|.l)l£‘. for very Icirig 'pcriods'at temperatures at which
`sotneothcr form ofaggrcgatc would normally be formed.“
`A l_mqw_l::_dgc. o_f.ll1t_:' various biological surface-aciivé agents
`which. the-surfactant aggrcgatémay e_ncou_mcI ft} vfvo is also
`esscntial._'as lh_c_sc may alter or oven destroy the agfirtghtcl For
`example the endogenous micclle-fanning bile $:1lts.cnc_duntcred
`in_ {the ._srnall
`intéslinc have been shown to solubilizc orally
`adniinigtcrgd liposomcs. thereby reéls;-nsing any irfatcrlsolublc
`solute trapped inside the carrier.
`
`2.3 Modified Phase Structures
`
`In addition to the equilibrium pl-msc slrtlcturcs mcntionccl
`above, thcr¢.ar.c'a few non-equilibrium and modified surfactant
`phase: siructlures that are currently finding opfilicniion in‘ drug
`delivery.
`
`‘iiaoreasing surfactant concentration
`‘oi!-in-water‘
`.
`‘water-I'n—oil'
`‘mirror p|:xm:‘
`
`n
`u
`1
`-
`,
`I
`_
`l
`H30 Micellc (L. ) < Hcxatgonul ($1,): Lnmcllnr (L,) < Reversed Hexagonal (H 3) ~: Reversed-'Miocllc'(L;] Solid
`I
`I
`I
`I
`1
`t
`
`Cubil: (I,)
`
`Cubil: (v,) t
`
`Cubirl {v_,)
`
`cubil-. {1,)
`
`Figure 2 idealized phtzsn: sequent: in surfactant-water systcans. (Moditiqd from reference 6; terminology :15 in reference 1'.)
`
`PAGE 4 OF 10
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`SURFJ\CTA1\lTSYSTEl\«‘lS: Tl-IEIR USE IN DRUG DELIVERY-——l\{l. I. Lr’§\\*'RlZl\lC‘E
`
`ell‘)
`
`2.3.!
`
`l-"firicles
`
`vesicles are genera lly formed by dispersing lamcllar phases in an
`excess of water“ (or rton-aqueous polar solvents such as ethy-
`lene glycol, dimethylforrnarnide), or in the case cl‘ reversed
`vesicles in an excess ofoil.” The resulting-vesicles are approxi-
`matcly spherical structures. dispersed in a water or an oil
`eoatimturn. Vesicles produced from phospholipids have been
`widely investigated as drug delivery velticles. Unlike the phase
`structuresmentioned earlier, however. these non—equi|ibriutu
`structures are prepared using -methods such as -sonication and
`will eventually re-equiiibratc back into _the lantcllar phases from
`which they originate.“ This inherent
`instability has -caused
`considerable problems will: the wide-spread"commercial exploi-
`tation of vesicular delivery ‘systems. For :1 Few surfaetattts.
`however, the vesicular phase‘-‘is an cqu_ilib_rittm "structure: for
`example, the ionic gangliosidc GM3, a glucosidic ampliiphile of
`biological origin, forms‘ vesicles spontantzously in water,-'3 tvhile
`some combinations o_l‘non-ionie‘stt_rl"_a'ctants have been shown to
`form reversed vesicles spontaneously.‘ ‘
`
`2.3.2 Pnlynterlzed Aggregates‘
`Attempts have been niade to use .polyrnerization to stubitizc
`various nascent phasc.structur_es. For example micelles. ' 5 enbie
`phases.” and vesicles.’ 1' with the exception of micelles {which
`as yet it has not proven possible to polymerize) polymerization
`of these structures gives "aggregates exh_ibit_ing the significant
`adv'ar_ttage that they do.:t1o't-su'fl'cr'brcak doxvnupon dilutionln
`I'lI't’J. H0\'tl'O\-’C]‘-,- because of their size (ranging from tens to
`hundreds ofztml these a'ggregatc.s'ca11 cause problems asthcy are‘
`not readily e_;t_:crctcd from the body; bcnce'_.such systems wit]
`probably have limited clinical use.»_altl'_toughtl1cymay have rt use
`inoral adtninistralidn. lttfin tlttcntpt to .ovcrco'rat: the problcrn.
`biodegradable polymerized aggregates-are._prescnt_ly being inves-
`tigated.“ When" preparing"dituig-containing_pIolymeriz'ed zi"g'gr"e-
`gutes it is ‘important to'.:ch_'o'osc'..t_he_ 'appr_op'rit'1te $tage'l?o'r'.drug
`addition; adding t‘he=drug‘beforc polyrneriuttion may cause-tlie
`drug to be ir_reversib_ly"b'ou1'1d tn "the aggregate,'.-tvhile'addi'tion' of‘
`the drug alter polj'm.criz:i[iott may lead. "to low levels of
`entrapment.
`
`2.4 Drug Aggregates
`A number ol‘-‘drugs are thcrascl_ves tttnohiphilic and may aggre-
`gate into various st-rtiettires. most l're'quer't'.tly_ s'rrt:il|='mieell'ar type;
`s1rt_:cl.Ltr_cs.' In tlI_e_.sc oases the-drug ':tg'grcgttte'_co uld-act as itsjown
`vehicle. if the" drug; loading were not too high. It has "been
`postulated t!1at.the'l'o.m1_:ttion of vesicles consistititt 61‘.pure drug
`(pharmaeosomes) should also lie-l‘cas'iblc.' ”.Unfot_'t.unate_ly.most
`drugs-‘are not tipophilic-ertough to_'forn1 \i'c.slclcs_ca_sil}* without
`derivatizalion with .maler_i_:t.lfs_ like fatty-_acids.'9 However vditl:
`certain drugs it- may be"-piJssi.ble.'--to produce vesicles over" a
`narrow pH. range using thc;appropri:rte-_ratio ofampttiphiticsalt
`to free drug. The tight control over-pH tltatwould be necessary.
`however. means that sut':h'vesicles are unlikely to provide usefttl
`drug delivery systems.‘ An alternative -ztpprottch to prclducing
`pharrnncosomes.hats-rcccntlybeen rcpor.tc.d- in which a'biodc-
`gradable micelle-fornting_-drugzconjunct has been synthesized
`from the hydrophobic dr.tig= ad riarnycin and-a polymer corn-
`posed of polyoxycthylene glycol ‘and polyasparlie acid." This
`approach has the benefit that whilcit may be possible to dilute
`out the mieelle, {he'd rugvvill probably not precipitate because of
`the water solubility of the monomeric drug conjunct, Since
`neither of these types of derivatized drug structures consist of
`drug alone. they can tlte'rcl'ore not be considered to. be truedrug
`aggregates.
`
`2-.5 inflttertee of Oil
`when oil is added to a binary mixture of surfactant-and water :1
`tvitole variety of phase‘ s'tru'cturcs may be formed. Several of
`these structures currently have a use in drug delivery, For
`
`example microcmutsions. macroemulsions, and multiple emul-
`sions.‘ Others such as selficmulsifying systems“ and vesicles
`encapsulated in -.vater—in-oil emulsions are at present under
`investigation‘.-“
`
`3 Choice of Phase Structure for Drug Delivery
`When Cit-2IOSing,t.| phase structure for drug delivery ‘.1 nttntbor of
`[actors need to be considered. in particular. how the physica-
`chemical properties of the phase structure relate to the intended
`application. ii. For example, it surfactant system is required for
`topical use the phase structure chosen should be of sttfficierttly
`high viscosity to enable the prcpttrtttiort to be retained on the
`skin surface. _\vltilc at the saint: time allowing it to be spread
`readily over the surface of the slain. In contrast, iI‘a system. is
`intended for administration intravenously it should be ofsufiiv
`ciently low viscosity not to cause pain upon injection. Another
`importttnt Factor to be considered is the capacity oftlte aggregate
`for the drug to be incorporated. Miccllnr solutions, by virtue of
`low sttrfactztnt concentrations. generally exhibit
`the lowest
`capacity for drug, while in contrast cubic and other liquid
`crystzzlline phases can Frequently tolerate very high drug load:
`ings.“-3* Recently it has been realized that the toxicity of :1
`pa rticulttr surfactant may depend upon the nature ofits aggre-
`gate. For ‘example,
`the same sttrfactant has been sliotvn to
`exhibit a significantly reduced toxicity when present in :t vesicu-
`lar asopposcd to a mieellar solution.
`Table 2 gives some ol” the physico-chemical characteristics
`itttportztnt Ior Formulation purposes. together with the possible
`pharmaceutical applications of each phase structure. It should
`be "noted that while Table 2 gives the average properties ofottclt
`phase, the. variations in-each case maybe quite significttntt For
`exum}‘)lc_; while SolLttions'conlttit'ting .rpl'tert't'r2lt1tict:llcs generally
`exl1ib_it'l'o_ w‘ v_i_s_co_sitie's, those containing long red sltaperl micelles
`frequently exhibit very high viscosities. Similarly, cubic-ph_a'scs
`.can-display at wide range ol‘stifl'n'ess; some"-sztrnples are as hard as
`plc._‘<ig|;t_ss.wl1ile-in otltets the phases are suffieicntly flexible that
`they Etlmost "flow."
`lt_is'-important wlten considering the use of surfactant "phase
`structures as delivery vehicles to remember that-e surfactattt
`aggregate C_Etrll10l' be considered an inert carrier. and that the
`drug and indeed other additives such as preservatives and
`flavourings.*.may (depending upon the" amount present) dra-
`matically alter t!te.c_mc and, in .some.cases, the type and range of
`:tggrc_g.'ttcs' fortncd. Unfortunately very little work hos -been
`performed in this area and is difficult to predict the effect. of :1
`drug __(.or.i.ndeed.:tny oLhcr._az_]ditive)_on a phase st_r_uct_t1re as it is
`expected to vary according to tvl1ctltcr..the 'additivo'{a) is water
`sol able, (b) adsorbs at the aggregate surface. (c) co-aggregates
`with the su r'l‘ac.tant, or (cl) resides in the interior of the aggregate.-
`Evidence. suggests, however, that the phasestrueturecxpericnces
`the most di_srttptioa when the additive is itsclfsnrfacc active. For
`oxantplc, the presence of the drug ligrtocaine hydt‘o':.:hloridc’al
`co_ncc:1_trations greater than about 5 wt% converts tltlleubic
`structure l‘orm'ed from 10 wt% monoolein in water -into at
`lamcllar phase. ‘-9 The influence ofthe presence ofcirugis-l‘urt|t'er
`complicated bccausernost drugs are administered as salts, hence
`the amount of arnpltiphilic salt to lipophilic l'ree'drug varies
`according to pH. Consequently the effect of the drug'__on the
`phase structure may vary with the pH of‘ thefittrrounding
`environment. This-effect is more likely to be significant ifiottie
`surfactanisare used. Yet another cotnplication is'th'a't ifthcdrug
`promotes :1 phase transition. this transition may conceivably be
`reversed as the release ofa surface~activc drug from the aggre-
`gate proceeds.‘ '3' This phase reversal may lead to two different
`patterns of drug release.
`
`‘ Elnvourirtgs are very important ifsurlectnnls are to be given orally: surfac-
`lants do not taste very pleasant. Also. because cl’ their effect on nu.-mlu—.tncs,
`surlitclattts may numb llte p'.ll.i.onI'stI’tDl1l'iI,
`
`PAGE 5 OF 10
`
`PAGE 5 OF 10
`
`

`
`430
`
`CIHEMICAL SOCiE'l"r‘ REVIEWS. 1994
`
`Table 2 Some pl'l}'SltID-Cl'Il2lTllC:ll properties and potential ph:11'1natct:tttit:n| ttp])|§t::t1ioIts ofstlrfaclatnl phase structure
`Phase
`Surf:iei:mt
`Structure
`Conccntrutioll
`
`I-‘ossible Use
`
`Appt-urttrtcc
`
`\-’lSc0.'ill)'
`
`Statuhilimtion Capacity
`
`Min.-cllcs
`
`Clear. IIt.ln—hirI2friI1gcnt
`
`Cubic Pltztsc CIcnr. non-hircl'rin_i_:ent
`
`Low
`Least viscous phase
`
`Ver_v high
`Most viscous phase
`
`I-lcxttgonul
`
`Cleur.r’t:loutl)-bircfrinttcnl
`
`\’is'cous
`
`Low -1 ;impl1ipl1ilic and non— (1-—2:3"z"n
`polur solutes only
`
`annphiphilic rind !l\‘ll‘l-
`High
`polar solutes
`Low ~ \\r'1'llC‘I"S0lttl.‘llT sololcs
`
`\:’:ir_ics
`Cicnernlly gre:t1::r
`than 30%
`
`Solution for most routes of
`deliver)‘
`Protection ofltthilc
`compounds
`Viscous preparation for
`sustained release
`intrnrnusculnr.
`sttbcutelrtcous. run] ‘and
`topical
`Protection oflahilc
`compounds
`Prohuhly high - timphiphilic Wide range possible Sustained release.
`and non~po1:tr solutes
`ptirtieulnrly topical
`Low — it-:tter-soluble solutes
`
`Lzmtellttr
`
`Cle:tr,'C!ou_tl)'
`birefringent
`
`Frliriy viscous
`
`ill_ll]’llll]_'lll.lllC Wide rtlngc possible Stlslnittcd release,
`Prohnhlv hi_t_:l1
`untl non-polar solutes
`pztrtteulatrly topical
`Low - tvattcr-soluble Soltilels
`
`Vesicles
`
`Clenrleloudy birefringeitt Lttw viscosity
`
`High - nmphipltilic and uon- Fairly low
`polar solotcs*
`Generally less
`Low — \v:tlcr—soluhlc solutes
`than 10 wt%
`
`Solid
`
`W:ix__v solid
`
`Still
`
`Not ltnntvn
`
`ltlll wt“/9
`
`Most r_ti_I._Itcs of
`ttdminlslmtion except oral
`Protecti'ort'ttl'lrtl:iile
`compounds
`Solid dispersion For oral use
`
`“ The sucilubltizlltion eupztcinr recorded here refers iovcsicles produced by nun-cqtnlillritlm methods; those formed .'.|1onI:mron5l}: are expected to exhibit very low
`capacity fur nmlthipitilh: anti non-polnr drug,-5 (see-Section 5.4).
`
`
`4 Choice of Surfactant
`
`Surfactants are well known to exert zt 'wi_tlc'rat_1gc ofbiologicul,
`pltttrmacologicztl, -and to;-tit:_ol_ogit::'t_l cflccts 911'.-titan.‘ Tliarcforc
`tltc-Single n1o$t.i_mpo'rt:tnt l'uc_Ior- intltc choice o[£t'stIrFac'_l1t11l. or
`combination" cl“ surl':_Jc|.‘:1nts.
`is ‘toxicity. Unfortunately i_hi,s;
`pro}:'t2r:_y is-hard to assess. The reasons for this an": many, not the
`least being the dilliculiy in finding no-appropriate‘ measure of
`toxicity.-especially when'sr:rcct1ing ncxv iiujflltclants. Generally.
`nctrtc "oral _loxit_:olo_gical-studies" are routinely performed. on all
`new surfactants regardless of their intended usage. Altliough
`tltis-infornzntion is v:1lt_t:t__blc it catnnot adequately predict _Cl.‘Ii'0 nic
`toxicity.--A. l‘t'1r,thcr complication is the unjtit':.rst:tiirl:t_t:le_-reiuc-
`tnncc o{‘.the.'Phrtrmzu:eutic.al Companies to t:nt_cr into the full
`scale claronic toxicity studies needed for :1". proper assessment ofn
`new surfactant For drug delivery purposcs;.:t toxicity sttttly
`currently costsin the order ol‘lD million GB pounds. Onlya very
`limited number of su'rfactttnts -'ar_c'- _gcncrz'zll'y considered for
`forniulalioti purposes. Usually only those surfnctanls are used
`that have been used in pharma'cc.'utic:tl fonnulations for many
`years and are therefore generally recognized as sal‘c,_ even though
`some of there "surfactants may thcniseives not liev'e'bcen tested
`For clironic toxicity!
`From :1 toxi_colog_ic:1l point of view, non-ionic surl':1ct‘:.1nts,are
`generally regarded as the most suitable for pliomtnccttlicnl
`forrnulntion-.*-3 Even so the range ofnon-ionic surfactants used
`is very limited. Tween 80 [polyoxycrhylctie (23) so'rlJit:tn'mono-
`olejrl ctlicr} and Crcniorphor ISL [polyoxycthylcnc {=10} castor
`oil] alt;-probably the two most common. There are. however, -at
`large number of non-ionic surfactants contrnercinily available.
`Some of the more common examples are shown in Table 2. A
`surfactant is.cornposcd oI'tl:'i'cc distinct portionsrzt iiydrophilic
`S(.‘gJ‘]1€:l‘ll.,
`:1
`ltyclrophobic portion, unti
`El _SCl‘t1l-pfllaf
`linker.
`Consequently it is thco'rcticttIly possible to join together any
`combination of segments to produce :1 surfactant with the
`required properties; for example biodegradable surfactants can
`be readily achieved by the tIse.olun ester lirtl-zngc, while bilaycr
`{vesicle} and rnicellc lbrming surl‘:ici-.mts can be produced from
`dialkyl and monoalkyl chain surfactaztts respectively. Despite
`the wide range ols urfactants potentially available, most we rlccrs
`tend to use surfnctants that have been prcviotisly used in‘
`
`form ulation. thereby limiting tltcmsclvcs co nsldcrztbly. There is.
`ltowcver. u. will need to pro't:lu_(:c'1'tt'.'_w- surfactants, in order_to'
`rcalizcjtltc full potential of surfactant systems-_in drug delivery.
`Yet
`the number of surfactants that Ct‘IIl_'b.C synlhesitzetl
`is
`enormous. In nn.at_tcmpt touddrcss the p_ro_bl_cr_n_ol_' design not!
`synthesis of new l_:l.oc0mpnt_ible
`surl'at:'lan'ts,
`a
`p"r.ogr':trn
`VESICA 3 5 hats been developed. w_it_h_ _a-view _to_ .p1_'cdi_cti:_1g which
`potential surfatctnnts would prefcrentiiilly form -.1 purtictller
`aggregate type. In this way the ntnn.bcr'_of'surfact‘nnis that need
`to be synthesized could be greatly reduced.
`
`5 Phase Structures in Drug Delivery
`5.] Normal Mlccllcs
`
`The increased solubility in n.- micellar solution of an organic
`substance. insoluble or sparingly soluble in writer, is ,t_t- well
`established phenomenon. Indeed the soluhilization of water-
`insolublc drugs by micelles has long been i_nvcstigatcd as it mantis
`of improving -solubility for drug delivery,
`in particular" for
`parenteral or oral admittistration, but also for opltthalmic,
`topical, rectal, and nasal delivery.‘-2 The projection oflabilc
`drugs from the environment
`tltroiigh solubilizetion within
`micelles has also been examined. Consequently an cnonnous
`nun‘: bar of papers examine the incorporation" ofa-tvide vn ricty of
`drugs into micelles-forrncd from :t large‘ ‘variety of surfactants,
`and in particular non-ionic sttrl_'actants.of the type shown in
`Tablc 3.1-’ There are, however. only a_ fewprcoducts "on" the
`tnurlcet that can be-considered to be miccllar systems. This is
`mainly because solubiiizalion capacity is usually toq low to be
`of practicztl use. with only it few mg of drug sdlubilizcd per g of
`surfactant. a5tstl1e.avert1gcd0scol'n drugis in the order ortens of
`mg and. as the concentration of the miccllatt solution-is never
`more than 20 wt% surfactant. this means that solubilizntion is
`not feasible except in :1 few instances tvhercvcry potent lipophilic
`drugs. tag. testosterone. are incorporated.
`Attempts have been made to design nonvionic -surfactants
`with an improved solubilizmion capacity. An early approach
`involved the prodtiction oflargcrrnicclles. Despite an increased
`rniccllc size. sol ttbilizution decreased upon lengthening the liyr.l—
`ropliobic cliain;
`this decrease was attributed to deleterious
`
`PAGE 6 OF 10
`
`PAGE 6 OF 10
`
`

`
`SURFAC'l‘r\NT5YS'l'Ei\‘lS: Tl-{Elli USE lN DRUG iJl3LlVERY-wit-I. .l. LA‘-VRENCIIE
`
`-Ill
`
`l-lydrophilic Group
`
`-
`
`Table 3 Commonly encountered non-ionic surlhclttttttt
`Cnntntot:
`I-lydrophobic Group Linker Moeity 'N:nne
`Cltolertcrol
`Ether
`Solulnn
`Long cbnin ztlcohol Ether
`Brij
`Long Chtllll acid
`Ester
`Myrij
`'
`L '
`h '
`:
`‘d
`' .
`" '
`,cr,:r:..t:..:°*
`::’.:E::"“ i::::::
`Alley] nmicle
`Amide
`-----
`Alley] untinc
`.-tnrine
`-~--—
`Polyoxypropylene
`Ether
`Pluronnc
`Lung cltnin
`Ester
`—- - --
`triglycerides
`Long chuin alcohol Ether
`_
`Long.e!t:tirt acid
`Ester
`Sug“
`Long chain acid
`Ester
`Sorhitttn ring
`Long, chain acid,
`Ether
`Crown ctl2cr-
`Tertinry amine oxide Long ttlkyl chain
`—--——.
`
`-- ---
`—- ---
`Spun
`--
`-..-.
`
`changes in the po_lyox-yetltylcne chains nearest to the core, the
`main lOI:1lS__0r.SUlll_blllZ6.Il0l'l for most drugs.“ As the at-nount of
`drug 's'olubilize_d in the core is usttttlly less Illttlll :1 few percent of
`the total drug incorporated in the tniccile. the same ‘group
`attempted to promote soi_ubillz':_tti<'>n in this region by the
`introduetiort ol':t semiqnolnr group into the hydrophobic eltttirr.
`Incorporating" a single "ether _linkug'e'fi'n the ltyd rophohe resulted
`in __n: m_f.tt'l_t_c(_i reduction in the tcnd_t_:ncy_ to uggregatc and, as at
`ctinseqttenoc. at significant 're'dt1tStion"in' 5o|ubi|i:r.atiott.2" ‘This
`modification tvas"0bvio'u_sly counterfproductivc and suggests
`t_htt__t'§c_ilttbi|i2_r_ttio_n'etirtrtot be improved lJ_)_'_flIlci'll‘tg theunturc of
`the hydrophobic"-zmgion itnd lhitl il. ma}'5'bc'-better to consider-
`r¢pl_ac__ing 1t.1."titI.s.t-:11.P9J¥v=t¥tEl*tr_lI;rm lend gno.ut=-.|.3.=It=i do s_u1;_-
`gest thtit it may be feasible to. zicltieve"signific'nnt— increases. in
`solubilization by u‘sing- alternative bend‘ groups st1'Cl‘I us the
`atnirte oxides.”
`_
`Even ifit is possible to incrcnsc_sol_ttl:pili?.attion to st stlllicicnt
`degree (ideally to about :1 H30 mg per _t_-, 'ol‘.surl‘atetant}'therc are
`still ::'m;n1ibei', ofproblcms with the use of ll'tiCl:ili}f.$0luli0l‘lS for
`drug t_1clivcry."Qnt: of.'tI_1e_maj or probtcnts is the In rgt:.dilulio_t1 the
`systcn1'c:-t'pcricn'ce's upon ndrriinislration. 'Tl'_i_is_dilu1io'n is put‘-
`ticulttrly large _:tFtcr'ornl and intrztvenoug;_admi_ni$tr_zt_tiot1, nn_d
`cttnctttise the .t1'nwanted-precipitation ofdrtlg. In the cast: ol‘o1-ul
`delivery this may lead to irritation of the gastrointestinal tract,
`while in the case ofintrztvcnous administration. pain may be
`experienced upon injection.
`_
`Other cn_mplica1_ing.factors cgtpericnced when using miccllnr
`solutions" include‘ the concomitant solubiliztttion of other addi-
`tives such :_tS_pre5ul'vt_ttivcs and sweetening agents: some surfac-
`I-ants taste l'ouI._cs;accially'ifad ministered am solution. Depend-
`ing upon their relative sitea ofincor'pora1'lion' in the micelles this
`on-solubilhuttion can eit_l1c_r_!t_:rt_d to udccrcnse or increase in drug
`solo bili2ation."- This potential problem of-c_on'co:nit:tnt §oIubili-
`zalion olztdditives is‘ not just limited to rniccllar systems and is
`encountered with all surfactant systems.
`Citving to their labile nature, micelles can only be used as drug
`carriers nndnot as turgctting systems, ullltough there is rt small
`a'n1otmt'of evidence"-that suggests it may be possible to alter the
`biodistribution of :1 drug by administering it in it rnicellar
`'$o|t.tlion.3°T This alteration has, however. been attributed (at
`least in -port} to z: direct clfe