European Journal of Pharmaceutics and Biopharmaceutics 76 (2010) 437442

ontents lists a!aila"le at #cience$irect

European Journal of Pharmaceutics and Biopharmaceutics

% o u r n a l h o m e p a &e ' ( ( ( ) e l s e ! i e r ) c o m * l o c a t e * e % p "

+esearch paper

, ne( mucoadhesi!e dosa&e form for the mana&ement of oral lichen planus' -ormulation stud. and clinical stud.
-rancesco ilur/o a0 hiara 1)2) 1ennari a0 -rancesca #elmin a0 Joel B) Epstein "0 1io!anni 2) 1aeta c 0 1iuseppe olella d0 Paola 2in&hetti a03
a

$epartment of $epartment of $epartment of d $epartment of

" c

Pharmaceutical #cience 44Pietro Pratesi50 6ni!ersit7 de&li #tudi di 2ilano0 8tal. 9ral 2edicine and $ia&nostic #ciences0 6ni!ersit. of 8llinois0 hica&o0 6nited #tates 9dontostomatolo&.0 6ni!ersit. of a&liari0 8tal. :ead and ;ec< Patholo&.0 88 6ni!ersit. of ;aples0 8tal.

a r t i c l e

i n f o

a " s t r a c t
@he (or< aimed at stud.in& a ne( mucoadhesi!e prolon&ed release ta"let containin& 24 l& clo"etasolA 17 propionate ( P) suita"le for the mana&ement of oral lichen planus) Bo( s(ella"le dosa&e forms (ere desi&ned ". com"inin& a mucoadhesi!e pol.mer0 i)e) pol.(sodium methacr.late0 meth.lmethacr.late)0 (ith h.droC.prop.lmeth.lcellulose and 2& l2) @his formulation (as selected to modif. the ta"let eroA sion rate in order to o"tain a release of P o!er a 6Ah period) , dou"leA"lind0 controlled stud. (as perA formed usin& three &roups of patient (n D 16) (ho recei!ed three applicationsAaAda. o!er 4 (ee<s of the de!eloped P ta"lets (&roup PA@)0 place"o ta"lets (&roup PAP) or commercial P ointment for cutaneous application (123 l&*application) eCtemporar. miCed (ith 9ra"aseE (&roup PA9)) ,t the end of the stud.0 pain and ulceration resol!ed in 13*16 and 11*16 patients of &roup PA@ and &roup PA90 respecA ti!el.) 8n the &roup PA90 a transient acute h.peraemic candidosis (n D 2) and taste alteration (n D 4) (ere also o"ser!ed) ;o chan&es in clinical si&ns of patients in the &roup PAP (ere e!ident) @he application of mucoadhesi!e ta"let containin& 24 l& P 3 times a da. appeared to "e effecti!e0 a!oidin& the side effects of the &enerall. used treatment) 2010 Else!ier B)F) ,ll ri&hts reser!ed)

,rticle histor.' +ecei!ed = June 2010 ,ccepted in re!ised form 2> Jul. 2010 ,!aila"le online 11 ,u&ust 2010 ?e.(ords' 9ral lichen planus 2ucoadhesi!e ta"let @opical corticosteroids

1) 8ntroduction 9ral lichen planus (9BP) is a rare chronic autoimmune mucocutaA neous inGammator. disease that ma. cause "ilateral (hite striaA tions0 papules or plaHues (ith or (ithout er.thema and ulceration in!ol!in& an. "uccal mucosae I102J) #.mptoms ran&e from none to painful oral lesions0 affectin& the Hualit.AofA life) urrent standard treatment is administered primaril.0 since there is no esta"lished therap.0 the current clinical treatment consists in the topical adminA istration of hi&hApotenc. topical corticosteroids0 such as clo"etasol propionate ( P) to control s.mptoms I304J) #ince "uccal P dosa&e forms are not commerciall. a!aila"le0 the administration is made usin& semisolid preparations for s<in application miCed (ith an adhesi!e paste0 namel. 9ra"aseE IK7J) @his approach presents se!eral dra("ac<s0 includin& difLculties in appl.in& the medication at !arious oral sites0 taste alterations0 limited contact time and

3 orrespondin& author) ,ddress' $epartment of Pharmaceutical #ciences 44Pietro Pratesi50 !ia 1) olom"o0 710 20133 2ilan0 8tal.) @el)' M3> 0 2 K032463>N faC' M3> 0 2 K03246K7) EAmail address' paola)min&hettiOunimi)it (P) 2in&hetti)) 0>3>A6411*Q A see front matter doi'10)1016*%)e%p")2010)07)014 2010 Else!ier B)F) ,ll ri&hts reser!ed)

possi"le s(allo(in& of a formulation not desi&ned for the "uccal route) @herefore0 to impro!e the patientPs compliance and reduce the ris<s of side effects0 the de!elopment of a mucoadhesi!e solid dosa&e form could "e of interest) #e!eral mucoadhesi!e dosa&e forms0 such as microparticles I=J0 patches I>J and ta"lets I10J0 could results suita"le for the treatment of 9BP) ;e!ertheless0 considerin& that 9BP is an orphan patholo&.0 ta"lets o"tained ". direct compresA sion could result ad!anta&eous "ecause their production is easier and cheaper compared to the other t(o dosa&e forms) @he present in!esti&ation aimed at e!aluatin& the utilit. of a 24 l& P mucoadhesi!e ta"let "ased upon a pol.(sodium methacr.A late0 meth.lmethacr.late) (P22)0 a mucoadhesi!e nonAs(ella"le pol.mer I>J) , t.pe of h.droC.meth.lcellulose (as selected amon& a series of h.drocolloids on the "ases of a preliminar. screenin&0 ma&nesium chloride (as chosen "ecause of its a"ilit. in reducin& P22 erosion rate I11J) @he formulati!e stud. (as focused on in !itro characteri/ation of ta"lets in order to deLne (hich formulaA tion fulLlled desira"le clinical characteristics) @he criteria of acceptance (ere "ased on mucoadhesi!e properties0 lac< of s(ellin& and dru& release o!er a 6Ah period) @he optimi/ed formulation (as tested in a dou"leA"lind0 place"oAcontrolled stud. in indi!iduals (ith 9BP and compared to 12K l& P in a con!entional ointment in 9ra"aseE)

1=2

-)

ilur/o et al) * European Journal of Pharmaceutics and Biopharmaceutics 76 (2010) 437442

2) 2aterials and methods 2)1) -ormulation stud. 2)1)1) 2aterials and ta"let preparation lo"etasol 17Apropionate ( P) (#8 9+0 8)0 ma&nesium chloride (, E-0 8)N 2ethocel ?4 2 (:P2 ?4 2)0 su"stitution' methoCA .l D 22R0 h.droC.propoC.l D =)1R0 nominal !iscosit. 2R in (ater' 4000 cP ( olorcon0 8)N Eudra&it #1000 pol.(methacr.lic acid0 meth.l methacr.late)0 molar proportions of the monomer units 1'20 molecular (ei&ht 13K0000 $altons (+Shm0 1)N rude (@.pe 88) mucin from porcine stomach (#i&ma hemical o)0 6#,)) P22 (as o"tained ". addin& 10R ((*() ;a9: aHueous solution to 1KR ((*() Eudra&it #100 aHueous suspension0 until complete saliLcation) @he aHueous solution I>J (as free/eAdried (E$T,+$# 2odul.o0 6#,)0 and the resultin& po(der (as milled ". an 6ltra entrifu&al 2ill (+E@# : U22000 1) eHuipped (ith rin& sie!es of 0)2K mm) @he composition of place"o and PAloaded ta"lets is sho(n in @a"le 1) Po(ders (ere miCed usin& a @ur"ula miCer (T,B @ur"ula0 :) for 10 min) @a"lets (7 mm diameter and =0 m& (ei&ht) (ere prepared ". direct compression usin& a sin&le punch ta"let press (?orsch0 t.pe E?90 1)) @he upper punch (as set as to o"tain ta"lets (ith a crushin& resistance of a"out 7 ?p) @he uniformit. of P conA tent in miCtures and ta"lets (as e!aluated accordin& to European Pharmacopoeia I12J) 2)1)2) ,@+A-@8+ spectroscop. ,"out 1K)0 m& sample (as placed on a Un#eAcr.stal mounted in ,@+ cell (Per<in Elmer0 6#,)) -@8+ measurements (ere performed (ith #pectrumE 9ne spectrophotometer (Per<in Elmer0 6#,)) @he spectra (ere recorded at 2 cm 1 resolution0 and 32 scans (ere 1 colA lected o!er the (a!enum"er re&ion 40006K0 cm ) @he anal.ses (ere performed on ra( pol.mers and h.drated s(ellin& la.ers) Place"o ta"let (as incu"ated in puriLed (ater0 and after 20 min the h.drated la.er (as carefull. remo!ed from the ta"let0 and it (as directl. applied on the ,@+ accessor. of the -@8+ spectrometer) 2)1)3) #(ellin& properties #(ellin& and erosion of P22 and the relati!e "lends (ere e!alA uated ". &ra!it. method) @a"lets of =0 m& (ere attached ". c.anoA acr.late &lue to a &lass plate and immersed in 30 ml of deioni/ed (ater under constant stirrin&) ,t predetermined time inter!als0 pol.meric ta"lets (ere remo!ed from the "ea<er0 rinsed0 (ei&hed and photo&raphed) @he !ariation ($T) of ta"let (ei&ht o!er time0 namel. (ater upta<e and mass loss0 (as calculated accordin& to the follo(in& eHuation'

$T V WTt

$t XD$t

W1X

(here Tt D (ei&ht of (et ta"lets at the time t0 $t D initial (ei&ht of dr. ta"lets at time t) 2)1)4) Erosion rate Place"o compacts (2K0 m&0 13 mm diameter0 @a"le 1) (ere preA pared usin& a h.draulic press (+88 h.draulic press0 6?) (ith a compaction force of 10 tons and a holdin& time of 10 min) 8n order to eCpose a sin&le face (ith constant area to the medium0 all surA faces eCcept one "ase (ere coated ". partial immersion in =R (* ( cellulose acetate propionate solution in dichloromethane) @he erosion rate of ta"lets (as determined Huantitati!el. ". LCin& the compact eccentricall. under the paddle at the distance of 1)= cm from the rotatin& aCis) ,s dissolution medium0 K00 ml of deionised (ater at 37)0 Y 0)K (ere used and stirrin& speed (as 100 rpm) @he dissol!ed amounts (ere spectrophotometricall. asA sa.ed at < D 213 nm) Erosion rate (1) (as determined from the slope0 calculated ". linear re&ression0 of the cur!e o"tained ". plottin& the dissol!ed amount of the copol.mer per unit area (m&*cm2) !ersus time (min)) 2)1)K) 8n !itro mucoadhesi!e test @he teCture anal.sis (as performed usin& a soft(areAcontrolled d.namometer (,1*2 B0 ,cHuati0 8) (ith a K da; force cell as preA !iousl. descri"ed I>J0 usin& mucin as the adherent su"strate I13 1KJ) BrieG.0 GatAfaced place"o and PAloaded compacts ((ei&ht' 170 m&0 diameter' 11)2= mm) (ere o"tained ". appl.in& a comA pression force of 10 tons for 30 s ". means of a h.draulic press (1lenrothes0 6?)) @he testin& material compacts (ere attached to the mo"ile steel punch ". c.anoacr.late &lue) 2ucin compacts ((ei&ht' 130 m&0 diameter' 11)2= mm) (ere o"tained ". appl.in& a compression force of 10 tons for 60 s) @he mucin compact (as atA tached ". c.anoacr.late &lue to a steel plate LCed at the "ottom of the tensile apparatus and h.drated (ith =0 ll deioni/ed (ater upon K min to o"tain a %ell. surface la.er) 6pon ma<in& contact "eA t(een the pol.meric compact and the h.drated mucin0 a constant force of 1)3 ; (as imposed for 360 s) @he mucoadhesi!e perforA mance (as measured in terms of the force reHuired to separate the "ioadhesi!e compact from the mucin (maCimum detachment force0 2$-) upon an elon&ation of 10 mm at the constant rate of 0)1 mm*s) @he area under the cur!e of the detachment force !ersus the elon&ation represents the (or< or ener&. ((or< of adhesion0 T,) reHuired detachin& t(o compacts) @he stainless steel punch (as used as ne&ati!e control and :P2 compacts as positi!e one) @he results are eCpressed as mean Y standard de!iation (n D 4))

@a"le 1 omposition of place"o (series P)0 -orm)

PAloaded ta"lets (series -) and technolo&ical characteri/ation) P content (l&) :P2 10 10 10 10 2& l2 10 10 10 10 23 2K 24 24 Y Y Y Y 1 0 1 0 4)=20 3)KK1 3)107 1)K7> 4)>70 3)423 3)307 1)K02 Y Y Y Y Y Y Y Y 0)211 0)226 0)214 0)1>6 0)1K> 0)201 0)1>2 0)1=3 K)K6 4)41 4)42 3)2K K)63 4)22 4)K1 3)=1 Y Y Y Y Y Y Y Y 0)62 0)77 1)63 0)11 1)37 0)31 1)00 0)42 2)K= 2)0= 2)2= 1)26 3)3> 1)K6 2)7K 2)3> Y Y Y Y Y Y Y Y 0)23 1)17 0)7K 0)10 1)1= 0)0> 1)14 0)16 2K7 Y 2=1 Y 2== Y 330 Y K= 74 =6 34 1100 (m& min*cm )
a 2

omposition (R0 (*() P P22 100 >0 >0 =0 100 >0 >0 =0

2$- (;)

"

T, (mJ)

8F+@ (min)

P1 P2 P3 P4 -1 -2 -3 -4
a " c d

0)03 0)03 0)03 0)03

1100' erosion rate) 2$-' maCimum detachment force) T,' (or< of adhesion) 8F+@' in !i!o residence time)

2)1)6) $ru& content assa. @he ta"lets (ere crushed in a mortar0 and the po(der (as susA pended in 20 ml mo"ile phase (,c ;*:290 K0*K0 !*!)) @he P conA tent (as determined ". the follo(in& :PB method usin& :P1100 hemstation (:e(lett Pac<ard0 6#,)) hromato&raphic conditions) ,nal.tical column' Taters #pherisor" 9$#2 (4)6 1K0 mm0 3 lm)N mo"ile phase' ,c ;*:29 (K0*K0 !*!)N Go( rate' 1)0 ml* minN (a!elen&th set' 240 nmN in%ection !olume' 20 ll) @he dru& concentrations (ere determined from standard cur!es in the ran&e of 0)0KK l&*ml) 2)1)7) 8n !itro dru& release $issolution test (as carried out in closed !ials and stirred in a sha<er incu"ator (K0 stro<es*min) at 37 Y 0)K ) @he ta"lets (ere &lued to the "ottom of KAml !ials containin& 4 ml dissolution medA ium (deioni/ed (ater)) ,t each time point0 the medium (as comA pletel. (ithdra(n for anal.sis0 diluted (ith 1 ml acetonitrile0 and the amount of P released (as tested ". :PB (#ection 2)1)6)) @he (ithdra(n (ater (as replaced (ith eHual !olumes of fresh medium) 2)1)=) 8n !i!o mucoadhesion stud. @he stud. (as conducted in accordance (ith the ethical princiA ples ori&inatin& from the $eclaration of :elsin<i and follo(ed the 8 :A1 P &uidelines of 17*01*1>>7 and (as in compliance (ith loA cal re&ulator. reHuirements) ,ll su"%ects (ere completel. inA formed concernin& the pertinent details and the purpose of the stud.) , (ritten consent form (as completed ". each su"%ect prior to dispensin& test materials) @he stud. (as conducted on siC health. human !olunteers (a&ed 2K2= .ears) usin& 2K m& place"o ta"lets attached to upper "uccal sulcus in the canine fossa) FolunA teers (ere allo(ed to drin< durin& the stud.0 (hile solid food and smo<in& (ere prohi"ited) Folunteers (ere as<ed to record the time of insertion and time at end of adhesion (permanence time) and an. mucosal irritation or discomfort in mouth) 2)1)>) #tatistical anal.ses @ests for si&niLcant differences "et(een means (ere performed ". #tudent tAtest or oneA(a. ,;9F, ". usin& the soft(are #P## 11 (#pss 8nc)0 6#,)) $ifferences (ere considered si&niLcant at the p Z 0)0K le!el) 2)2) $ou"leA"lind controlled clinical trial 2)2)1) #u"%ect 9ne in!esti&ator outcomes of therap.)

@a"le 2 #i&ns and s.mptomatic scorin& s.stems) #i&n +eticular ,trophic Erosi!e #.mptom ,s.mptomatic patients Patients (ith mild s.mptoms that did not affect Hualit.AofAlife 2oderate s.mptoms that (ere "othersome to the patients and needed medical attention #e!ere s.mptoms that si&niLcantl. interfered (ith patientsP Hualit.AofAlife #core 0 1 2 3a

8n the case of patients (ith intraoral manifestations of more than one t.pe of 9BP0 the hi&hest score (as recorded)

K1)K .ears)) Each enrolled patient si&ned informed consent0 and the procedures of this stud. (ere in accordance (ith the ethical standards on human eCperimentation (institutional and national) and (ith the :elsin<i $eclaration of 1>7K0 as re!ised in 2000) -olA lo(in& informed consent0 the inclusion and eCclusion criteria (ere conLrmed) 2)2)2) +andomi/in& protocol and stud. desi&n @he patients (ere assi&ned to three &roups consistin& of 16 su"A %ects ". the in!esti&ators) @reatment assi&nment (as "lind to the clinical in!esti&ator) BeA fore randomi/ation0 a letter (as assi&ned to a prearran&ed theraA peutic protocol) @his seHuence of num"ers (as <no(n onl. to another in!esti&ator (ho pro!ided the stud. medications for each &roup) Patient of each &roup recei!ed the de!eloped P ta"lets (&roup PA@)0 the correspondin& place"o ta"let (&roup PAP) or P semisolid preparation (123 l&*application) (&roup PA9)) P ta"lets and place"o ta"lets (ere dispensed in identical (hite containers mar<ed , and B) @he P semisolid preparation (as prepared ". usin& a commercial P ointment for cutaneous application ( lo"esol 0 #herin& Plou&h) eCtemporar. miCed (ith 9ra"aseE) Patients of each &roup recei!ed the products to appl. three times a da. o!er a 4A(ee< period) Patients (ere instructed in ho( to place ta"lets in the canine fossa) #u"%ects of &roup PA9 (ere informed ho( to prepare and appl. the ointment in 9ra"aseE) Patients (ere as<ed to record the len&th of the adhesion time of the ta"let and potential side efA fects) #u"%ects and the clinical in!esti&ator did not <no( the therA ap. to (hich the. (ere assi&ned) ,t (ee<l. !isits durin& the 4A(ee< trial0 the clinical in!esti&ator recorded the s.mptoms in a fourApoint descripti!eAHualitati!e scale as follo(s' 0 D no e!idence of diseaseN 1 D mild in!ol!ementN 2 D moderate in!ol!ementN 3 D se!ere in!ol!ement) ,ll patients (ere monitored for ad!erse e!ents and (ere e!aluated for clinical si&ns and s.mptoms of candidiasis ((hite adherent patches0 er.A thema and oral "urnin&)0 the presence of moon face0 hirsutism0 Guid retention and (ei&ht increase) Patients (ere tested for "lood &luA cose le!els and "lood pressure) Patients (ere also inter!ie(ed to asA sess mood chan&es0 &astrointestinal disorders0 eas. "ruisin& and taste loss) 2)2)3) Biops. collection Biopsies (= mm diameter tissue samples) (ere ta<en from all su"%ects (ithin one (ee< of the clinical trial and t(o (ee<s follo(A in& completion of treatment from the same re&ion) ,ll specimens (ere LCed in formalin 10R PB# "uffer0 em"edded in parafLn and proA cessed for haematoC.linAeosin stainin&) ,t time 0 and after the therA ap.0 K ml "lood samples (ere collected ". !enipuncture0 in oCalated !acutainers and centrifu&ed for cortisol le!els)

recruited

su"%ects

and

e!aluated

the

2)2)1)1) 8nclusion criteria) @he dia&nosis of 9BP (as made follo(in& the clinical and histolo&ical criteria deLned ". the Torld :ealth 9r&ani/ation (T:9) I16J) ) Patients (ere o"ser!ed in the $epartA ment of 9ral 2edicine of the 6ni!ersit7 de&li #tudi di ;apoli -ederico 88 for a minimum of three months "efore the "e&innin& of the trial and presented clinical si&ns of 9BP I171=J) @he dia&A nosis determined ". clinical o"ser!ance (as conLrmed ". re!ie(in& preAtreatment "iopsies samples ta<en (ithin a (ee< "efore the "e&innin& of the trial as reported in #ection 2)2)3) , score s.stem for si&ns of 9BP (as assi&ned on the "asis of increasin& se!erit. and s.mptoms (@a"le 2)) : F M patients also (ere enrolled) 2)2)1)2) ECclusion criteria) Patients (ho sho(ed se!erel. impaired renal or hepatic functions and (omen of child"earin& a&e (ere eCA cluded) Patients (ith a histor. of &laucoma (ere eCcluded) Based on these criteria0 4= aucasian patients (ere enrolled in the stud. (26 (omen and 22 men0 a&ed 3272 .ears0 median

-i&) 1) @he s(ellin& properties of the four ta"let formulations o!er time) @he miCture eChi"ited a different performance upon h.dration dependin& on the ta"let composition) Then 10R ((*() 2& l2 (as added (AhA and insert B)0 the pattern (as compara"le to that of pure P22 (A%A and insert ,)' the ta"lets dissol!ed (ithout s(ellin&) @a"lets containin& 10R ((*() :P2 (A;A and insert ) or "oth 2& l2 and :P2 (A[A and insert $) formed a sli&ht s(ellin& la.er (ithin the Lrst 10 min follo(ed ". erosion)

-i&) 2) ,@+A-@8+ spectra of h.drated place"o formulations)

3) +esults and discussion 3)1) -ormulation stud. 3)1)1) Place"o ta"lets 6pon contact (ith (ater0 @a"lets P1 made of the pure P22 rapA idl. h.drated and a sli&ht increase in their si/e (as o"ser!ed (ithin 10 min) @hen0 P22 started to erode (ith concomitant (ei&ht loss and the ta"let completel. dissol!ed in a"out >0 min) @a"lets P2 containin& 10R (*( 2& l2 did not s(ell si&niLcantl.0 and a deA crease (ith time in ta"let (ei&ht loss (as measured) @he addition of :P2 (@a"let P3) caused a si&niLcant increase in ta"let (ei&ht and diameter0 (hich increased from 7 mm to 10)K mmN after(ards0 the ta"let (ei&ht loss (as similar to the formulation containin& 2& l2 (-i&) 1)) Then the miCture of :P2 and 2& l2 (as added to P22 (@a"let P4)0 the increase in ta"let dimension due to h.draA tion (as closer to that of the pure P22 and its (ei&ht remained almost constant o!er >0 min) 2oreo!er0 the determination of the ta"let erosion rate (1) e!idenced that this formulation (as the most effecti!e in reducin& the P22 dissolution (@a"le 1)) 8n order to eCplain the differences o"ser!ed in the ta"let "eha!iour upon h.dration0 ,@+A-@8+ spectroscop. measurements 1 (ere performed) ,fter h.dration of ta"lets0 a "and at 164K cm assi&ned to the s.mmetric stretch of the (ater molecules (as clearl. detecta"le in all the formulations) ,@+A-@8+ spectra of @a"let P1 made of the pure P22 (-i&) 2) sho(ed the characteristic "and of the O9 stretchin& !i"ration of the esteric &roup at a"out 1712 cm 1 and t(o "ands at 1K4= cm 1 and 1347 cm 1 correA spondin& to the antiAs.mmetrical a( 99 ) and s.mmetrical s( 99 ) !i"ration of the , 99 structure0 respecti!el. I1>J) 1 2oreo!er0 the "ands at 124>0 11>7 and 1163 cm arise mainl. from stretchin& modes of the ester &roup I20J) @he spectrum of h.drated :P2 sho(ed t(o main "ands at a"out 3370 cm 1 and 1640 cm 10 (hich (ere attri"uted to (ater 1 (-i&) 2) and a "road "and "et(een 1200 and >00 cm correspondA in& to ,9 and :C I21J) @he latter pea<s (ere not detected in @a"A lets P3 and P4 as the. (ere mas<ed "ehind the "ands of P22) -urthermore0 in the case of @a"let P30 no shifts of the P22 "ands (ere recorded (-i&) 2) su&&estin& the a"sence of interactions "et(een the t(o materials) @he spectra of the h.drated ta"lets containin& 2& l2 (ere

,s alread. descri"ed0 in the h.drated @a"lets P20 the metal ion stron&l. interacted (ith the O9 and 99 moieties of P22 I1>J0 (hich led to a chan&e in the char&e distri"ution on the ,9 esteric !i"ration) 8ndeed0 the "ands attri"uted to the stretchA in& !i"rations of ,9, moiet. of the esteric &roup shifted toA (ards hi&her (a!enum"ers (-i&) 2)) Then "oth 2& l2 and :P2 (ere present (@a"let P4)0 chan&es in!ol!ed m( , ,9) that si&niLA cantl. shifted to(ards hi&her (a!enum"ers (from 124> to 1 2M 1260 cm )) @his data su&&ested that 2& in the h.drated ta"let caused a different distri"ution of the char&e on the esteric &roup of P22 formin& h.dro&en "onds (ith :P2 ) #uch h.pothesis (as supported ". the shift of m( ,9, ) "and to(ards lo(er (a!enum"ers (ith respect to those re&istered in the &el la.er of 2M @a"let P2) @he interactions amon& P220 2& and :P2 can reA duce the a"ilit. of (ater to h.drate @a"let P40 causin& a mar<ed reduction of the ta"let erosion rate and s(ellin&) @he mucoadhesi!e properties of the formulations are sho(n in @a"le 1) ,s alread. descri"ed0 the presence of the 2& l2 (@a"let P2 mainl. characteri/ed ". chan&es in the "ands of P22 ester &roups)

and P3) caused a statisticall. si&niLcant decrease in the 2$- of P22 (p Z 0)04) due to ph.sical crossAlin<in& of the copol.mer) @he formation of crossAlin<s "et(een the pol.mer chains did not allo( them the freedom of mo!ement and GeCi"ilit. reHuired for the penetration into the mucus &el net(or<) 2oreo!er0 diffusion of (ater into the pol.mer net(or< occurs at a lo(er rate resultin& in decreased s(ellin& of the pol.mer and a decreased rate of interA penetration "et(een P22 and mucin) :o(e!er0 2$- and T, !alA ues (ere statisticall. hi&her than those re&istered (ith the ne&ati!e control (2$-' 2)=1 Y 0)20 ;N T,' 0)6K Y 0)01 mJ)) 8nformation reported ". !olunteers of the panel test conLrmed the in !itro data) @he residence time (as lon&est for ta"lets conA tainin& :P2 and 2& l2 (@a"le 1)0 and the !olunteers descri"ed discomfort due to increased s(ellin& onl. ta"lets made of "oth P22 and :P2 (@a"lets P3)) 8n all cases0 no mucosal irritation (as reported) 3)1)2) $ru&Aloaded ta"lets ,s eCpected0 the presence of P in the pol.mer "lends did not further modif. "oth the ta"let erosion rate and the in !itro mucoA adhesi!e properties and teCture proLles) @he results sho(ed that onl. for the @a"let -40 2$- and T, (ere si&niLcantl. lo(er than those of the correspondin& place"o "lends (p Z 0)0K)) @he nonA interference of P on mucoadhesi!e properties and erosion rate can "e %ustiLed considerin& that the dru& content (as less than 0)02KR and the dru&0 "ein& a cr.stalline solid0 does not modif.

@a"le 3 lassiLcation of 9BP in patients enrolled in each &roup (22 men0 26 (omen0 a!era&e a&e K1)K)) 9BP t.pe 1roup #tart +eticular ,trophic Erosi!e 2iCed ;o si&ns @otal K 3 4 4 0 16 PA@ End 0 1 0 2 13 16 1roup #tart 6 3 K 2 0 16 PAP End 3 3 K 2 3 16 1roup #tart 4 2 K K 0 16 PA9 End 0 1 2 2 11 16

@a"le 4 #core for s.mptoms at the "e&innin& and at the end of the stud.) -i&) 3) +elease (R) of P from the "uccoadhesi!e ta"lets made of the pure P22 (A%A)0 or miCin& 10R (*( 2& l2 (AhA)0 or 10R (*( :P2 (A;A) or a miCture thereof

Symptom (score) Group CP-T Group CP-P Group CP-O

#tart ,"sence of s.mptoms (0) 2ild s.mptoms (1) 2oderate s.mptoms (2) #e!ere s.mptoms (3) @otal 2 K 6 3 16 End 13 2 1 0 16 #tart 3 = 4 1 16 End 3 7 4 2 16 #tart 4 6 K 1 16 End 11 3 2 0 16

(A[A))

the structure of the pol.meric net(or<) 8ndeed0 the (a!enum"er and &eometr. of the main "ands of the spectra recorded on the dr. and h.drated PAloaded ta"lets o!erlapped (ith the correA spondin& spectra of place"o ta"lets (data not sho(n)) @he in !itro release of P from the ta"let made of pure P22 (@a"let -1) (as completed in >0 min (-i&) 3) as predicted ". the erosion rate of the pol.mer (@a"le 1)) @he addition of 10R (*( 2& l2 (@a"let -2) caused a decrease in dru& release due to the 2M crossAlin<in& in pol.mer chains in presence of 2& ) , similar reA lease proLle (as e!ident (hen 10R (*( :P2 (as added (ta"let -3)) ,s eCpected ". the characteri/ation of the place"o ta"lets0 onl. the com"ination of 10R (*( 2& l2 and 10R (*( :P2 in formuA lation -4 resulted effecti!e in prolon&in& P release o!er a 6Ah period (-i&) 3)) Possi"le eCplanation of the results could "e the crossAlin<in& of P22 chains in presence of ma&nesium ions0 (hich mi&ht lo(er the mo"ilit. of (ater molecules entrapped into pol.A mer net(or<) 8n this case0 the dru& release (as dela.ed from @a"let -4 "ecause of the formation of a hi&hl. !iscous &el "arrier of the entrapped :P2 that (as effecti!e in maintainin& ta"let cohesi!eness) #ince @a"let -4 could effecti!el. control P release o!er a 4Ah period0 and the correspondin& place"o ta"lets (@a"let P4) had an in !i!o residence time of a"out 6 h0 this formulation (as selected for the clinical stud.) 3)2) linical trial of 9BP

s.stemic a"sorption of

P) ;o ad!erse effects related to the treatA

@he patients enrolled in the &roups PA@ and PAP reported the eCcellent adhesion of the P ta"lets in the "uccal ca!it. (ith resiA dence time a!era&in& 46 h) @he mucoadhesi!e ta"lets did not cause irritation or pain0 and the su"%ects reported the ta"let tasted neutral or sli&htl. salt.) $ata on the preA and postAtreatment e!olution of 9BP are disA pla.ed in @a"les 3 and 4) ;o patient dropouts occurred in the stud.) @he histolo&ical Lndin&s sho(ed a reduction of h.per<eraA tosis and acanthosis of the epithelium at the end of the treatment and a decrease in the "andAli<e inGammator. inLltrate in the samA ples from the &roups PA@ and &roup PA90 and no chan&es (ere seen in the place"o &roup (&roup PAP)) Blood cortisol le!els0 normall. ran&in& from K to 2K l&*dl in the mornin&0 (ere not statisticall. different amon& the three &roups preA (&roup PA@' 6)= l&*dl to 23)K l&*dlN &roup PAP' 4)K l&*dl to 21)3 l&*dlN &roup PA9' =)1 l&*dl to 2K l&*dl) and postAtreatA ment (&roup PA@' K)K l&*dl to 1>)K l&*dlN &roup PAP' K)> l&*dl to 22)4 l&*dlN &roup PA9' K)1 l&*dl to 23 l&*dl)0 indicatin& limited

ment (ere recorded0 eCcept for 2 episodes of transient acute er.A thematous candidosis durin& the last treatment (ee< for t(o patients in &roup PA9 (ho (ere treated (ith n.statin at the end of the trial) @aste loss (as reported for four patients of the &roup PA9) 8n the indi!iduals of &roup PAP0 there (as an increase in s.mptoms0 as reported in @a"le 4) @o assess the utilit. topical therap. of 9BP0 16 patients (ith difA ferent clinical t.pes of 9BP (se!ere reticular0 atrophic and erosi!e) (ere treated ". appl.in& mucoadhesi!e ta"lets containin& a lo( dose of P (24 l&*ta"let) three times a da.) ,t the end of the treatment period0 oral pain and ulceration had resol!ed (complete response) in 13*16 patients in &roup PA@ (-i&) 4) and 11*16 in the &roup PA9 (ith remission of atroph. and erosion and reticular lesions (score 0)) @here (as no chan&e in the &roup PAP su"%ects (place"o ta"lets)) -or "oth si&ns and s.mptoms0 2*16 patients of the &roup PA@ and 3*16 of &roup PA 9 sho(ed score 10 and 1*16 of the &roup PA@ and 2*16 of the &roup PA9 reported score 2 for si&ns and 1 for s.mptoms) @he results of this stud. sho(ed that the use of lo( concentraA tion P in mucoadhesi!e ta"lets offers an efLcacious treatment of different clinical t.pes of 9BP) Pre!ious studies of topical steroid for mana&ement of oral mucosal disease ha!e assessed dru& deli!er. in nonAsustained reA lease forms) Bo 2u/io et al) treated oral aphthous lesions and liA chen planus ". appl.in& P (ith a "ioadhesi!e s.stem (ith impro!ement in oral lesions IKJ) Bo/adaA;ur et al) used P miCed in an adhesi!e paste to treat patients (ith se!ere erosi!e disease of the oral mucosa0 reportin& a complete response in 62)KR of paA tients and an eCcellent response in 2>)7RN the. descri"ed the treatA ment as efLcacious and safe I4J) #il!erman et al) used 0)02KR Guocinolone in 9ra"aseE paste to treat patients (ith erosi!e 9BP) @he. concluded that the treatment (as of some "eneLt to 61)>R (>6*1KK) of the patients in their series0 e!en thou&h onl. 14)1R (22*1KK) of the patients (ere s.mptomAfree I2J) 1on/ale/A 2oles et al) ha!e recentl. sho(n eCcellent outcomes in the treatA ment of se!ere erosi!e &in&i!al lesions ". topical application of P in custom tra.s (ith 100R of success attri"uted to the impro!ed deli!er. to all lesions throu&h the use of the tra.0 the hi&her conA centration used (0)0KR !s) 0)02KR)0 and the duration of contact "eA t(een the dru& and the lesion I22J) ;e!ertheless0 in this stud.0 a control &roup (as not enrolled0 and 1000000 86*cc of n.statin in

!ehicle ma. ha!e utilit. in the deli!er. of antiAinGammator. medA ications and other a&ents for treatment of oral conditions) +eferences
I1J #)$) Fincent0 P)1) -otos0 ?),) Ba<er0 @)P) Tilliams0 9ral lichen planus' the clinical0 historical0 and therapeutic features of 100 cases0 9ral #ur&) 9ral 2ed) 9ral Pathol) 70 (1>>0) 16K171) I2J #) #il!erman0 2) 1ors<.0 -) Bo/adaA;ur0 ?) 1iannotti0 , prospecti!e stud. of Lndin&s and mana&ement in 214 patients (ith oral lichen planus0 9ral #ur&) 9ral 2ed) 9ral Pathol) 72 (1>>1) 66K670) I3J ) #cull.0 $) Eisen0 2) arro//o0 B) 2c artan0 ) 2c rear.0 That is the rationale for treatin& oral lichen planus\0 9ral $is K (1>>>) 1=11=2) I4J -) Bo/adaA;ur0 ) 2iranda0 +) 2ali<si0 $ou"leA"lind clinical trial of 0)0KR clo"etasol propionate ointment in 9ra"ase and 0)0KR Guocinonide ointment in 9ra"ase in the treatment of patients (ith oral !esiculoerosi!e diseases0 9ral #ur&) 9ral 2ed) 9ral Pathol) 77 (1>>4) K>=604) IKJ B) Bo 2u/io0 ,) della Falle0 2)$) 2i&no&na0 1) Pannone0 P) Bucci0 E) Bucci0 J) #ciu""a0 @he treatment of oral aphthous ulceration or erosi!e lichen planus (ith topical clo"etasol propionate in three preparations' a clinical and pilot stud. on K4 patients0 J) 9ral Pathol) 2ed) 30 (2001) 611617) I6J P) +odstrom0 2) :a<e"er&0 2) Jontel0 Erosi!e oral lichen planus treated (ith clo"etasol propionate and triamcinolone acetonide in 9ra"ase' a dou"leA"lind clinical trial0 J) $ermatol) @reat) K (1>>4) 710) I7J ,)?) #in&la0 2) ha(la0 ,) #in&h0 Potential applications of ar"omer in oral mucoadhesi!e controlled dru& deli!er. s.stem' a re!ie(0 $ru& $e!) 8nd) Pharm) 26 (2000) >13>24) I=J ?)P)+) ho(dar.0 ])#) +ao0 2ucoadhesi!e microspheres for controlled dru& deli!er.0 Biol) Pharma) Bull) 27 (2004) 17171724) I>J -) ilur/o0 P) 2in&hetti0 -) #elmin0 ,) asira&hi0 B) 2ontanari0 Pol.methacr.late salts as ne( lo(As(ella"le mucoadhesi!e materials0 J) ontrol) +el) == (2003) 43K3) I10J B) Perioli0 F) ,m"ro&i0 $) +u"ini0 #) 1io!a&noli0 2) +icci0 P) Blasi0 ) +ossi0 ;o!el mucoadhesi!e "uccal formulation containin& metronida/ole for the treatment of periodontal disease0 J) ontrol) +elease >K (2004) K21K33) I11J -) ilur/o0 -) #elmin0 P) 2in&hetti0 B) 2ontanari0 @he effects of "i!alent inor&anic salts on the mucoadhesi!e performance of a pol.meth.lA methacr.late sodium salt0 8nt) J) Pharm) 301 (200K) 6270) I12J Ph) Eur) 2ethacr.lic acidAmeth.l methacr.late copol.mer (1'2) in European Pharmacopoeia0 siCth ed)0 200=0 p) 2374)) I13J E) Ja""ari0 ;) Tisnies(s<i0 ;),) Peppas0 E!idence of mucoadhesion ". chain interpenetration at a pol.(acr.lic acid)*mucin interface usin& ,@+A-@8+ spectroscop.0 J) ontrol) +elease 26 (1>>3) >>10=) I14J #) @am"uric0 $)^)2) rai&0 , comparison of different in !itro methods for measurin& mucoadhesi!e performance0 Eur) J) Pharm) Biopharm) 44 (1>>7) 1K>167) I1KJ J)2) Bla"ot0 +):) 2an/o0 $),) ,llemandi0 $ru& release from car"omer' car"omer sodium salt matrices (ith potential use as mucoadhesi!e dru& deli!er. s.stem0 8nt) J) Pharm) 276 (2004) K>66) I16J 8)+) ?ramer0 +)B) Bucas0 J)J) Pind"or&0 B):) #o"in0 T:9 colla"oratin& centre for oral precancerous lesions) $eLnition of leu<opla<ia and related lesions' an aid to studies on oral precancer0 9ral #ur&) 9ral 2ed) 9ral Pathol) 46 (1>7=) K1= K3>) I17J #) 2a&rin0 ,) raCi0 ) -a"iano0 +)1) #imonetti0 1) -iorentino0 B) 2arino0 9) $iHuattro0 F) $i 2arco0 9) Boiacono0 +) Folpes0 P) ,lmasio0 2)#) 6rdea0 P) ;eu(ald0 +) #anche/APescador0 J) $etmer0 J) ) Til"er0 B) Pa&liaro0 :epatitis !iremia in chronic li!er disease' relationship to interferon or corticosteroid treatment0 :epatolo&. 1> (1>>4) 27327>) I1=J -) 1om"os0 B) appello0 1)2) 1aeta0 2)8) Ba +otonda0 +) #erpico0 ,) 2iro0 .closporin in a "ioadhesi!e formulation in the therap. of oral erosi!e lichen planus) , clinicoAeCperimental e!aluation0 2iner!a #tomatol) 41 (1>>4) 3=K 3=>) I1>J -) ilur/o0 )1)2) 1ennari0 -) #elmin0 1) Fistoli0 Effects of metal ions on enteroA solu"le pol.(methacr.lic acidAmeth.l methacr.late) coatin&' a com"ined anal.sis ". ,@+A-@8+ spectroscop. and computational approaches0 2ol) Pharm) 7 (2010) 421430) I20J B)J) Bellam.0 @he 8nfrared #pectra of ompleC 2olecules0 third ed)0 !ol) 10 hapman and :all0 Bondon0 6?0 1>7K) I21J ) #ammon0 1) Ba%(a0 P) @immins0 )$) 2elia0 @he application of attenuated total reGectance -ourier transform infrared spectroscop. to monitor the concentration and state of (ater in solutions of a thermall. responsi!e cellulose ether durin& &elation0 Pol.mer 47 (1>>4) K77K=4) I22J 2),) 1on/ale/A2oles0 8) +ui/A,!ila0 ,) +odri&ue/A,rchilla0 P) 2oralesA1arcia0 -) 2esaA,&uado0 ,) BasconesA2artine/0 2) Bra!o0 @reatment of se!ere erosi!e &in&i!al lesions ". topical application of clo"etasol propionate in custom tra.s0 9ral #ur&) 9ral 2ed) 9ral Pathol) 9ral +adiol) Endod) >K (2003) 6==6>2)

-i&) 4) +eticularAerosi!e lichen planus "efore (a) and after (") treatment (ith lo( concentration of P in mucoadhesi!e ta"lets) (-or interpretation of the references to colour in this L&ure le&end0 the reader is referred to the (e" !ersion of this article)))

paste (as also administered "ecause of the lar&e surface area in contact (ith the dru&0 the hi&h concentration of P used and the occlusi!e nature of the tra. method) Because 9BP is chronic condition0 treatin& the s.mptoms is eCtremel. important in addressin& Hualit.AofAlife) @his stud. aimed at increasin& the contact time to a"out K h to allo( a deA crease in steroid concentration in order to reduce potential side effects (i)e) candida infection) and impro!e the patientsP compliA ance) @he mucoadhesi!e ta"let did not cause side effects0 cortisol le!els in plasma (ere not altered0 no Lndin&s of andida infecA tion (ere seen durin& the treatment0 and the administration of an antiAm.cotic a&ent (as not reHuired) 2oreo!er0 there (ere no increases in "lood pressure or episodes of h.per&l.caemia amon& patients (ith a histor. of dia"etes or controlled h.pertension) 8n conclusion0 :P2 and 2& l2 are effecti!e in controllin& P22 h.dration*erosion and0 conseHuentl.0 dru& release (ithout si&niLA cantl. modif.in& mucoadhesion) 2oreo!er0 the lac< of mucosal irritation and ad!erse effects conLrmed the suita"ilit. of this comA "ination to prepare mucoadhesi!e ta"lets) @he application of 24 l& P ta"let ma. "e an efLcacious and safe treatment of 9BP than semisolid preparation) @his preliminar. stud. su&&ests that this