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A novel formulation of solubilised amphotericin B designed for ophthalmic use

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A novel formulation of solubilised amphotericin B designed for ophthalmic use
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  A novel formulation of solubilised amphotericin B designed for ophthalmic use D.R. Serrano 1 , H.K. Ruiz-Saldaña 1 , G. Molero 2 , M.P. Ballesteros 1 , J.J. Torrado 1,*1 ar!a"ia # Te"nolo$ia ar!a"euti"a, a"ultad de ar!a"ia, %ni&ersidad'o!(lutense de Madrid, Plaza Ra!on # 'a)al, 2++, Madrid, S(ain 2 Mi"roiolo$ia , a"ultad de ar!a"ia, %ni&ersidad 'o!(lutense de Madrid,Plaza Ra!on # 'a)al, 2++, Madrid, S(ain * 'orres(ondin$ aut/or. Tel.0  313142+5 6a70   313184. E-mail address: torrado1@farm.ucm.es  Abstract  9!(/oteri"in B :9!B; is a <ide s(e"tru! anti6un$al <it/ lo< in"iden"e o6 "lini"al resistan"e. Ho<e&er, t/ere are no li"ensed to(i"al 6or!ulations.=7te!(oraneous (re(arations o6 9!B are 6re>uentl# (re(ared 6ro! a&ailale!ar?eted (arenteral 6or!ulations. Herein, a solution o6 9!B <it/ @-"#"lode7trinis des"ried as suitale 6or to(i"al ad!inistration as e#e dro(s. T/is no&el6or!ulation is "/ara"terized # its ailit# to soluilize 9!B and to !aintain itsanti6un$al a"ti&it#, (/#si"o"/e!i"al stailit# and sterilit# o&er + da#s. 9nti6un$ala"ti&it# a$ainst C. albicans  <as si$ni6i"antl# /i$/er :A; 6or t/e ne<6or!ulation t/an t/at otained <it/ un$izone C  ased e7te!(oraneous(re(ared sus(ension. (ti!al +.1 9!B E 1+ "#"lode7trin 6or!ulationre!ained sterile and <it/ an a""e(tale os!olarit#, (H and (arti"le size 6or o(/t/al!i" use o&er  <ee?s. 'o!(le7ation <it/ @-"#"lode7trins i!(ro&ed 9!B"/e!i"al stailit# "o!(ared to t/e re6eren"e e#e dro(s sus(ension ased onun$izone C . T/ese results illustrate t/e 6easiilit# o6 an o(/t/al!i" 9!B6or!ulation eas# enou$/ to e li"ensed or (re(ared in "o!!unit# and /os(ital(/ar!a"ies. Keywords : '#"lode7trins5 9!(/oteri"in B5 e#e dro(s5 stailit#5 anti6un$ala"ti&it#.  un$al ?eratitis </i"/ is !ainl# "aused # Candida  is res(onsile 6or "orneallindness. Fo<ada#s, it is t/e se"ond !ost "o!!on "ause o6 lindness inde&elo(in$ "ountries and t/e 6irst "ause in 9sia :Kaur et al., 2++;. res/l#(re(ared to(i"al a!(/oteri"in B :+.1-+.; is t/e standard treat!ent 6or t/eseo"ular in6e"tions :T/o!as, 2++;. =#e dro( solutions are t/e !ost "on&enientdosa$e 6or! 6or o"ular ad!inistration :Tiru"/erai et al., 2++2;. T/us, (atientsrel# on e7te!(oraneousl# dis(ensed o66-lael 6or!ulations (re(ared #(/ar!a"ists. Fe&ert/eless, a>ueous sus(ensions o6 9!B are di66i"ult to 6ilter sterilize and "ause lo"al irritation asso"iated <it/ t/e (arti"le size :Rat/ore etal., 2++3;. un$izone C  is "onsidered t/e standard 9!B 6or!ulation. Ho<e&er, it"ontains deo7#"/olate t/at renders its instillation (ain6ul leadin$ to (oor "o!(lian"e. i(idi" 6or!ulations, su"/ as li(oso!al 9!Biso!e C  "an e a $oodo(tion :Morand et al., 2++8; ut "ost li!its t/is o66-lael use. Hen"e, t/ere is a"lini"al need to de&elo( an o"ular 9!B solution and t/is is t/e ai! o6 t/is <or?.'#"lode7trins are ale to en/an"e t/e lo"al ioa&ailailit# o6 dru$s and t/eir useas soluilizer and stailizer a$ents /as een a((ro&ed 6or o(/t/al!i"a((li"ations :o6tsson et al., 1333, o6tsson et al., 2++2;. 9!B soluilization ist/e 6irst ste( 6or t/e de&elo(!ent o6 an o(/t/al!i" solution. T<o di66erent6or!ulations <ere (re(ared de(endin$ on t/e 9!B "on"entration :+.+A or +.1;. To otain a +.+A "on"entration, A.8A $ o6 @-"#"lode7trin :'a&a!a7 ,SP; <ere dissol&edin A+ ! o6 eit/er saline solution :+.3, <I&; or a de7trosesolution :A, <I&;. n"e dissol&ed, sodiu! /#dro7ide <as added to in"reaset/e (H to 12.+ and A8.A !$ o6 9!B :su((lied # 9zelis, S(ain; <ere added. 9ssoon as 9!B <as dissol&ed, ort/o(/os(ori" a"id <as added to ad)ust (H to8.. inall#, eit/er saline or de7trose solution <ere added u( to 1++ !. T/e  otained 9!B solution <as sterilized # 6ilterin$ :+.22 !, Minisart FM C Sartorius; in a la!inar 6lo< /ood. T/e os!olarit# in A de7trose solution <as4.4  +.2 !s!I :Knauer os!olari!eter;. t/er t/ree 6or!ulations :<it/+.1 9!B "on"entration; <ere si!ilarl# (re(ared usin$ deionized <ater andt/ree di66erent @-"#"lode7trin "on"entrations :1+, 12.A and 1A;. To ensuresterilit# on"e t/e sealed "ontainer is o(ened, +.++A T/i!erosal C :Si$!a- 9ldri"/ C ; <as added as an antise(ti" a$ent :Handoo? o6 (/ar!a"euti"ale7"i(ients, 2++3;. T/e os!olarit# o6 +.1 9!B - 1+ "#"lode7trin <as 212. +.2 !s!I </i"/ is <ell tolerated # t/e e#e :ilson et al., 2++1;. T/reere(li"ates o6 ea"/ 6or!ulation <ere (re(ared. Statisti"al anal#sis :Tu?e#Ls test E 9F9 one-<a#; <ere "arried out <it/ Minita C 1A "onsiderin$ (-&alues N+.+Aas statisti"al si$ni6i"ant di66eren"e. 9!B a"ti&it# de(ends on its a$$re$ation state, </i"/ is in6luen"ed # t/e6or!ulation and "an e studied # s(e"tro(/oto!etr# :San"/ez-Brunete et al.,2++5 =s(ada et al., 2++a;. 9!B is in t/e !ono!er 6or! in t/e "#"lode7trin6or!ulations and in t/e di!er 6or! in un$izone C . 9nti6un$al a"ti&it# o6 t/e ne<and re6eren"e 6or!ulations <ere tested a$ainst Candida albicans  '='T 13# t/e a$ar di66usion assa# :=uro(ean P/ar!a"o(oeia, 2++3;. 9nti6un$alsensiti&it# <as assa#ed in a$ar Mueller Hinton !ediu! su((le!ented <it/$lu"ose :2 <I&; and +.A $I! !et/#lene lue :see 6urt/er details in t/esu((le!entar# !aterials;. 9nti6un$al a"ti&it# o6 t/e +.+A 9!B E A"#"lode7trin 6or!ulation <it/ no T/i!erosal C <as statisti"all# si$ni6i"antl#:PN+.+A; /i$/er :A; t/an t/e re6eren"e 6or!ulation un$izone C :Tale 1;.Treat!ent o6 6un$al ?eratitis is re>uired o&er - <ee?s to a"/ie&e "o!(letere!ission. T/us, t/e anti6un$al a"ti&it# as <ell as t/e stailit#Isterilit# /as to e  $uaranteed 6or t/is (eriod o6 ti!e. Sterilit# o6 t/e 6or!ulation <as a"/ie&ed #6iltration and t/e addition o6 +.++A o6 T/i!erosal C . Tale 1 and 2 s/o< t/esterilit# tests "arried out <it/ di66erent 9!B 6or!ulations :+.+A and +.1 atda# + as !onodose 6or!ulations and +.1 at da# + si!ulatin$ a !ultidosere$i!e; # a "losed-!e!rane 6iltration !et/od :Steritest, Milli(ore C ;.Tr#(ti"ase So# Brot/ and luid T/io$l#"ollate Mediu! <ere used. Sa!(les<ere in"uated 6or 1 da#s. T/e asen"e o6 turidit# in ot/ !edia in all t/e6or!ulations indi"ated no !i"roor$anis! $ro<t/ and t/us, sterilit#. 9$$re$ation e66e"t <as studied # laser di6ra"to!etr# :Mi"rotra" SA++; andd#na!i" li$/t s"atterin$ :Oetatra";. 9n in"reased a$$re$ation tenden"# </ensa!(les <ere stored at lo< te!(eratures :A  '; <as oser&ed :Tale 1;.'o!(le7ation <it/ "#"lode7trins is s/o<n to dela# t/e sel6 a$$re$ation o6 9!Balt/ou$/ at /i$/er (ro(ortions t/an 12.A indu"es a$$re$ation :Tale 2;. 9dditionall#, solid (arti"les 6or o(/t/al!i" use s/ould not sur(ass A-1+ Q! o6 dia!eter 6or (atient "o!6ort :Rat/ore et al., 2++3; </i"/ indi"ates t/at"#"lode7trin "on"entrations et<een A to 12.A <ould e suitale 6or "lini"aluse alon$ + da#s. '/e!i"al de$radation <as assa#ed # a &alidated HP' !et/od :=s(ada etal., 2++;. '#"lode7trins dela#ed 9!B "/e!i"al de$radation :Tale 1 and 2;.un$izone C "on"entration <as redu"ed :(N+.+A; "o!(ared to 9!B :+.1; E"#"lode7trin :1+; 6or!ulation in !ore t/an 1+ at da# 8 and a + at da# +.Stora$e o6 sa!(les at lo< te!(erature si$ni6i"antl# dela#ed 9!B "/e!i"alde$radation, alt/ou$/ it in"reased 9!B a$$re$ation.
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